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Introduction: Longitudinal changes in health-related quality of life (HRQoL) are important in patients with chronic lymphocytic leukemia (CLL). GIBB (NCT02320487) is an open-label, single-arm phase II study of obinutuzumab (GA101; G) in combination with bendamustine (G-Benda) in patients with previously untreated CLL. A previous report from the GIBB study demonstrated an investigator-assessed objective response rate of 89.2%, a complete response rate of 49.0%, and no unexpected safety signals with G-Benda (Sharman et al. J Clin Oncol 2017). Here we report the final HRQoL data over 3 years from the GIBB study. Methods: Enrolled patients received G-Benda by intravenous infusion over six 28-day cycles: G 100mg on Day (D)1, 900mg on D2, and 1000mg on D8 and D15 of Cycle (C)1, then 1000mg on D1 of C2-6; benda 90mg/m2 on D2-3 of C1, and on D1-2 of C2-6. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) includes a global health status measure, 5 functional scales (physical, emotional, cognitive, social, and role functioning), 8 symptom scales/items (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, and diarrhea), and an item on financial difficulties (Aaronson et al. J Natl Cancer Inst 1993). The EORTC Quality of Life Questionnaire-Chronic Lymphocytic Leukemia 16 (QLQ-CLL16) is a 16-item module, specific to CLL, containing 4 multi-item scales (fatigue, treatment side effects, disease symptoms, and infection) and 2 single items (social activities and future health worries). Both questionnaires were completed by patients on C1D1 (baseline), C3D1, and C6D1, at the end of induction (EOI) treatment (defined as +28 days from C6D1 or early treatment termination visit), at the response visit (defined as 2-3 months after the EOI treatment for all patients who received study treatment and had not experienced disease progression), and every 3 months thereafter at follow-up visits for up to 2 years. In total, there were 14 timepoints where data were collected. HRQoL scores were linear transformed to a 0-100-point scale. Mean baseline scores and mean score changes from baseline at each visit were evaluated. A threshold of ≥10-point change in score represents a clinically meaningful difference. For symptoms, negative change scores from baseline reflect an improvement in symptom burden. For global health status and functioning, positive change scores from baseline reflect improvements. Results: The trial enrolled 102 patients. Median age was 61 years and 68.4% of patients were male. Ninety-eight patients (96%) completed a questionnaire at baseline and at least 1 other questionnaire during a follow-up visit. Questionnaire completion rates at 14 time points ranged from 96% at baseline to 66% at 27 months follow-up (Table 1). According to the EORTC QLQ-C30 (Figure 1), improvements were observed for global health status at all follow-up visits, and clinically meaningful improvements were observed at the response visit, 3 months follow-up, and 27 months follow-up. Clinically meaningful improvements in role functioning were observed at EOI and persisted throughout the 27-month follow-up. For fatigue, clinically meaningful improvements were observed at every visit starting from the end of treatment (EOT) visit. Improvements were also observed for insomnia with mean reductions from baseline ≥10 points at various time points during follow-up. There was no worsening in other patient-reported symptoms or functional status over time. Similarly, with the EORTC QLQ-CLL16 (Figure 2), clinically meaningful improvements in symptoms were observed for fatigue, disease symptoms, and future health worries during treatment, at the EOT and/or throughout the follow-up. The largest improvement was observed for fatigue (-24.7) at the 24-month follow-up and future health worries (-25.4) at the 27-month follow-up. Conclusions: We previously reported that G-Benda is an effective regimen for first-line treatment of CLL with no unexpected safety signals. The HRQoL data from the GIBB trial suggest that G-Benda treatment consistently improved patient HRQoL over time. Several clinically meaningful improvements were observed in HRQoL, including global health status, functioning, symptoms, and future health worries. Disclosures Danilov: AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; MEI: Research Funding; Bristol-Meyers Squibb: Research Funding; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; Takeda Oncology: Research Funding; Genentech: Consultancy, Research Funding; Bristol-Meyers Squibb: Research Funding; Takeda Oncology: Research Funding; Aptose Biosciences: Research Funding; Aptose Biosciences: Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy; Bayer Oncology: Consultancy, Research Funding; Celgene: Consultancy; Pharmacyclics: Consultancy; Janssen: Consultancy; Curis: Consultancy; Seattle Genetics: Consultancy; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; Gilead Sciences: Consultancy, Research Funding; Bayer Oncology: Consultancy, Research Funding; Curis: Consultancy; Seattle Genetics: Consultancy; MEI: Research Funding; TG Therapeutics: Consultancy; Celgene: Consultancy; Gilead Sciences: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Abbvie: Consultancy; Abbvie: Consultancy. Yimer:AstraZeneca: Speakers Bureau; Janssen: Speakers Bureau; Seattle Genetics: Honoraria; Celgene: Honoraria; Clovis Oncology: Equity Ownership; Puma Biotechnology: Equity Ownership; Amgen: Consultancy. Boxer:Gerson Lerman: Consultancy; Best Doctors: Consultancy; Takeda: Honoraria, Speakers Bureau; AbbVie: Honoraria, Speakers Bureau. Burke:Celgene: Consultancy; Gilead: Consultancy; Roche/Genentech: Consultancy. Babu:Genentech: Research Funding. Li:Genentech: Employment; Roche: Equity Ownership. Mun:Genentech: Employment, Equity Ownership. Trask:Genentech: Employment, Equity Ownership. Masaquel:Roche: Equity Ownership; Genentech: Employment. Sharman:Acerta: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: GAZYVA (obinutuzumab) is a CD20-directed cytolytic antibody and is indicated: in combination with chlorambucil, for the treatment of patients with previously untreated chronic lymphocytic leukemia; in combination with bendamustine followed by GAZYVA monotherapy, for the treatment of patients with follicular lymphoma (FL) who relapsed after, or are refractory to, a rituximab-containing regimen

PURPOSE Zanubrutinib is a potent, irreversible next-generation Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target kinase inhibition. We hypothesized that complete/sustained BTK occupancy may improve efficacy outcomes and increased BTK specificity may minimize off-target inhibition-related toxicities. PATIENTS AND METHODS ALPINE (ClinicalTrials.gov identifier: NCT03734016 ) is a global, randomized, open-label phase III study of zanubrutinib versus ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia. The primary end point was investigator-assessed overall response rate (ORR). The preplanned interim analysis was scheduled approximately 12 months after the first 415 patients were enrolled. RESULTS Between November 1, 2018, and December 14, 2020, 652 patients were enrolled. We present the interim analysis of the first 415 enrolled patients randomly assigned to receive zanubrutinib (n = 207) or ibrutinib (n = 208). At 15 months of median follow-up, ORR (partial or complete response) was significantly higher with zanubrutinib (78.3%; 95% CI, 72.0 to 83.7) versus ibrutinib (62.5%; 95% CI, 55.5 to 69.1; two-sided P < .001). ORR was higher with zanubrutinib versus ibrutinib in subgroups with del(17p)/ TP53 mutations (80.5% v 50.0%) and del(11q) (83.6% v 69.1%); 12-month progression-free survival in all patients was higher with zanubrutinib (94.9%) versus ibrutinib (84.0%; hazard ratio, 0.40; 95% CI, 0.23 to 0.69). Atrial fibrillation rate was significantly lower with zanubrutinib versus ibrutinib (2.5% v 10.1%; two-sided P = .001). Rates of cardiac events, major hemorrhages, and adverse events leading to treatment discontinuation/death were lower with zanubrutinib. CONCLUSION Zanubrutinib had a significantly higher ORR, lower atrial fibrillation rate, and improved progression-free survival and overall cardiac safety profile versus ibrutinib. These data support improved efficacy/safety outcomes with selective BTK inhibition.

In a multinational, phase 3, head-to-head trial, ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, was compared with zanubrutinib, a BTK inhibitor with greater specificity, as treatment for relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). In prespecified interim analyses, zanubrutinib was superior to ibrutinib with respect to overall response (the primary end point). Data from the final analysis of progression-free survival are now available.We randomly assigned, in a 1:1 ratio, patients with relapsed or refractory CLL or SLL who had received at least one previous course of therapy to receive zanubrutinib or ibrutinib until the occurrence of disease progression or unacceptable toxic effects. In this final analysis, progression-free survival (a key secondary end point) was assessed with the use of a hierarchical testing strategy to determine whether zanubrutinib was noninferior to ibrutinib. If noninferiority was established, the superiority of zanubrutinib was assessed and claimed if the two-sided P value was less than 0.05.At a median follow-up of 29.6 months, zanubrutinib was found to be superior to ibrutinib with respect to progression-free survival among 652 patients (hazard ratio for disease progression or death, 0.65; 95% confidence interval, [CI], 0.49 to 0.86; P = 0.002), as assessed by the investigators; the results were similar to those as assessed by an independent-review committee. At 24 months, the investigator-assessed rates of progression-free survival were 78.4% in the zanubrutinib group and 65.9% in the ibrutinib group. Among patients with a 17p deletion, aIn patients with relapsed or refractory CLL or SLL, progression-free survival was significantly longer among patients who received zanubrutinib than among those who received ibrutinib, and zanubrutinib was associated with fewer cardiac adverse events. (Funded by BeiGene; ALPINE ClinicalTrials.gov number, NCT03734016.).

Background Early cancer detection could identify tumors at a time when outcomes are superior and treatment is less morbid. This prospective case-control sub-study (from NCT02889978 and NCT03085888) assessed the performance of targeted methylation analysis of circulating cell-free DNA (cfDNA) to detect and localize multiple cancer types across all stages at high specificity. Participants and methods The 6689 participants [2482 cancer (>50 cancer types), 4207 non-cancer] were divided into training and validation sets. Plasma cfDNA underwent bisulfite sequencing targeting a panel of >100 000 informative methylation regions. A classifier was developed and validated for cancer detection and tissue of origin (TOO) localization. Results Performance was consistent in training and validation sets. In validation, specificity was 99.3% [95% confidence interval (CI): 98.3% to 99.8%; 0.7% false-positive rate (FPR)]. Stage I–III sensitivity was 67.3% (CI: 60.7% to 73.3%) in a pre-specified set of 12 cancer types (anus, bladder, colon/rectum, esophagus, head and neck, liver/bile-duct, lung, lymphoma, ovary, pancreas, plasma cell neoplasm, stomach), which account for ∼63% of US cancer deaths annually, and was 43.9% (CI: 39.4% to 48.5%) in all cancer types. Detection increased with increasing stage: in the pre-specified cancer types sensitivity was 39% (CI: 27% to 52%) in stage I, 69% (CI: 56% to 80%) in stage II, 83% (CI: 75% to 90%) in stage III, and 92% (CI: 86% to 96%) in stage IV. In all cancer types sensitivity was 18% (CI: 13% to 25%) in stage I, 43% (CI: 35% to 51%) in stage II, 81% (CI: 73% to 87%) in stage III, and 93% (CI: 87% to 96%) in stage IV. TOO was predicted in 96% of samples with cancer-like signal; of those, the TOO localization was accurate in 93%. Conclusions cfDNA sequencing leveraging informative methylation patterns detected more than 50 cancer types across stages. Considering the potential value of early detection in deadly malignancies, further evaluation of this test is justified in prospective population-level studies.

Background: Currently approved CAR T cell therapies are generally administered as inpatient treatment at university medical centers due to concerns about the frequency, onset, severity, and management of AEs, including cytokine release syndrome (CRS) and neurological events (NEs). Infusion and monitoring of patients who receive CAR T cell therapy at nonuniversity medical centers and in outpatient settings have not been specifically studied. Liso-cel is an investigational, CD19-directed, defined composition, 4-1BB CAR T cell product administered at equal target doses of CD8+ and CD4+ CAR+ T cells. The liso-cel clinical program allows outpatient treatment per investigator discretion, with standardized guidelines for safety monitoring and AE management. Here we present preliminary safety and efficacy outcomes of liso-cel in relapsed/refractory (R/R) aggressive large B-cell lymphoma (LBCL) across inpatient and outpatient settings at nonuniversity medical centers in the OUTREACH study (NCT03744676). Methods: This open-label, multicenter, phase 2 study enrolled adult patients with R/R LBCL at nonuniversity medical centers, including those with university affiliations and centers naïve to CAR T cell therapy. Inclusion criteria included ECOG PS of 0-1, PET-positive disease, adequate organ function, and R/R disease after ≥2 lines of prior systemic therapy including chemoimmunotherapy. Prior autologous HSCT was permitted, but prior allogeneic HSCT was prohibited. After leukapheresis and 3 days of lymphodepleting chemotherapy, patients received liso-cel infusion at a dose of 100 × 106 CAR+ T cells. The primary endpoint was incidence of grade ≥3 CRS, NEs, prolonged cytopenias through day 29, and infections. Secondary endpoints included safety and overall response rate (ORR). All study sites had a multidisciplinary CAR T cell therapy team and standard operating procedures for toxicity monitoring/management of patients treated and/or monitored as outpatients. CRS was graded as per 2014 Lee criteria; NEs were defined as liso-cel-related investigator-assessed events and graded as per NCI CTCAE v4.03. Results: At data cutoff, 34 patients were treated with liso-cel (inpatients, n = 12; outpatients, n = 22); 5 patients were treated at non-Foundation for the Accreditation of Cellular Therapy (FACT)-accredited sites. Demographics and baseline disease characteristics were similar between inpatients and outpatients (Table); overall, median age was 66 years (range, 34-83), 68% had diffuse LBCL not otherwise specified, and 88% were refractory to last therapy. CRS was reported in 4 inpatients (33%) and 9 outpatients (41%), with no grade ≥3 events. NEs were reported in 3 inpatients (25%) and 6 outpatients (27%), with 1 grade 3 event in the outpatient group. Median (range) time to onset of CRS and NEs, respectively, was 2.5 (1-3) and 10 (5-16) days for inpatients and 6 (2-9) and 8.5 (6-13) days for outpatients. Tocilizumab and/or corticosteroid use for CRS and/or NE management was generally low (inpatients, n = 2 [17%]; outpatients, n = 5 [23%]). Overall, the most common (≥45%) treatment-emergent AEs (TEAEs) were neutropenia (76%), leukopenia (50%), and anemia (47%). Prolonged cytopenias (grade ≥3 lab values at Day 29) were reported for 7 (21%) patients. No grade 5 TEAEs were reported. Early (≤ study Day 4) and overall hospitalization in outpatients was 18% and 50%, respectively; median time to hospitalization was 5 (2-9) days and median length of stay was 6 (1-18) days. Among efficacy-evaluable patients (n = 31), ORR was 75% for inpatients and 84% for outpatients; CR rate was 50% and 68%, respectively. Of the 5 patients treated at non-FACT-accredited sites (inpatients, n = 1; outpatients, n = 4), 2 had CRS and/or NEs, but none were grade ≥3 events; none of these patients received tocilizumab or corticosteroids. Of these 5 patients, 1 achieved CR and 1 achieved PR; 2 had stable disease and 1 had progressive disease. Conclusions: Patients with R/R aggressive LBCL were successfully treated with liso-cel and monitored for CAR T cell therapy-related toxicities at nonuniversity medical centers in inpatient and outpatient settings using standard operating procedures and multidisciplinary teams. Incidences of severe CRS and NEs were low, as was tocilizumab and/or corticosteroid use. Liso-cel showed encouraging preliminary efficacy in both inpatients and outpatients. This trial is ongoing and actively recruiting. Disclosures Freytes: Sanofi: Speakers Bureau. Stevens:Amgen, MorphoSys: Consultancy. Varela:Neximmune: Consultancy, Current equity holder in private company. Cherry:Kite: Other: Ad Board; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Ad Board; Epizyme: Other: Ad Board . Essell:Kite: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Courtright:AbbVie: Other: Investigator in AbbVie-sponsored clinical trials.. Fanning:Takeda: Consultancy, Speakers Bureau; Abbvie: Consultancy; Sanofi Aventis: Speakers Bureau; TG Therapeautics: Consultancy; Bristol Myers Squibb: Consultancy, Speakers Bureau; Prisma Health: Current Employment. Yimer:Sanofi: Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; BeiGene: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Epizyme: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months; Karyopharm: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Celgene, a Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Speakers Bureau; TG Therapeutics: Consultancy; Texas Oncology: Current Employment. Trede:Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb Company: Current equity holder in publicly-traded company. Youssef:Bristol-Myers Squibb Company: Current Employment, Current equity holder in publicly-traded company. Lymp:Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb Company: Current equity holder in publicly-traded company. Bachier:Juno Therapeutics, a Bristol-Myers Squibb Company: Honoraria; CRISPR: Honoraria; AlloVir: Honoraria; Sanofi: Speakers Bureau.

Background Long-term PI-based treatment is associated with improved outcomes in MM. Nonetheless, prolonged therapy with parenteral PIs (e.g. bortezomib) can be challenging in the real world, with median duration of therapy (DOT) of 4-7 months. Barriers to this long-term approach may include the burden of repeated intravenous/subcutaneous administration, difficulty travelling to/accessing treatment centers (e.g. due to environmental factors, travel restrictions, social/family situations), patient preference for treatment outside of a hospital or clinic setting, comorbidities, and toxicity. The US MM-6 study (NCT03173092) is investigating in-class transition (iCT) from parenteral bortezomib-based induction to all-oral ixazomib-based therapy (ixazomib-lenalidomide-dexamethasone; IRd) in the diverse US community population with the aim of increasing PI-based treatment duration while maintaining quality of life and improving outcomes. We report updated efficacy and safety for the first 101 patients. Methods Transplant-ineligible/delayed-transplant (>24 months) NDMM patients with stable disease or better after 3 cycles of bortezomib-based induction are being enrolled at US community sites (including Veterans Affairs hospitals) to receive IRd (ixazomib 4 mg, days 1, 8, 15; lenalidomide 25 mg, days 1-21; dexamethasone 40 mg, days 1, 8, 15, 22) for up to 39 x 28-day cycles or until progression/toxicity. The primary endpoint is progression-free survival (PFS); key secondary endpoints include rates of partial (PR), very good PR (VGPR), and complete response (CR), and DOT. Results As of June 1 2020, 101 patients had been treated at 21 sites. Median age was 73 years (range 48-90), with 46% aged ≥75 years; 16% and 10% were of African American and Hispanic ethnicity, respectively. Table 1 summarizes the key characteristics of these real-world patients. A total of 95% of patients had ≥1 comorbidity at the start of IRd therapy including renal and urinary disorders (38%), cardiac disorders (29%), peripheral neuropathy (PN; 14%), and diabetes mellitus (13%) (Table 2). With 53 (52%) patients remaining on therapy and enrollment ongoing, mean duration of PI therapy from the start of bortezomib-based induction was 12.4 months, and mean duration of IRd therapy after iCT was 9.2 months (Table 3). Patients have received up to 29.4 months (31 cycles) of IRd to date. The overall response rate (ORR) after bortezomib-based induction was 62% (7% CR, 32% ≥VGPR). After iCT to IRd, the ORR increased to 71%, with the CR and ≥VGPR rates increasing to 29% and 53%, respectively (Figure); of 33 patients with stable disease following bortezomib-based induction, 14 (42%) achieved CR (n=10) or VGPR (n=4) after iCT. With a median follow-up of 12 months and enrollment ongoing, 13 patients had progressed and two had died during PFS analysis. The 12-month PFS rate was 84% (95% CI, 73-91) from the start of bortezomib-based induction and 80% (95% CI, 69-88) from the start of IRd. During IRd treatment to date, 91% of patients have had treatment-emergent adverse events (TEAEs) (54% grade ≥3). Grade 3 TEAEs (≥5% of patients) were diarrhea (8%), pneumonia (7%), and syncope (5%). TEAEs led to study drug modification in 52% of patients and discontinuation in 7% of patients; 37% had serious TEAEs. Diarrhea, nausea, and vomiting occurred in 43%, 23%, and 14% of patients (8%, 2%, 2% grade 3), and led to dose modification in 11%, 5%, and 2%. PN (not elsewhere classified; high-level term) occurred in 32% of patients (2% grade 3) and led to dose modification in 9%. There were three on-study deaths (i.e. occurring Conclusions US MM-6 patients reflect the heterogeneous real-world US MM population; the population for this study includes patients from the community who may not be eligible for traditional clinical trials. These updated data in mostly elderly, comorbid, NDMM patients treated in the community setting demonstrate the feasibility and tolerability of iCT to IRd after 3 cycles of bortezomib-based induction; approximately half of patients remain on treatment, and enrollment is ongoing. iCT to IRd resulted in improved responses, with increased rates of ≥VGPR, and prolonged DOT and may thereby improve outcomes for real-world patients. iCT to an all oral regimen could also prevent treatment interruptions for patients who are unable to or prefer not to travel in the context of travel restrictions or other factors. Disclosures Girnius: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Yimer:TG Therapeutics: Consultancy; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Sanofi: Speakers Bureau; Texas Oncology: Current Employment; BeiGene: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Celgene, a Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Karyopharm: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Epizyme: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months. Noga:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Manda:AbbVie: Other: Investigator in AbbVie-sponsored clinical trials. Lyons:Texas Oncology/US Oncology: Current Employment; Novartis: Honoraria. Bogard:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Whidden:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Cherepanov:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Lu:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Aiello:Takeda: Honoraria; Travera: Honoraria; Celgene: Honoraria; Karyopharm: Honoraria. Richter:Celgene: Consultancy, Speakers Bureau; Adaptive Biotechnologies: Consultancy, Speakers Bureau; Janssen: Speakers Bureau; Sanofi: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy; AstraZeneca: Consultancy; Secura Bio: Consultancy; Bristol Myers Squibb: Consultancy; X4 Pharmaceuticals: Consultancy; Oncopeptides: Consultancy; Antengene: Consultancy. Rifkin:McKesson: Current equity holder in publicly-traded company, Ended employment in the past 24 months, Other: Stock ownership; Takeda, Amgen, Celgene, BMS, Mylan, Coherus BioSciences, Fresenius: Consultancy; AbbVie: Other: Investigator in AbbVie sponsored clinical trials; Takeda, Amgen, BMS (Celgene): Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Real-world evaluation of long-term proteasome inhibition with ixazomib in combination with lenalidomide and dexamethasone for the treatment of newly diagnosed multiple myeloma in non-transplant patients with stable disease after 3 cycles of a bortezomib-based induction.

Summary This United States community study evaluated the combination of daratumumab, bortezomib, cyclophosphamide and dexamethasone (D‐VCd) in newly diagnosed multiple myeloma (NDMM) and relapsed multiple myeloma (RMM). Patients received 4–8 induction cycles of bortezomib 1·5 mg/m2, cyclophosphamide 300 mg/m2 and dexamethasone 40 mg weekly. Intravenous daratumumab 16 mg/kg was administered as approved except for a split‐first dose in Cycle 1. Eligible patients underwent autologous stem cell transplantation. All patients received ≤12 daratumumab maintenance doses monthly. Eighty‐six NDMM and 14 RMM patients received ≥1 treatment dose. In NDMM patients, very good partial response or better (≥VGPR) and overall response rates after 4 induction cycles were 44% (primary endpoint) and 79%, respectively, and 56% and 81% at end of induction. The 12‐month progression‐free survival (PFS) rate was 87%. Efficacy was also observed in RMM patients. Fatigue (59%) and neutropenia (13%) were the most frequent treatment‐emergent adverse event (TEAE) and grade 3/4 TEAE, respectively. Infusion reactions occurred in 54% of patients, primarily during the first dose, and were mild (2% grade 3). The first 2 daratumumab infusions were 4·5 and 3·8 h (median). Overall, D‐VCd was well tolerated, split‐first daratumumab dosing was feasible, the ≥VGPR rate after 4 cycles was 44% and the 1‐year PFS rate was 87%.

The single-arm, multicenter, phase 2 GIBB study (NCT02320487) investigated bendamustine plus obinutuzumab (BG) in previously untreated CLL. Patients (N = 102) received six cycles of intravenous obi...

Background The ongoing US MM-6 study is investigating in-class transition (iCT) from parenteral bortezomib-based induction to all-oral ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) with the aim of increasing proteasome inhibitor (PI)-based treatment adherence/duration while maintaining quality of life (QoL) and improving outcomes. Patients and Methods US community sites are enrolling non-transplant-eligible newly diagnosed multiple myeloma (MM) patients with no evidence of progressive disease after 3 cycles of bortezomib-based therapy to receive ixazomib-Rd (up to 39 cycles or until progression/toxicity). Patients use mobile/wearable digital devices to collect actigraphy (activity/sleep) data and electronically complete QoL/treatment satisfaction/medication adherence questionnaires. Primary endpoint: progression-free survival (PFS); key secondary endpoints include response rates and therapy duration. Results At data cutoff, 84 patients had been treated (median age 73 years; 44% ≥ 75 years; 49% male; 15% black/African American; 10% Hispanic/Latino); 62% of patients remain on therapy. Mean duration of total PI therapy was 10.1 months and of ixazomib-Rd was 7.3 months. With 8 months median follow-up, 12-month PFS rate was 86% (95% confidence interval, 73–93) from both the start of bortezomib-based treatment and the start of ixazomib-Rd. Overall response rate was 62% (complete response [CR], 4%; very good partial response [VGPR], 25%; partial response [PR], 33%) after bortezomib-based induction and 70% (CR, 26%; VGPR, 29%; PR, 15%) after iCT. The ixazomib-Rd safety profile was consistent with previous clinical trial data. QoL/treatment satisfaction were maintained. Conclusion US MM-6 patients are representative of the real-world US MM population; iCT may permit prolonged PI-based therapy with promising efficacy, without impacting patients’ QoL/treatment satisfaction., Graphical abstract, While long-term proteasome inhibitor therapy improves outcomes in multiple myeloma, many patients cannot tolerate long-term treatment or may require/prefer to continue treatment outside the hospital/clinic. US MM-6 evaluates in-class transition from parenteral bortezomib- to oral ixazomib-based therapy in routine clinical practice. Preliminary results indicate feasibility, prolonged duration of therapy, and promising efficacy and treatment adherence/satisfaction.

Introduction: Patients with relapsed or refractory diffuse large B-cell lymphoma (RR DLBCL) who cannot tolerate or who are not eligible for autologous or chimeric antigen receptor T cell (CAR-T) therapy have limited therapeutic options and suboptimal long-term outcomes. In patients who were not eligible for HSCT, the rituximab plus gemcitabine, dexamethasone and cisplatin (R-GDP) regimen (and variations using methylprednisolone or carboplatin/oxaliplatin) have shown an overall response rates (ORR) of ~50%, a complete response (CR) rate of ~25% (Gopal, Leuk Lymphoma, 2010), and a median progression-free survival (PFS) and an overall survival (OS) of 3 and 9 months, respectively (Crump, Hematol Oncol Clin N Am. 2016; Gopal Leuk Lymphoma, 2010; Ng, Br J Cancer, 2005; Sirohi, Hematology, 2007; Barton, Eur J Haematol. 2015; Moccia Leuk Lymphoma, 2017). Selinexor is an oral small molecule selective inhibitor of exportin-1 (XPO1) mediated nuclear export (SINE) compound leading to activation of tumor suppressor proteins and reduction in oncoprotein levels. It also reduces the expression of deoxyribonucleic acid (DNA) damage repair proteins and therefore potentiates DNA damage-based therapies leading to an increased death of cancer cells. Selinexor has synergistic effects with gemcitabine and cisplatin, and enhanced anti-lymphoma effects with dexamethasone. In the SADAL study (n=134), single-agent oral selinexor 60 mg twice weekly induced an ORR of 29% and a CR rate of 13% in patients with RR DLBCL. The response rates were consistent across various subgroups including patients Selinexor in combination with R-GDP was evaluated in a Phase 1 clinical trial (SELINDA), in which patients with DLBCL received either 40 or 60 mg selinexor once or twice weekly in combination with standard dose R-GDP. The recommended phase 2 dose for further exploration was 40 or 60 mg once weekly with an ORR of 60-80%. Therefore, combining selinexor with R-GDP is expected to improve response rates, and continuation of treatment with single-agent selinexor is expected to prolong the duration of responses, improve PFS (and potentially OS) in patients with RR DLBCL. Materials and methods: XPORT-DLBCL-030 is a Phase 2/3, multicenter study. The Phase 2 portion of the study is an open-label randomized study to identify the optimal dose of selinexor (40 or 60 mg) in combination with R-GDP in patients (n=120) with RR DLBCL. Patients ≥18 years with 1-3 prior lines of therapy and ECOG performance status ≤2 who are not intended for HSCT or CAR-T therapy are randomized 1:1:1 to one of 3 treatment arms: Arm 1: selinexor 40 mg+R-GDP (S40+R-GDP); Arm 2: selinexor 60 mg+R-GDP (S60 + R-GDP); Arm 3: R-GDP. Combination treatment will be given for up to 6 cycles (21 days/cycle). After completing the SR-GDP combination therapy (EoC), patients in Arms 1 and 2 who reach at least partial response (PR), will receive weekly single-agent selinexor 60 mg (28 days/cycle) as "continuous therapy" until disease progression (PD) or unacceptable toxicity. After PD, patients will be followed up for survival. Patients in the R-GDP arm will be followed up for PD and survival. Patients who are ineligible for HSCT due to an active disease, or those who have primary refractory DLBCL, defined as no response or relapse within 6 months after ending first-line treatment, will be allowed to enroll in the study (up to 15% and 25%, respectively of all patients enrolled). The primary endpoint of the study is ORR according to the Lugano 2014 criteria. Secondary endpoints include PFS, OS, ORR-EoC, DOR and incidence and severity of adverse events. Figure 1 Figure 1. Disclosures Pinto: Takeda: Consultancy; MSD: Honoraria; Incyte: Honoraria; Roche: Honoraria, Speakers Bureau; Bristol Myers Squibb-CELGENE: Honoraria. Yimer: Texas Oncology: Current Employment; Pharmacyclics: Speakers Bureau; Amgen: Speakers Bureau; Sanofi: Speakers Bureau; GSK: Speakers Bureau; Beigene: Speakers Bureau; Janssen: Speakers Bureau; Astrazeneca: Speakers Bureau; Karyopharm: Current equity holder in publicly-traded company, Speakers Bureau. Manda: Morphosys: Honoraria; Genmab: Current equity holder in publicly-traded company. Canales: Sanofi: Consultancy; Incyte: Consultancy; Novartis: Consultancy, Honoraria; Sandoz: Honoraria, Speakers Bureau; iQone: Honoraria; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Gilead/Kite: Consultancy, Honoraria; Eusa Pharma: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria. Jurczak: European Medicines Agency, Sandoz-Novartis, Janssen China R&D, BeiGene, Epizyme, Acerta, AstraZeneca: Consultancy; AbbVie, AstraZeneca, Bayer, BeiGene, Celtrion, Celgene, Debbiopharm, Epizyme, Incyte, Janssen, Loxo Oncology, Merck, Mei Pharma, Morphosys, Novo Nordisk, Roche, Sandoz, Takeda, TG Therapeutics, Pharmacyclics, Affirmed, Gilead Sciences, Nordic Nanovecto: Research Funding; Jagiellonian University: Ended employment in the past 24 months; Maria Sklodowska-Curie National Research Institute of Oncology: Current Employment; AstraZeneca, BeiGene, Janssen, Loxo Oncology, Sandoz, Roche: Membership on an entity's Board of Directors or advisory committees. Sureda: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; Roche: Other: Support for attending meetings and/or travel; Bluebird: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau. Ma: Karyopharm Therapeutics Inc.: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Li: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Ingalls: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Arriola: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Arazy: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Shah: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Shacham: Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Kauffman: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Nowakowski: Celgene, NanoString Technologies, MorphoSys: Research Funding; Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Background: Use of long-term PI-based therapy can improve outcomes across treatment settings in MM. However, there are various physical, geographical, and/or socioeconomic barriers to prolonged therapy with parenteral PIs in community practice. The US MM-6 study (NCT03173092) is assessing in-class transition (iCT) from parenteral bortezomib (V)-based induction to all-oral ixazomib-based therapy with ixazomib-lenalidomide-dexamethasone (IRd) in the diverse US community population. The objective of the study is to increase the duration of PI-based treatment, while maintaining quality of life and improving outcomes. We previously reported efficacy and safety results for the first 101 US MM-6 patients (Girnius Blood 2020). Here we have analyzed updated data for this patient subset with an additional 11 months of follow-up to further evaluate efficacy and safety, and to determine reasons for premature (within 4 cycles of IRd) discontinuation. Methods: Transplant-ineligible/delayed-transplant (≥24 months) NDMM patients at US community sites, who had achieved stable disease or better after 3 cycles of V-based induction, received IRd (ixazomib 4 mg, days 1, 8, 15; lenalidomide 25 mg, days 1-21; dexamethasone 40 mg, days 1, 8, 15, 22) for up to 39 × 28-day cycles or until disease progression or unacceptable toxicity. The primary endpoint is 2-year progression-free survival (PFS). Rates of partial response (PR), very good PR (VGPR), and complete response (CR), and duration of therapy are key secondary endpoints. For the current analysis, sites with patients who discontinued US MM-6 were queried for more detailed information. Results: As of June 1, 2020, 101 patients had been enrolled and treated at 21 sites. Median age was 73 years (range, 48-90 years), with 81% aged >65 years; 97% had ≥1 comorbidity at the start of IRd therapy. Efficacy data after an additional 11 months of follow-up (data cut-off: May 4, 2021) showed that iCT to IRd improved responses (Table 1). Overall response rate (ORR) had improved from 65% (CR 9%, VGPR 25%, PR 32%), at the end of 3 cycles of V-based induction, to 78% (molecular CR [mCR] 1%, stringent CR [sCR] 3%, CR 32%, VGPR 25%, PR 17%) following iCT to IRd. Thirty-three patients (33%) were still ongoing on therapy at the latest data cut-off; median duration of IRd was 11.7 months and overall median duration of therapy (for all PI-based therapy, including V-based induction) was 14.6 months. At a median follow-up of 18.5 months, the 18-month PFS rate was 84%. The safety profile of IRd was consistent with previous clinical studies. Grade ≥3 treatment-emergent adverse events (TEAEs) were reported in 64% of patients and treatment-related serious TEAEs in 12% (including 4 on-study deaths), while 16% of TEAEs led to study drug discontinuation. Sixty-eight patients (67%) had completed or discontinued the study since first patient enrolment on November 15, 2017. Among these patients, 14 (21%) discontinued within 2 cycles of IRd and 27 (40%) discontinued within 4 cycles; reasons for discontinuation are presented in Table 2. Conclusions: With longer follow-up, use of iCT from V-based induction to IRd to achieve long-term PI-based therapy in NDMM patients demonstrates efficacy via improved response rates and acceptable PFS in this real-world setting. Over 80% of US MM-6 patients were aged >65 years and most had ≥1 comorbidity prior to study entry. The rate of patients discontinuing within 4 cycles of iCT (7 cycles of PI-based therapy in total) is concerning because these patients may not receive the full benefit of long-term PI-based treatment. To date, the majority of premature discontinuations were reported as being due to patient request (44%) followed by TEAEs (30%). Expanded site education and closer patient follow-up to reduce premature discontinuations will be addressed in the planned US MM7 iCT study in relapsed/refractory MM. Figure 1 Figure 1. Disclosures Rifkin: Coherus: Membership on an entity's Board of Directors or advisory committees; Fresenius-Kabi: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; McKesson: Current Employment, Current equity holder in publicly-traded company; Amgen: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb (Celgene): Membership on an entity's Board of Directors or advisory committees. Noga: Takeda Oncology: Current Employment. Girnius: Beigene: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Honoraria, Speakers Bureau; Genentech: Honoraria; Celgene: Speakers Bureau; BMS: Honoraria, Speakers Bureau. Bogard: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Manda: Morphosys: Honoraria; Genmab: Current equity holder in publicly-traded company. Yimer: Texas Oncology: Current Employment; Pharmacyclics: Speakers Bureau; Amgen: Speakers Bureau; Sanofi: Speakers Bureau; GSK: Speakers Bureau; Beigene: Speakers Bureau; Janssen: Speakers Bureau; Astrazeneca: Speakers Bureau; Karyopharm: Current equity holder in publicly-traded company, Speakers Bureau. Whidden: Takeda Oncology: Current Employment. Birhiray: Bayer: Honoraria; Incyte: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Seattle Genetics: Honoraria; Coheris: Honoraria; Kyte Pharma: Honoraria; Celgene: Honoraria; Helsin: Honoraria; Amgen: Honoraria, Speakers Bureau; Pfizer: Speakers Bureau; BMS: Speakers Bureau; Tessaro: Speakers Bureau; AstraZeneca: Speakers Bureau; Alexion: Consultancy; Abbvie: Consultancy, Honoraria; Lilly: Speakers Bureau; Exelexis: Speakers Bureau; Clovis Oncology: Speakers Bureau; Sanofi Oncology: Speakers Bureau; Genomic Health: Speakers Bureau; Puma: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Jansen Bioncology: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Twumasi-Ankrah: Takeda: Current Employment. Guo: Takeda Oncology: Current Employment. Bernal-Mizrachi: Kodikaz Therapeutic Solutions: Consultancy, Current holder of individual stocks in a privately-held company, Patents & Royalties; Bigene: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Winship Cancer Institute of Emory University: Current Employment. OffLabel Disclosure: Real-world evaluation of long-term use of the oral proteasome inhibitor ixazomib in combination with lenalidomide and dexamethasone for the treatment of newly diagnosed multiple myeloma in non-transplant patients with stable disease after 3 cycles of a bortezomib-based induction

Background: SUMOylation, a post-translational modification analogous to ubiquitination, attaches a small, ubiquitin-like modifier (SUMO) to target proteins. SUMOylation plays a central role in the immune system by regulating type I interferon (IFN-I) expression, thereby functioning to constrain the innate immune response (Decque Nat Immunol 2016), and limit tumor immune surveillance. The SUMOylation pathway is often overexpressed in multiple myeloma (MM) and is associated with poor outcomes (Driscoll Blood 2010). TAK-981 is a first-in-class, small-molecule inhibitor of SUMO-activating enzyme, which blocks the SUMOylation cascade (Langston J Med Chem 2021) and increases IFN-I production and signaling in innate immune cells (Nakamura AACR 2019). In ex vivo assays, TAK-981 activated the IFN-I pathway, increased phagocytic activity of monocyte-derived macrophages, and increased natural killer (NK) cell cytotoxicity via IFN-I signaling (Nakamura AACR 2019). The ability of TAK-981 to promote activation of macrophages and NK cells provides a mechanistic rationale for its use in combination with monoclonal antibodies (mAbs) reliant on antibody-dependent cellular cytotoxicity and phagocytosis; in vivo experiments have demonstrated synergistic activity between TAK-981 and rituximab, and between TAK-981 and the anti-CD38 mAbs daratumumab (dara) (Nakamura SITC 2020) or mezagitamab (meza; TAK-079; Figure 1). Patients with MM who have disease refractory to the three most effective classes of anti-myeloma therapies (proteasome inhibitors [PIs], immunomodulatory drugs [IMiDs], and anti-CD38 mAbs) have a poor prognosis, with median survival 9.2 months (Gandhi Leukemia 2019). Given the incurable nature of advanced MM and the highly complex mechanisms of resistance, continued efforts to better understand MM biology at the time of relapse and to translate this into effective treatment combinations are needed. Combination therapies that engage the immune system to treat MM may offer substantial clinical benefit. Methods: To be eligible for this multicenter, open-label, Phase 1b/2 trial (NCT04776018), patients must have failed at least 3 prior lines of anti-myeloma therapy, have MM disease that is triple-class refractory (defined as refractory/intolerant to ≥1 PI and ≥1 IMiD, and refractory to ≥1 anti-CD38 mAb), and have demonstrated disease progression on their last therapy. Prior CAR-T therapy is allowed. Patients will be assigned to TAK-981 plus subcutaneous (SC) meza (Phase 1 Part 1) or SC dara (dara and hyaluronidase-fihj; Phase 1 Part 2). The primary objectives of Phase 1b are to determine safety and tolerability, and to select the recommended Phase 2 dose (RP2D) and schedule for TAK-981 with each mAb; secondary objectives are to evaluate preliminary antitumor activity, to characterize TAK-981 pharmacokinetics (PK), and to explore pharmacodynamic (PD) markers of TAK-981 target engagement and SUMOylation pathway inhibition. Approximately 30 patients will participate in the Phase 1b Part 1 dose escalation of TAK-981 plus meza (~15 patients per dosing schedule), and ~15 patients will participate in the Phase 1b Part 2 dose escalation of TAK-981 plus SC dara. The primary objective of Phase 2 is to evaluate the efficacy of TAK-981 at the RP2D in combination with an anti-CD38 mAb; ~36 patients will be enrolled. In Phase 1b, patients will receive TAK-981 via a 1-hour intravenous infusion either on days 1, 4, 8, 11, and 15 (twice weekly; BIW) or on days, 1, 8, 15, and 22 (weekly; QW) for 2x 28-day cycles, then 8x every other week, then monthly. Meza 600 mg SC or dara 1800 mg SC will be given 8x weekly, 8x every other week, then monthly, in a 28-day cycle (Figure 2). Treatment will continue until disease progression or unacceptable toxicity (max. 24 cycles). TAK-981 dose escalation will proceed from 60 mg BIW, a dose shown to be pharmacologically active in a first-in-human, single-agent TAK-981 study (TAK-981-1002; data on file). Dose escalation will be guided by Bayesian Optimal Internal Design with Informative Prior (iBOIN) plus consideration of other safety, clinical, PK, and PD data. The iBOIN design selects the true maximum tolerated dose (if any) with high accuracy by allocating more patients to dose levels with a prior dose-limiting toxicity probability closest to the target of 0.3. This study is currently enrolling patients, with the first patient dosed in May 2021. Figure 1 Figure 1. Disclosures Lonial: AMGEN: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Research Funding; Merck: Honoraria; Abbvie: Consultancy, Honoraria. Boccia: BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau; Takeda: Honoraria, Research Funding, Speakers Bureau; Amgen: Research Funding, Speakers Bureau; Epizyme: Honoraria, Speakers Bureau; Morphosis: Honoraria, Speakers Bureau. Yimer: Beigene: Speakers Bureau; Astrazeneca: Speakers Bureau; Karyopharm: Current equity holder in publicly-traded company, Speakers Bureau; Janssen: Speakers Bureau; GSK: Speakers Bureau; Sanofi: Speakers Bureau; Amgen: Speakers Bureau; Pharmacyclics: Speakers Bureau; Texas Oncology: Current Employment. Levy: Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Morphosys: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Dova: Consultancy, Other: Promotional speaker; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Amgen Inc.: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; GSK: Consultancy, Other: Promotional speaker; Epizyme: Consultancy, Other: Promotional speaker; Novartis: Consultancy, Other: Promotional speaker; AbbVie: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Beigene: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau. Abonour: Takeda: Research Funding; GSK: Consultancy, Honoraria, Research Funding; Celgene-BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jensen: Honoraria, Research Funding. Mohan: Medical College of Wisconsin: Current Employment. Girnius: BMS: Honoraria, Speakers Bureau; Celgene: Speakers Bureau; Genentech: Honoraria; GSK: Honoraria, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Beigene: Speakers Bureau. Rosenbaum: Takeda: Honoraria; Akcea: Honoraria; Janssen: Honoraria. Nadeem: Karyopharm: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Berg: Takeda: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Chao: Takeda: Current Employment. Berger: Takeda Development Center Americas, Inc.: Current Employment. Nakamura: Takeda Development Center Americas, Inc.: Current Employment. Zhang: Takeda: Current Employment. Song: Takeda Pharmaceuticals International Co.: Current Employment. Ward: Takeda: Current Employment. Proscurshim: Takeda Pharmaceuticals: Current Employment, Current holder of individual stocks in a privately-held company. Kumar: Novartis: Research Funding; Tenebio: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Honoraria; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Genentech: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Beigene: Consultancy; Bluebird Bio: Consultancy; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Oncopeptides: Consultancy; Amgen: Consultancy, Research Funding; Carsgen: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. OffLabel Disclosure: Study of the investigational agent TAK-981 in combination with daratumumab and hyaluronidase-fihj or the investigational agent mezagitamab (TAK-079).

Background: CAR T cell therapies are generally administered in an inpt setting owing to concerns of AE management. Infusion and monitoring of pts who receive CAR T cell therapy at nonuniversity medical centers (NMC) and in outpt settings have not been studied specifically. Liso-cel is an autologous CD19-directed, defined composition, 4-1BB CAR T cell product administered at equal target doses of CD8 + and CD4 + CAR + T cells. In TRANSCEND NHL 001 (NCT02631044) in pts with third- or later-line LBCL, liso-cel treatment showed an ORR of 73% (CR rate, 53%), with grade ≥ 3 cytokine release syndrome (CRS) in 2%, and grade ≥ 3 neurological events (NE) in 10% of pts (Abramson et al. Lancet 2020). We report outcomes of liso-cel in pts with R/R LBCL across inpt and outpt settings at NMCs in the United States treated in the OUTREACH study (NCT03744676). Methods: The study enrolled pts at NMCs, including those with university affiliations and centers naïve to CAR T cell therapy. Adults with R/R PET-positive LBCL after ≥ 2 lines of therapy and ECOG PS ≤ 1 were eligible. Pts with grade 3-4 cytopenias, mild to moderate organ function (LVEF ≥ 40%; serum CrCl > 30 mL/min), secondary CNS lymphoma, and prior autologous HSCT were eligible. After leukapheresis and lymphodepleting chemotherapy (LDC), pts received liso-cel at a target dose of 100 × 10 6 CAR + T cells. Primary endpoint was incidence of grade ≥ 3 CRS, NEs, prolonged cytopenias (Day 29 grade ≥ 3 lab values), and infections. Secondary endpoints included safety, ORR, CR rate, duration of response (DOR), and liso-cel PK. B-cell depletion analyses were exploratory. AEs, including NEs, were graded using NCI CTCAE v4.03; CRS was graded per Lee criteria (2014). NEs were defined as investigator-identified neurological AEs related to liso-cel. All study sites had a multidisciplinary CAR T cell therapy team and standard operating procedures (SOP) for outpt monitoring of toxicity and admission for CRS/NE management. Results: At data cutoff, 71 pts were treated with liso-cel at NMCs; 52 and 19 were monitored as outpts and inpts, respectively. Median age was 65 years (range, 28-83; ≥ 65 years, 51%; ≥ 75 years, 18%); 65% of pts had de novo DLBCL, 68% had screening ECOG PS of 1, 82% were chemotherapy refractory, 31% had ≥ 3 prior therapies, and 48% had markers of high tumor burden (pre-LDC LDH ≥ 500 U/L or SPD ≥ 50 cm 2). Demographics and baseline disease characteristics were generally similar in outpts and inpts, respectively, with differences of ≥ 20% noted in incidences of high-grade B-cell lymphoma (4% vs 42%) and DLBCL transformed from indolent lymphoma (29% vs 0%). Overall, any-grade CRS occurred in 39% of pts (no grade ≥ 3) and NEs in 32% (grade 3-4, 10%); 27% received tocilizumab and/or corticosteroids for CRS or NEs. Incidences of any-grade CRS and NEs were similar in outpts and inpts, while grade ≥ 3 NEs, infections, and prolonged cytopenias were numerically higher in outpts, but similar to pivotal trial observations (Table). The most common treatment-emergent AEs were neutropenia (68%), leukopenia (45%), CRS (39%), anemia (38%), thrombocytopenia (37%), and fatigue (35%). No grade 5 AEs were reported. Early (study Day ≤ 4) and overall hospitalization occurred in 33% and 69% of outpts, respectively; median time to hospitalization was 5.0 days (range 2-141) in outpts. The median (range) length of initial hospital stay after liso-cel administration was 6.0 days (1-28; n = 36) for outpts versus 10.0 days (0-31; n = 19) for inpts; 31% of outpts were not hospitalized. All pts were efficacy evaluable. The ORR was 77% and the CR rate was 51%. Median DOR was 14.8 months (95% CI, 3.9‒not reached [NR]) for outpts and was NR (95% CI, 2.0‒NR) for inpts at a median follow-up of 8.1 months and 11.3 months, respectively (Table). PK profiles were similar in outpts and inpts. Target depletion of CD19 + B cells in peripheral blood was also similar between oupts and inpts, and was maintained over the period of 1 year. Conclusions: Pts with R/R LBCL were successfully treated with liso-cel in outpt and inpt settings at NMCs and monitored for CAR T cell therapy-related toxicities using SOPs and multidisciplinary teams. Liso-cel demonstrated durable clinical activity with a favorable safety profile in both outpts and inpts. Incidences of severe CRS and NEs were low, as was tocilizumab and/or corticosteroid use. These data support liso-cel administration at NMCs and in the outpt setting. Figure 1 Figure 1. Disclosures Bachier: Novartis: Membership on an entity's Board of Directors or advisory committees; Mana: Membership on an entity's Board of Directors or advisory committees; Nkarta: Membership on an entity's Board of Directors or advisory committees; Autolus: Membership on an entity's Board of Directors or advisory committees; CRISPR: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Varela: Kite: Speakers Bureau; Nexlmmune: Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cherry: BMS: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees. Fanning: Sanofi: Speakers Bureau; Takeda: Speakers Bureau; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees; TG Pharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees. Essell: Gilead: Current Employment, Speakers Bureau; BMS: Speakers Bureau. Yimer: Texas Oncology: Current Employment; Pharmacyclics: Speakers Bureau; Amgen: Speakers Bureau; Sanofi: Speakers Bureau; GSK: Speakers Bureau; Beigene: Speakers Bureau; Janssen: Speakers Bureau; Astrazeneca: Speakers Bureau; Karyopharm: Current equity holder in publicly-traded company, Speakers Bureau. Sharman: AstraZeneca: Consultancy; AbbVie: Consultancy; BMS: Consultancy; TG Therapeutics: Consultancy; Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; Lilly: Consultancy. Espinola: BMS: Current Employment, Current equity holder in publicly-traded company. Mailley: BMS: Current Employment, Current equity holder in publicly-traded company. Avilion: BMS: Current Employment, Current equity holder in publicly-traded company. Ogasawara: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Ou: BMS: Current Employment. Shaughnessy: Sanofi: Honoraria, Speakers Bureau; Kite: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau.

Background: Bruton tyrosine kinase inhibitors (BTKis) are important tools to treat B-cell malignancies. However, duration of treatment may be limited by adverse events (AEs). Zanubrutinib (zanu) is a BTKi approved for mantle cell lymphoma (MCL) and is in development for other hematologic malignancies. Data from phase 3 head-to-head trials of zanu vs ibrutinib (ibr) in pts with Waldenström macroglobulinemia (WM) or chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) demonstrated that pts treated with zanu showed lower rates of AEs leading to discontinuation (Blood 2020;136(18):2038-50; EHA 2021 LB1900). Preliminary results from BGB-3111-215 (NCT04116437) show that zanu was well-tolerated in pts who discontinued ibr and/or acalabrutinib (acala) treatment due to AEs (EHA 2021 EP642). Here, we report updated results from the BGB-3111-215 study with a median follow-up of 9 months. Methods: This study is an ongoing US, phase 2, multicenter, single-arm, open-label study. The safety and efficacy of zanu monotherapy (160 mg twice daily or 320 mg once daily) were evaluated in pts with B-cell malignancies who met criteria for continued treatment after having become intolerant to prior BTKi therapy. Pts were divided into cohort 1 (pts who were intolerant to ibr only) and cohort 2 (pts who were intolerant to acala alone/and ibr). Pts with documented progressive disease (PD) on prior BTKi therapy were excluded. Efficacy and safety, including recurrence of intolerant AEs to the prior BTKi, were evaluated. AEs were assessed for severity, seriousness, and relation to zanu; as well as dose reductions, holds, or discontinuations. Response was assessed by investigators based on response criteria for their respective indications (Blood 2008;131:2745; J Clin Oncol 2012;30:2820; J Clin Oncol 2014;32:3059; Br J Haemtol 2013;160:171). Disease parameters from study entry were the baseline for response assessment. Mutational analysis was performed on pts who discontinued treatment, and data will be shared once available. To support clinical findings, kinase selectivity was assessed using Kinome profiling at 100X IC50 (against BTK) for zanu, ibr, acala and its major metabolite, M27 (Reaction Biology Corp). Results: As of 7 June 2021 (data cutoff), 57 pts (n=44 CLL/SLL; n=9 WM; n=2 MCL; n=2 marginal zone lymphoma [MZL]) were enrolled in cohort 1, and 7 pts were enrolled in cohort 2 (n=4 CLL; n=1 WM; n=1 MCL; n=1 MZL). All received ≥1 dose of zanu and were analyzed for safety. The median age was 71 years (range, 49-91) in cohort 1 and 71 years (range, 65-76) in cohort 2; median duration of treatment was 8.7 months (range, 0.6-17.9) in cohort 1 and 8.2 months (range, 6.4-11.4) in cohort 2; median number of prior regimens was 1 (range, 1-12) in cohort 1 and 3 (range, 2-5) in cohort 2. Within cohort 2, 5 pts were intolerant to both ibr and acala. Median number of intolerant events per pt for both cohorts 1 and 2 was 2 (range, 1-5). Overall, 73% of pts did not experience recurrence of their ibr or acala intolerant events and 79% of recurrent events recurred at a lower severity (Figure 1). At cutoff, 54 pts remained on treatment. Reasons for treatment discontinuation were AEs (n=4), PD (n=4), physician's decision (n=1), and consent withdrawal (n=1). Grade ≥3 AEs were reported in 18 pts (28%), and serious AEs occurred in 7 pts (11%). AEs requiring dose interruptions occurred in 17 pts (27%), and AEs leading to dose reduction occurred in 3 pts (5%). One death, due to COVID-19, was reported. Pts demonstrated maintained (41%) and improved (53%) response with zanu treatment from their reported best overall response on prior BTKis for a total disease control rate of 94% (including a 42% partial response rate in pts with CLL/SLL, 30% in pts with WM, and a 20% very good partial response rate in pts with WM). Zanu also demonstrated good selectivity by kinase profiling. It showed >50% inhibition on 7/370 kinases, while ibr, acala, and M27 had more off-target binding (17, 15 and 23 kinases, respectively) at their respective 100X IC50 (BTK) concentrations (Figure 2). Conclusion: In pts with B-cell malignancies intolerant to ibr and/or acala, zanu treatment resulted in continued disease control or improved response. Zanu was well-tolerated, and most AEs that led to discontinuation of previous BTKi therapy did not recur or recurred at a lower grade. In support of clinical findings, differentiation between BTKi selectivity profiles favor zanu over ibr and acala. Figure 1 Figure 1. Disclosures Shadman: Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, and Atara Biotherapeutics, Adaptimmune: Consultancy; Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding; Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, and Atara Biotherapeutics, Adaptimmune: Membership on an entity's Board of Directors or advisory committees. Flinn: Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Levy: Epizyme: Consultancy, Other: Promotional speaker; Amgen Inc.: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Other: Promotional speaker; Morphosys: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Beigene: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Novartis: Consultancy, Other: Promotional speaker; Dova: Consultancy, Other: Promotional speaker; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau. Burke: SeaGen: Consultancy, Speakers Bureau; Beigene: Consultancy, Speakers Bureau; MorphoSys: Consultancy; Bristol Myers Squibb: Consultancy; AstraZeneca: Consultancy; Epizyme: Consultancy; Verastem: Consultancy; Kura: Consultancy; Kymera: Consultancy; AbbVie: Consultancy; Adaptive Biotechnologies: Consultancy; Roche/Genentech: Consultancy; X4 Pharmaceuticals: Consultancy. Cultrera: Beigene: Research Funding. Yimer: Astrazeneca: Speakers Bureau; Karyopharm: Current equity holder in publicly-traded company, Speakers Bureau; Janssen: Speakers Bureau; Beigene: Speakers Bureau; GSK: Speakers Bureau; Sanofi: Speakers Bureau; Amgen: Speakers Bureau; Pharmacyclics: Speakers Bureau; Texas Oncology: Current Employment. Chaudhry: Medical Oncology Associates, PS (dba Summit Cancer Centers): Current Employment; Novartis, Immunomedics: Current holder of individual stocks in a privately-held company. Gandhi: TG Therapeutics: Honoraria; Karyopharm Therapeutics: Honoraria; GlaxoSmithKline: Honoraria. Kingsley: Comprehensive Cancer Centers of Nevada: Current Employment. Tumula: Texas Oncology: Current Employment. Manda: Morphosys: Honoraria; Genmab: Current equity holder in publicly-traded company. Chen: BeiGene: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Cohen: BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: Travel, Accommodations, Expenses. By: BeiGene, Ltd: Current Employment. Xu: Beigene: Current Employment; AstraZeneca: Ended employment in the past 24 months. Liu: BeiGene Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Sharman: TG Therapeutics: Consultancy; Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie Company: Consultancy; BMS: Consultancy; AbbVie: Consultancy; BeiGene: Consultancy; AstraZeneca: Consultancy; Lilly: Consultancy.

Background: Venetoclax (VEN), an oral B-cell lymphoma 2 inhibitor, is approved for use in adult patients (pts) with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). As a targeted and highly active antitumor agent, VEN induces rapid and profound tumor reduction. Inpatient monitoring for initial doses of VEN is recommended by US Prescribing Information for pts with medium tumor burden and reduced renal function or high tumor burden. Administration of debulking agents, such as obinutuzumab (G), help reduce tumor burden and, consequently, facilitate subsequent administration of VEN in the outpatient setting. However, tumor reduction data are needed to definitively establish the utility of a debulking strategy. This study performed disease restaging after every 2 cycles of debulking to evaluate the safety and efficacy of G ± bendamustine (B) as a debulking regimen before VEN treatment in the outpatient community setting. The safety and efficacy of subsequent VEN+G treatment after debulking was also evaluated. Methods: This open-label, Phase 3b study (NCT03406156) enrolled adult pts with previously untreated CLL/SLL (except those with 17p deletion) who had medium (any lymph node [LN] 5 to Results: Of 120 pts treated, 81 received G for debulking and 39 received G+B. As of 13 May 2021, 2 pts remained on study treatment, 108 were in posttreatment follow-up, and 10 had discontinued the study for reasons including death (n=7), withdrawn consent (n=2), and COVID-19 infection (n=1). At baseline, 82.5% of pts had ALC ≥25x10 9/L, 33.3% had LN ≥5 cm, and 24.2%/75.0%/0.8% had high/medium/low tumor burden, respectively. Low tumor burden was achieved in 91.6% (109/119) of evaluable pts receiving G±B debulking. In the all-treated population (N=120), the objective response rate (ORR) was 90.0% and the CR/CRi rate was 35.8%. Among pts receiving VEN with disease assessment at EoT (N=76), the ORR was 98.7% and the CR/CRi rate was 44.7% (Table). The best uMRD4 rates in peripheral blood were 89.2% (107/120) for all-treated and 98.2% (107/109) for evaluable pts. Among evaluable pts, the uMRD4 rates were 100% (100/100) and 97.1% (68/70) at EoCT and EoT, respectively. Among pts with MRD assessments at both timepoints (N=67), 19.4% had a deepening of their MRD response from EoCT to EoT, and 67.2% maintained the same MRD level (Figure). At a median follow-up of 24.0 mo, 7 deaths (6 related to COVID-19 infection and 1 from cardiac complication after pancreatic mass resection) and no incidences of disease progression were reported; the estimated 18-mo PFS was 94.1%. In pts treated with G vs G+B debulking, respectively, the incidences of Grade ≥3 TEAEs were 71.6% vs 84.6% (most common was neutropenia at 28.4% vs 41.0%) and serious AEs were 23.5% vs 17.9% (most common were pneumonia and COVID-19 pneumonia, each at 3.7% vs 2.6%). Conclusion: In this study, most (91.6%) pts achieved low tumor burden after debulking. The uMRD4 rate was 98.2% among MRD-evaluable pts (89.2% among all pts), with 100% and 97.1% uMRD4 rates at EoCT and EoT, respectively. Overall, these results highlight the utility of G±B as an effective debulking strategy that can facilitate VEN treatment initiation in the outpatient setting. The efficacy and safety results are consistent with other VEN+G trials. Preventive measures for COVID-19 should be continuously emphasized for pts with CLL. Figure 1 Figure 1. Disclosures Flinn: AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Andorsky: AbbVie: Research Funding; Celgene/Bristol Myers Squibb: Consultancy; Celgene/Bristol Myers Squibb: Research Funding; Epizyme: Research Funding; AstraZeneca: Other: served on steering committees; AbbVie: Consultancy. Melear: TG Therapeutics: Speakers Bureau; Astrazeneca: Speakers Bureau; Janssen: Speakers Bureau. Manda: Morphosys: Honoraria; Genmab: Current equity holder in publicly-traded company. Kolibaba: TG Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Atara Biotechm: Consultancy; McKesson Specialty Health: Consultancy; Sunitomo Dainippon Pharma: Consultancy; Tolero Pharma: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Yimer: GSK: Speakers Bureau; Beigene: Speakers Bureau; Janssen: Speakers Bureau; Astrazeneca: Speakers Bureau; Karyopharm: Current equity holder in publicly-traded company, Speakers Bureau; Sanofi: Speakers Bureau; Amgen: Speakers Bureau; Pharmacyclics: Speakers Bureau; Texas Oncology: Current Employment. Burke: Kura: Consultancy; Epizyme: Consultancy; Kymera: Consultancy; Adaptive Biotechnologies: Consultancy; Roche/Genentech: Consultancy; Beigene: Consultancy, Speakers Bureau; MorphoSys: Consultancy; Verastem: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy; Bristol Myers Squibb: Consultancy; X4 Pharmaceuticals: Consultancy; SeaGen: Consultancy, Speakers Bureau. Fanning: BMS: Speakers Bureau; TG Pharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genmab: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sanofi: Speakers Bureau; Takeda: Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees. Islas-Ohlmayer: OHC/USON: Current Employment; AbbVie: Honoraria; Rigel: Honoraria, Speakers Bureau. Vizkelety: AbbVie: Current Employment, Current equity holder in publicly-traded company. Pesko: AbbVie: Current Employment, Current equity holder in publicly-traded company. Chyla: AbbVie: Current Employment, Current equity holder in publicly-traded company. Jiang: AbbVie: Current Employment, Current equity holder in publicly-traded company. Sharman: Pharmacyclics LLC, an AbbVie Company: Consultancy; BMS: Consultancy; Lilly: Consultancy; BeiGene: Consultancy; Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; TG Therapeutics: Consultancy; AbbVie: Consultancy.

Background: Venetoclax (Ven), a highly selective BCL-2 inhibitor, combined with azacitidine (Aza) suppresses oxidative phosphorylation, which selectively targets leukemia stem cells that drive initiation and perpetuation of acute myeloid leukemia (AML; Pollyea. Nat Med. 2018;24:1859), an aggressive malignancy most common in older adults. Safety and efficacy of Ven combined with the hypomethylating agents (HMA) Aza or decitabine (Dec) for the treatment of newly diagnosed AML in patients (pts) who are ineligible to receive intensive chemotherapy has been demonstrated (DiNardo. Blood. 2019;133:7; DiNardo. N Engl J Med. 2020;383:617). Phase 1 and Phase 3 studies initiated Ven + HMA in an inpatient setting due to the nature of the study design and concerns of tumor lysis syndrome (TLS) based on chronic lymphocytic leukemia treatment with Ven. Safety and efficacy of Ven + HMA treatment initiation in an exclusively outpatient setting is being evaluated in an ongoing Phase 3b, single-arm, multicenter, open-label study (NCT03941964). Here, we present pt baseline (BL) characteristics and safety during initial outpatient dose ramp-up of Ven + HMA. Methods: Pts with untreated AML with an ECOG performance status of 0-3 who were ineligible to receive intensive chemotherapy, had no evidence of spontaneous TLS at BL, and deemed an appropriate candidate for outpatient initiation of Ven + HMA by the investigator were eligible. Enrolled pts received Ven (100 mg on Cycle [C] 1 Day [D] 1, 200 mg C1D2, 400 mg C1D3-D28, and 400 mg daily for each 28-day cycle thereafter) in combination with Aza (75 mg/m 2 intravenously [IV] or subcutaneously for 7 days) or Dec (20 mg/m 2 IV for 5 days), beginning on D1 of each cycle, as per institutional practice, for ≤6 cycles. After the study period ended, pts could continue receiving commercially acquired standard-of-care treatments with Ven and Aza or Dec. Ven dosing was modified for concomitant use with moderate and strong CYP3A inhibitors (CYP3Ai). Ven and HMA dosing adjustments were permitted for the management of adverse events (AEs). TLS prophylaxis was initiated in all pts before the first dose of study drug or first new escalated dose. Pts were screened for BL TLS markers. BL AML characteristics, such as blast count and cytogenetics, were examined. The incidence of TLS per Howard Criteria (Howard. N Engl J Med. 2011;364:1844) was assessed for 5 days starting after the first dose of Ven. Results: At the data cutoff (April 30, 2021), 53 pts were enrolled, with 27 receiving Ven + Aza and 26 receiving Ven + Dec (Table). Among all pts, the median age was 76 years (range, 66-94), 89% of pts had an ECOG performance status of 0-1, and 60% were ineligible for standard induction therapy due to age ≥75 years. Overall, 15% and 38% of pts were transfusion-dependent on platelets or red blood cells, respectively. Grade 4 neutropenia was present at BL in 51% of pts; renal and hepatic impairment were present at BL in 79% and 19%, respectively. Most pts had intermediate (47%) or poor (43%) cytogenetic risk. De novo AML was the most common type of disease (75%), followed by secondary (17%) and therapy-related AML (8%). Thirteen pts (25%) had ≥50% bone marrow blasts, and the median blast count was 30% (range, 0-90). In some pts, mutations in biomarkers of interest (FLT3, IDH1/2, NPM1, and TP53) were detected; an analysis will be presented. Nineteen pts (36%) received prophylactic anti-infective moderate or strong CYP3Ai. During Ven ramp-up, there were no cases of clinical TLS and 2 cases (4% of pts) of laboratory TLS; both pts were hospitalized and managed with dose interruption and medical intervention, and neither case led to treatment or study discontinuation. Three pts were hospitalized during Ven ramp-up for other serious AEs. Conclusion: In our study of pts receiving Ven + HMA in an outpatient setting at US community-based oncology centers, most had an ECOG performance status of 0-1 and were not platelet or red blood cell transfusion-dependent. Disease was primarily de novo AML, and 74% of pts had bone marrow blast counts Figure 1 Figure 1. Disclosures Manda: Genmab: Current equity holder in publicly-traded company; Morphosys: Honoraria. Benton: AbbVie: Consultancy; Karyopharm: Consultancy; Pharmaessentia: Consultancy. Yimer: Astrazeneca: Speakers Bureau; Janssen: Speakers Bureau; Karyopharm: Current equity holder in publicly-traded company, Speakers Bureau; Beigene: Speakers Bureau; GSK: Speakers Bureau; Sanofi: Speakers Bureau; Amgen: Speakers Bureau; Pharmacyclics: Speakers Bureau; Texas Oncology: Current Employment. Renshaw: Amgen: Speakers Bureau; SeaGen: Consultancy; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Texas Oncology: Current Employment. Geils: Amgen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Janssen Oncology: Honoraria, Speakers Bureau. Fanning: Sanofi: Speakers Bureau; TG Pharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genmab: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Takeda: Speakers Bureau; BMS: Speakers Bureau. Melear: Astrazeneca: Speakers Bureau; TG Therapeutics: Speakers Bureau; Janssen: Speakers Bureau. Sharman: BMS: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy; TG Therapeutics: Consultancy; BeiGene: Consultancy; Lilly: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Kang: AbbVie: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Svensson: AbbVie: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Pai: AbbVie: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company.

Introduction Brentuximab vedotin (BV) and nivolumab are both active and well tolerated in patients (pts) with classical Hodgkin lymphoma (cHL) and were previously studied in first salvage (overall response rate [ORR] 85%; complete response [CR] 67%) (Advani 2021) and as firstline therapy in older adults (ORR 95%; CR 79%) (Yasenchak 2019). BV is approved for the treatment of adults with treatment-naïve Stage III or IV cHL in combination with doxorubicin, vinblastine, and dacarbazine (AVD) (Connors 2017) and targets CD30, a receptor expressed on the Reed-Sternberg cells. Nivolumab is approved for treatment of adults with relapsed/refractory cHL and restores antitumor immunity by blocking the PD-1 receptor on activated T-cells. The combination of BV plus nivolumab demonstrated promising activity that supports this combination when evaluated as a frontline treatment option for pts over 60 years of age with cHL (Friedberg 2018). Additionally, in pts with non-bulky Stage I or II cHL, treatment with BV plus doxorubicin and dacarbazine (AD) resulted in a CR rate of 97% at end of treatment (EOT), as well as a promising 4-year progression-free survival (PFS) estimate of 91%. Importantly, there were no cases of ≥Grade 3 peripheral neuropathy and only 9% were Grade 2 (Abramson 2021). Herein, we present preliminary safety results from Part B of this phase 2 study, where combination treatment with AN+AD (BV, nivolumab, doxorubicin, and dacarbazine) was well tolerated without excessive dose modifications or discontinuations and is consistent with the known safety profiles of the individual components of this treatment regimen. Methods SGN35-027 (NCT03646123) is an open-label, multiple part, multicenter, phase 2 clinical trial. Part B of this study enrolled pts with Ann Arbor Stage I or II cHL with bulky mediastinal disease (defined as ≥ 10 cm) or Stage III or IV cHL. Pts received up to 6 cycles of AN+AD (consisting of BV 1.2 mg/kg, nivolumab 240 mg, doxorubicin 25 mg/m 2, and dacarbazine 375 mg/m 2). All study drugs were administered by IV infusion on Days 1 and 15 of each 28-day cycle. The primary endpoint was CR rate at EOT. Secondary endpoints included safety, tolerability, overall response rate, and PFS. Disease response and progression was assessed by investigators using the Lugano Classification Revised Staging System for nodal non-Hodgkin and Hodgkin Lymphomas (Cheson 2014) and Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC) (Cheson 2016) at Cycle 2 and EOT. Results In Part B, the majority of the 58 pts enrolled were white (86%), not of Hispanic or Latino/a or Spanish origins (79%), and less than 65 years old (95%). Median age was 35 years (range: 19-78 years). Twenty-nine percent of pts had Stage II cHL with bulky mediastinal disease, while the remainder had Stage III (17%) or Stage IV (50%) cHL. Of the 58 pts enrolled, 57 received at least one dose of study treatment. Of the 57 pts who received at least one dose of study treatment, 1 pt discontinued treatment (all study drugs) by the end of Cycle 2 due to treatment-emergent adverse events (TEAEs). By end of Cycle 2, the majority of TEAEs were Grades 1 and 2; 16% of pts experienced ≥Grade 3 TEAEs. Nausea, fatigue, and alopecia were the most frequently reported treatment-related TEAEs (51%, 33%, and 26% of pts, respectively). No febrile neutropenia was observed, and there were no Grade 5 adverse events. Two pts (4%) experienced treatment-related treatment-emergent serious adverse events; 1 pt (2%) experienced hypophysitis and aseptic meningitis, and discontinued treatment, and 1 pt (2%) experienced pneumonitis. Preliminary efficacy results are anticipated for presentation. Conclusions Preliminary results demonstrate that AN+AD is well-tolerated, and no new safety signals were observed. The omission of bleomycin and vinblastine may have contributed to the absence of certain AEs, such as febrile neutropenia. This study of AN+AD is ongoing, and updated safety and efficacy results will be presented at the meeting. Disclosures Lee: BMS: Honoraria, Research Funding; Aptitude Health: Honoraria; Century Therapeutics: Consultancy; Pharmacyclics: Research Funding; Guidepoint: Honoraria; Oncternal: Research Funding; Seagen: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Janssen: Honoraria. Flinn: Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Melear: Astrazeneca: Speakers Bureau; TG Therapeutics: Speakers Bureau; Janssen: Speakers Bureau. Ramchandren: curis: Research Funding; MERCK: Consultancy, Research Funding; pharmacyclics: Consultancy, Research Funding; seattle genetics: Consultancy, Research Funding; BMS: Consultancy; Trillium: Research Funding. Friedman: Seagen Inc.: Research Funding. Burke: MorphoSys: Consultancy; Beigene: Consultancy, Speakers Bureau; AbbVie: Consultancy; Epizyme: Consultancy; Adaptive Biotechnologies: Consultancy; Bristol Myers Squibb: Consultancy; Kymera: Consultancy; AstraZeneca: Consultancy; Verastem: Consultancy; Kura: Consultancy; X4 Pharmaceuticals: Consultancy; SeaGen: Consultancy, Speakers Bureau; Roche/Genentech: Consultancy. Linhares: Seagen Inc.: Research Funding. Peterson: Seagen Inc.: Research Funding. Raval: Abbvie Pharmaceuticals: Speakers Bureau; Adaptive Biotechnologies: Consultancy; ADCT Therapeutics: Consultancy, Speakers Bureau; Alexion Pharmaceuticals: Speakers Bureau; Amgen Biotechnology Company: Research Funding; Astellas Pharmaceuticals: Speakers Bureau; Astrazeneca Pharmaceuticals: Consultancy, Speakers Bureau; Beigene Pharmaceuticals: Speakers Bureau; Bristol Meyers Squibb Pharmaceuticals: Consultancy; Epizyme Pharmaceuticals: Consultancy, Speakers Bureau; Genetech Biotechnology Company: Research Funding; GlaxoSmithKline Pharmaceuticals: Consultancy; Incyte Pharmaceuticals Corporation: Speakers Bureau; Jazz Pharmaceuticals: Consultancy; Karyopharm Therapeutics: Consultancy; Morphosys Biotech Company: Speakers Bureau; Sanofi Genzyme: Consultancy; Seagen Biotechnology Company: Research Funding; Takeda Pharmaceuticals: Consultancy, Speakers Bureau. Chintapatla: Seagen Inc.: Research Funding. Feldman: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Study investigator. Yimer: Janssen: Speakers Bureau; Beigene: Speakers Bureau; Astrazeneca: Speakers Bureau; Karyopharm: Current equity holder in publicly-traded company, Speakers Bureau; GSK: Speakers Bureau; Sanofi: Speakers Bureau; Amgen: Speakers Bureau; Pharmacyclics: Speakers Bureau; Texas Oncology: Current Employment. Islas-Ohlmayer: Seagen Inc.: Research Funding. Dean: Seagen Inc.: Research Funding. Rana: Seagen Inc.: Research Funding. Gandhi: GlaxoSmithKline: Honoraria; Karyopharm Therapeutics: Honoraria; TG Therapeutics: Honoraria. Renshaw: Amgen: Speakers Bureau; SeaGen: Consultancy; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Texas Oncology: Current Employment. Gillespie-Twardy: Seagen Inc.: Research Funding. Ho: Seagen Inc.: Current Employment, Current equity holder in publicly-traded company. Fanale: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Guo: Seagen Inc.: Current Employment, Current equity holder in publicly-traded company. Yasenchak: Seagen Inc.: Research Funding.

Background: Venetoclax (VEN), a B-cell lymphoma 2 inhibitor, is an oral agent with demonstrated efficacy in patients (pts) with chronic lymphocytic leukemia (CLL). VEN treatment induces rapid tumor reduction, posing a risk for tumor lysis syndrome (TLS), particularly in pts with high tumor burden, and may require inpatient monitoring at the initiation of therapy. Agents such as obinutuzumab (G), ibrutinib, and bendamustine (B) have been used in clinical studies to debulk tumors prior to treatment with VEN. However, the benefits of these debulking regimens could not be established conclusively, as disease restaging was rarely performed. In the present study, disease restaging was performed every 2 cycles to evaluate the efficacy and safety of G, with or without B, as a debulking therapy in untreated pts with CLL, prior to VEN treatment in an outpatient community setting. Methods: This open-label, phase 3b trial (NCT03406156) enrolled adult pts with previously untreated CLL/small lymphocytic lymphoma (excluding those with 17p deletion) who had Eastern Cooperative Oncology Group performance status of ≤1 and medium (any lymph node [LN] 5 to 10 cm or with del(11q) and LN >5 cm. Restaging data were obtained after every 2 cycles of debulking therapy. When low tumor burden was achieved, VEN was administered (5-week ramp-up schedule) as combination therapy with G (VEN+G) for 5 months, and then as monotherapy (VEN mono) for a total of 1 year. Response assessments were scheduled at week 38 and week 65 post-VEN initiation. Adverse events (AEs) were monitored throughout the study. Primary endpoints were the reduction in tumor burden after debulking therapy and the complete remission (CR)/CR with incomplete marrow recovery (CRi) rates of pts subsequently treated with VEN. We report the results of a planned interim analysis when 50 pts had completed their week 38 disease assessment. Results: As of 3 Feb 2020, 117 pts were treated with study drug(s): 80 (68%) received G and 37 (32%) received G+B for debulking; 113 pts were active in study (7 in the debulking phase; 106 completed debulking therapy and initiated VEN, including 26 in posttreatment follow-up). Four pts discontinued study due to withdrawal by pt (n=2; 1 at debulking and 1 at VEN treatment phase) and physician decision (n=1; at VEN treatment phase) and other (n=1; at debulking). At baseline, 85% of pts had ALC ≥25 × 109/L, 9% had LN ≥10 cm, 23% had LN 5-10 cm; 74%/26% had medium/high TLS risk, respectively, per investigator assessment (1 pt with low TLS risk was enrolled and subsequently discontinued). After 2 cycles of debulking therapy, low tumor burden was achieved in 85% (89/105) of evaluable pts: 86% (63/73) with G and 81% (26/32) with G+B. Reductions by pt subgroups and genetic features are presented in Figure. For pts debulked with G, similar debulking efficacy was observed among the subgroups being explored (Figure). Of the 50 pts with a week 38 disease assessment, 17 pts had an initial response of partial remission and await confirmation per IWCLL criteria. Objective response rate was 96% (48/50) overall, with 95% (37/39) for those debulked with G and 100% (11/11) for those debulked with G+B. The rate of CR or CRi was 52% (26/50) overall, with 54% (21/39) achieving CR/CRi for those debulked with G and 45% (5/11) for those debulked with G+B (Figure). More grade ≥3 AEs were observed in pts receiving G+B than those receiving G: debulking, 62% vs 40%; VEN+G, 43% vs 34%; VEN mono, 41% vs 28%. Conclusions: Most pts (85%) achieved low tumor burden after 2 cycles of G±B. Similar debulking efficacy was observed across subgroups in pts debulked with G. In this early efficacy analysis, CR/CRi at week 38 was observed in 52% of pts treated with VEN after the debulking phase. Preliminary efficacy results from this study are consistent with other VEN studies in treatment-naive pts. Current study highlights the efficacy of the debulking strategy prior to treatment with VEN; this may allow more pts to have VEN ramp-up in outpatient setting. Figure Disclosures Flinn: Calithera Biosciences: Research Funding; Forma Therapeutics: Research Funding; F. Hoffmann-La Roche: Research Funding; Celgene: Research Funding; Merck: Research Funding; Curio Science: Consultancy; Pfizer: Research Funding; Seattle Genetics: Consultancy, Research Funding; Novartis: Research Funding; MorphoSys: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Trillium Therapeutics: Research Funding; Triphase Research & Development Corp.: Research Funding; Constellation Pharmaceuticals: Research Funding; Johnson & Johnson: Other; Teva: Research Funding; BeiGene: Consultancy, Research Funding; Curis: Research Funding; Nurix Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Yingli Pharmaceuticals ≠: Consultancy, Research Funding; Rhizen Pharmaceuticals: Research Funding; Roche: Consultancy, Research Funding; Vincera Pharma: Consultancy; Forty Seven: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Portola Pharmaceuticals: Research Funding; Takeda: Consultancy, Research Funding; Incyte: Research Funding; AstraZeneca: Consultancy, Research Funding; Karyopharm Therapeutics: Research Funding; Agios: Research Funding; ArQule: Research Funding; Kite Pharma: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; IGM Biosciences: Research Funding; Infinity Pharmaceuticals: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding; Acerta Pharma: Research Funding; AbbVie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Iksuda Therapeutics: Consultancy; Great Point Partners: Consultancy; Loxo: Research Funding; Genentech, Inc.: Research Funding. Andorsky:AstraZeneca: Research Funding; Celgene: Research Funding; AbbVie: Honoraria. Melear:Janssen: Speakers Bureau; AstraZeneca: Speakers Bureau. Manda:AbbVie: Other: Investigator in AbbVie-sponsored clinical trials. Anz:AbbVie: Other: Investigator in AbbVie-sponsored clinical trials. Kolibaba:Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Verastem: Honoraria; Cell Therapeutics: Research Funding; Celgene: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Atara Biotech: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Acerta: Research Funding; Compass Oncology: Ended employment in the past 24 months; McKesson Life Sciences: Consultancy; Sumitomo Dainippon Pharma Oncology: Consultancy, Other: travel, accommodations, expenses, . Yimer:Sanofi: Speakers Bureau; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; TG Therapeutics: Consultancy; Celgene, a Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; BeiGene: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Texas Oncology: Current Employment; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Epizyme: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months; Karyopharm: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau. Burke:Adaptive: Consultancy; Kura: Consultancy; Morphosys: Consultancy; Celgene: Consultancy; AbbVie: Consultancy; Bayer: Consultancy; Gilead: Consultancy; Seattle Genetics: Speakers Bureau; Roche: Consultancy; Bristol Myers Squibb: Consultancy; Verastem: Consultancy; Astra Zeneca: Consultancy; Epizyme: Consultancy; Adaptive Biotechnologies: Consultancy. Fanning:TG Therapeautics: Consultancy; Abbvie: Consultancy; Prisma Health: Current Employment; Sanofi Aventis: Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau. Courtright:AbbVie: Other: Investigator in AbbVie-sponsored clinical trials.. Islas-Ohlmayer:AbbVie: Other: Investigator in AbbVie-sponsored clinical trials.. Kambhampati:AbbVie: Other: Investigator in AbbVie-sponsored clinical trials.. Jiang:AbbVie: Current Employment, Other: may hold stock or options. Pesko:AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Vizkelety:AbbVie: Current Employment, Other: may hold stock or stock options.. Sharmokh:AbbVie: Current Employment, Current equity holder in publicly-traded company. Sharman:AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; BeiGene: Research Funding; Acerta: Consultancy, Research Funding; Roche: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding.

Background: Bruton tyrosine kinase (BTK) inhibitors (BTKi) have been shown to improve outcomes in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL); however, adverse events (AEs) were the most common reason for ibrutinib and acalabrutinib discontinuation (median time ≤6 mo; Mato et al, Haematologica 2018;103:874; Yazdy et al, Blood 2019; Supplement1: 4311). Off-target effects of ibrutinib have been implicated in BTKi-related AEs. Zanubrutinib, a BTKi approved for treatment of mantle cell lymphoma (MCL) and in development for other hematologic malignancies, was specifically engineered to optimize selectivity and maximize BTK occupancy. In the head-to-head ASPEN trial of zanubrutinib vs ibrutinib in patients with Waldenström macroglobulinemia (WM), zanubrutinib showed a lower rate of AEs leading to death, discontinuation, dose reduction, and dose holds (Dimopoulos et al, EHA 2020; Abstract S225). We conducted a prospective clinical trial of zanubrutinib in patients with relapsed/refractory B-cell malignancies who have become intolerant to prior BTKi (ibrutinib and/or acalabrutinib) therapy. Methods : In this ongoing phase 2, multicenter, US, single-arm, open-label study (NCT04116437; BGB-3111-215), the safety and efficacy of zanubrutinib monotherapy (160 mg twice daily or 320 mg once daily) is being evaluated in patients with B-cell malignancies who meet requirements for treatment and have become intolerant to prior BTKi therapy. An intolerant event was defined as an unacceptable toxicity where, in the opinion of the investigator (INV), treatment should be discontinued despite optimal supportive care as a result of 1 of the following: grade ≥2 nonhematologic toxicities for >7 days (with or without treatment), grade ≥3 nonhematologic toxicity of any duration, grade 3 neutropenia with infection or fever, or grade 4 hematologic toxicity that persists to the point that the INV chose to stop therapy due to toxicity and not disease progression (PD). All enrolled patients must not have documented PD during prior BTKi therapy. Response assessment was evaluated by INV for CLL per modified International Workshop on CLL criteria (Hallek et al, Blood 2008;131:2745; Cheson et al, J Clin Oncol 2012;30:2820), for SLL, MCL, and marginal zone lymphoma per Lugano criteria (Cheson et al, J Clin Oncol 2014;32:3059), and for WM per modified 6th International Workshop on WM criteria (Owen et al, Br J Haemtol 2013;160:171). Disease parameters (imaging and laboratory parameters) performed at study entry were used as the baseline for response assessment. Results : As of 01 June 2020 (data cutoff), 17 patients with CLL/SLL were enrolled, received ≥1 dose of zanubrutinib, and were analyzed for safety. Median age was 70 years (range, 49-91) and median duration of treatment exposure was 3.02 mo (range, 0.56-7.59). The median number of prior regimens was 1 (range, 1-3). All patients had received ibrutinib. At data cut off, no patients had received acalabrutinib. At data cutoff, 16 patients remained on zanubrutinib treatment. One patient withdrew herself from the study following an AE (grade 3 syncope) unrelated, as per INV, to study treatment. Of the 31 BTKi-related AEs associated with intolerance (Table 1), 30 (96.8%) did not recur, and 1 event (3.2%; atrial fibrillation) recurred at a lower grade (grade 3 vs 2) and for a shorter duration (14 vs 3 days) vs the initial ibrutinib-intolerant event. Ten patients (58.8%) reported ≥1 AE. AEs reported in ≥10% of patients on zanubrutinib included dizziness (n=3; 17.6%) and cough (n=2; 11.8%). Grade ≥3 AEs were reported in 2 patients (11.8%): neutropenia and syncope (n=1 each; 5.9%). AEs of interest included hemorrhage and infections (n=3 each, 17.6%) and anemia, neutropenia, and atrial fibrillation (n=1 each; 5.9%). No AEs led to dose modification or treatment discontinuation. No serious AEs or deaths were reported. As of data cutoff, 10 patients were evaluable for efficacy with ≥1 response assessment. All 10 patients achieved at least stable disease, and 60% of these patients achieved a deepening of response since initiating zanubrutinib. Enrollment is ongoing and the presentation will include additional patients. Conclusions : Zanubrutinib demonstrated efficacy and tolerability in CLL/SLL patients who were intolerant to previous BTKi. These data suggest that zanubrutinib may provide a potential option after intolerance to other BTKi. Disclosures Shadman: Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Atara Biotherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellectar: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG therapeutics: Research Funding; Sound Biologics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mustang Bio: Research Funding; MophoSys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Ended employment in the past 24 months; Sunesis: Research Funding; Gilead: Research Funding. Sharman:Celgene: Consultancy, Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; BeiGene: Research Funding; Roche: Consultancy, Research Funding; Acerta: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding. Levy:Amgen: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding; Baylor University Med Center: Current Employment; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Misleh:Medical Oncology Hematology Consultants (MOHC): Current Employment; High Mark Blue Cross: Membership on an entity's Board of Directors or advisory committees. Zafar:Bristol Meyers Squibb: Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); AstraZeneca: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Karyopharm: Honoraria; Sarah Canon Research Institute: Research Funding; Florida Cancer Specialists and Research Institute: Current Employment. Freeman:Summit Medical Group: Current Employment. Burke:Kura: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Adaptive: Consultancy; Morphosys: Consultancy; Bristol Myers Squibb: Consultancy; Roche: Consultancy; AbbVie: Consultancy; Bayer: Consultancy; Astra Zeneca: Consultancy; Verastem: Consultancy; Epizyme: Consultancy; Seattle Genetics: Speakers Bureau; Adaptive Biotechnologies: Consultancy. Cultrera:Amgen: Speakers Bureau; Florida Cancer Specialists + Research Institute: Current Employment; Celgene: Speakers Bureau; AcroTech: Speakers Bureau; Verastem: Speakers Bureau. Yimer:BeiGene: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Sanofi: Speakers Bureau; Epizyme: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months; Texas Oncology: Current Employment; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Karyopharm: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; TG Therapeutics: Consultancy; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Celgene, a Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees. Chen:BeiGene: Current Employment, Current equity holder in publicly-traded company. Zhang:BeiGene: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Cohen:BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Ro:BeiGene: Current Employment, Current equity holder in publicly-traded company; Amgen: Current equity holder in publicly-traded company. Huang:BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Flinn:Iksuda Therapeutics: Consultancy; Loxo: Research Funding; Kite Pharma: Consultancy, Research Funding; Karyopharm Therapeutics: Research Funding; IGM Biosciences: Research Funding; Infinity Pharmaceuticals: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding; Acerta Pharma: Research Funding; Incyte: Research Funding; Janssen: Consultancy, Research Funding; Great Point Partners: Consultancy; Genentech, Inc.: Research Funding; AstraZeneca: Consultancy, Research Funding; ArQule: Research Funding; Agios: Research Funding; Takeda: Consultancy, Research Funding; Forty Seven: Research Funding; Calithera Biosciences: Research Funding; BeiGene: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Trillium Therapeutics: Research Funding; Triphase Research & Development Corp.: Research Funding; Verastem: Consultancy, Research Funding; Yingli Pharmaceuticals ≠: Consultancy, Research Funding; Rhizen Pharmaceuticals: Research Funding; Johnson & Johnson: Other; Roche: Consultancy, Research Funding; Vincera Pharma: Consultancy; Celgene: Research Funding; Merck: Research Funding; Constellation Pharmaceuticals: Research Funding; Curio Science: Consultancy; MorphoSys: Consultancy, Research Funding; Curis: Research Funding; AbbVie: Consultancy, Research Funding; Teva: Research Funding; Pfizer: Research Funding; Nurix Therapeutics: Consultancy; Novartis: Research Funding; Seattle Genetics: Consultancy, Research Funding; Portola Pharmaceuticals: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Forma Therapeutics: Research Funding; F. Hoffmann-La Roche: Research Funding; Gilead Sciences: Consultancy, Research Funding. OffLabel Disclosure: Zanubrutinib has not been approved for R/R CLL/SLL, MZL, and WM in the US

Ambulatory patients receiving systemic cancer therapy are at varying risk for venous thromboembolism. However, the benefit of thromboprophylaxis in these patients is uncertain.In this double-blind, randomized trial involving high-risk ambulatory patients with cancer (Khorana score of ≥2, on a scale from 0 to 6, with higher scores indicating a higher risk of venous thromboembolism), we randomly assigned patients without deep-vein thrombosis at screening to receive rivaroxaban (at a dose of 10 mg) or placebo daily for up to 180 days, with screening every 8 weeks. The primary efficacy end point was a composite of objectively confirmed proximal deep-vein thrombosis in a lower limb, pulmonary embolism, symptomatic deep-vein thrombosis in an upper limb or distal deep-vein thrombosis in a lower limb, and death from venous thromboembolism and was assessed up to day 180. In a prespecified supportive analysis involving the same population, the same end point was assessed during the intervention period (first receipt of trial agent to last dose plus 2 days). The primary safety end point was major bleeding.Of 1080 enrolled patients, 49 (4.5%) had thrombosis at screening and did not undergo randomization. Of the 841 patients who underwent randomization, the primary end point occurred in 25 of 420 patients (6.0%) in the rivaroxaban group and in 37 of 421 (8.8%) in the placebo group (hazard ratio, 0.66; 95% confidence interval [CI], 0.40 to 1.09; P = 0.10) in the period up to day 180. In the prespecified intervention-period analysis, the primary end point occurred in 11 patients (2.6%) in the rivaroxaban group and in 27 (6.4%) in the placebo group (hazard ratio, 0.40; 95% CI, 0.20 to 0.80). Major bleeding occurred in 8 of 405 patients (2.0%) in the rivaroxaban group and in 4 of 404 (1.0%) in the placebo group (hazard ratio, 1.96; 95% CI, 0.59 to 6.49).In high-risk ambulatory patients with cancer, treatment with rivaroxaban did not result in a significantly lower incidence of venous thromboembolism or death due to venous thromboembolism in the 180-day trial period. During the intervention period, rivaroxaban led to a substantially lower incidence of such events, with a low incidence of major bleeding. (Funded by Janssen and others; CASSINI ClinicalTrials.gov number, NCT02555878.).

Summary Background Lenalidomide and dexamethasone has been a standard of care in transplant-ineligible patients with newly diagnosed multiple myeloma. The addition of a third drug to the combination is likely to improve treatment efficacy. KEYNOTE-185 assessed the efficacy and safety of lenalidomide and dexamethasone with and without pembrolizumab in patients with previously untreated multiple myeloma. Here, we present the results of an unplanned interim analysis done to assess the benefit–risk of the combination at the request of the US Food and Drug Administration (FDA). Methods KEYNOTE-185 was a randomised, open-label, phase 3 trial done at 95 medical centres across 15 countries (Australia, Canada, France, Germany, Ireland, Israel, Italy, Japan, New Zealand, Norway, Russia, South Africa, Spain, UK, and USA). Transplantation-ineligible patients aged 18 years and older with newly diagnosed multiple myeloma, Eastern Cooperative Oncology Group performance status of 0 or 1, and who were treatment naive were enrolled, and randomly assigned 1:1 to receive either pembrolizumab plus lenalidomide and dexamethasone or lenalidomide and dexamethasone alone using an interactive voice or integrated web response system. Patients received oral lenalidomide 25 mg on days 1–21 and oral dexamethasone 40 mg on days 1, 8, 15, and 22 of repeated 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The primary endpoint was progression-free survival, which was investigator-assessed because of early trial termination. Efficacy was analysed in all randomly assigned patients and safety was analysed in all patients who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov , number NCT02579863 , and it is closed for accrual. Findings Between Jan 7, 2016, and June 9, 2017, 301 patients were randomly assigned to the pembrolizumab plus lenalidomide and dexamethasone group (n=151) or the lenalidomide and dexamethasone group (n=150). On July 3, 2017, the FDA decided to halt the study because of the imbalance in the proportion of death between groups. At database cutoff (June 2, 2017), with a median follow-up of 6·6 months (IQR 3·4–9·6), 149 patients in the pembrolizumab plus lenalidomide and dexamethasone group and 145 in the lenalidomide and dexamethasone group had received their assigned study drug. Median progression-free survival was not reached in either group; progression-free survival estimates at 6-months were 82·0% (95% CI 73·2–88·1) versus 85·0% (76·8–90·5; hazard ratio [HR] 1·22; 95% CI 0·67–2·22; p=0·75). Serious adverse events were reported in 81 (54%) patients in the pembrolizumab plus lenalidomide and dexamethasone group versus 57 (39%) patients in the lenalidomide and dexamethasone group; the most common serious adverse events were pneumonia (nine [6%]) and pyrexia (seven [5%]) in the pembrolizumab plus lenalidomide and dexamethasone group and pneumonia (eight [6%]) and sepsis (two [1%]) in the lenalidomide and dexamethasone group. Six (4%) treatment-related deaths occurred in the pembrolizumab plus lenalidomide and dexamethasone group (cardiac arrest, cardiac failure, myocarditis, large intestine perforation, pneumonia, and pulmonary embolism) and two (1%) in the lenalidomide and dexamethasone group (upper gastrointestinal haemorrhage and respiratory failure). Interpretation The results from this unplanned, FDA-requested, interim analysis showed that the benefit–risk profile of pembrolizumab plus lenalidomide and dexamethasone is unfavourable for patients with newly diagnosed, previously untreated multiple myeloma. Long-term safety and survival follow-up is ongoing. Funding Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc (Kenilworth, NJ, USA).

Background: Bendamustine+rituximab (BR) is an effective chemoimmunotherapy for newly diagnosed chronic lymphocytic leukemia (CLL) and is the most commonly used chemoimmunotherapy in CLL patients requiring therapy (Seymour et al. Cancer. 2019). In a phase III study, the anti-CD20 antibody obinutuzumab (G) showed improved survival in combination with chlorambucil (clb) compared with rituximab (R)+clb, suggesting that G may be a better anti-CD20 monoclonal antibody to combine with bendamustine (B). Here, we report the final study results for the phase II, single-arm, open-label GIBB study (NCT02320487), in which the combination of bendamustine+obinutuzumab (BG) was evaluated in previously untreated patients with CLL. This is also one of the first studies to characterize the evolution of minimal residual disease (MRD) status over time in previously untreated CLL patients receiving chemoimmunotherapy. Methods: Newly diagnosed patients requiring treatment for CLL had ECOG PS 0-2, and adequate cell counts and organ function. BG treatment was given IV over six 28-day (d) cycles and included obinutuzumab (cycle 1: 100 mg d1, 900 mg d2, and 1000 mg on d8 and d15, and cycles 2-6: 1000 mg d1 of each cycle) plus bendamustine (90 mg/m2 cycle 1: d2 and d3; and cycles 2-6: d1 and d2). The primary end point was complete response (CR), including CR and incomplete CR (CRi), per 2008 iwCLL guidelines after induction treatment. Secondary end points included progression-free survival (PFS) and overall survival (OS). MRD negativity (MRD−) was defined as < 1 cell per 10,000 leukocytes (ie, 10−4) and was measured at baseline, end of treatment (28 d after cycle 6), clinical response assessment, and every 6 months thereafter for ≤ 2 years. Results: Overall, 102 patients were enrolled on this study. Patients had a median age of 61 years (range, 35-90), and 97% had ECOG PS of 0-1. Of 74 patients evaluated for IgVH status, 49 patients (66%) had unmutated IgVH. Overall, 79% of patients completed 6 cycles of BG. 50% of patients achieved a CR/CRi (95% CI, 40%-60%), which contributed to an 89% overall response rate (95% CI, 82%-95%). At a median follow-up of 34.3 mo, median PFS was 35.5 mo (95% CI, 35.0 mo to not reached) and median OS was not reached (Figure 1). Seven patients died during the study (3 from cardiac events not attributed to treatment by investigators and 4 from other non-progressive disease causes). The most common grade 3/4 treatment-emergent adverse events (> 5%) were neutropenia (25%), infusion-related reactions (9%), anemia (8%), thrombocytopenia (8%), pneumonia (6%), and tumor lysis syndrome (6%). The rate of grade 3/4 febrile neutropenia was 5%. Achievement of MRD− in evaluable peripheral blood and bone marrow at the clinical response assessment was shown in 33/74 (45%; 95% CI, 33%-57%) and 30/51 (59%; 95% CI, 44%-72%) patients, respectively. In the 79 patients (77%) who achieved MRD− in peripheral blood throughout the study, the median duration of MRD− response was 28.9 mo (95% CI, 23.0 to not reached). Of these 79 MRD− patients, 28 became MRD+, and the median time from identification of MRD+ status to progressive disease/death was 10.5 mo (95% CI, 6.3-17.9). An exploratory Cox proportional multivariate analysis identified 2 factors that were significantly associated with longer durations of MRD− responses: mutated (vs unmutated) IgVH with a HR = 0.13 (95% CI, 0.03-0.61), and CD38 ≥ 30% (vs < 30%) with a HR = 0.35 (95% CI, 0.14-0.92). When stratified by IgVH status, the PFS distributions for IgVH mutated and unmutated groups were similar (Figure 1). Median OS was not reached in all patients and irrespective of IgVH status. Conclusions: Final results for the GIBB study showed that the BG combination was an effective regimen for previously untreated patients with CLL, with no unexpected safety signals. Complete response and MRD− in peripheral blood were achieved in approximately half of all patients after induction treatment and persisted over time. IgVH mutated status was associated with a longer duration of MRD− and median PFS. In summary, BG is a clinically active CLL regimen with durable MRD− rates over time; overall outcomes are consistent with other firstline studies of anti-CD20 antibody and bendamustine combinations. Disclosures Sharman: Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding. Burke:Celgene: Consultancy; Gilead: Consultancy; Roche/Genentech: Consultancy. Yimer:Amgen: Consultancy; Puma Biotechnology: Equity Ownership; Clovis Oncology: Equity Ownership; Celgene: Honoraria; Seattle Genetics: Honoraria; Janssen: Speakers Bureau; AstraZeneca: Speakers Bureau. Boxer:Rigel: Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Arizona Oncology: Employment; Incyte: Speakers Bureau; Gerson Lerman: Consultancy; Best Doctors: Consultancy; Abbvie: Honoraria, Speakers Bureau. Babu:Fort Wayne Medical Oncology & Hematology: Employment; Bristol Myers Squibb: Consultancy, Research Funding; Fort Wayne Medical Oncology & Hematology: Equity Ownership; Abbvie: Research Funding; Eli Lilly: Honoraria, Research Funding; Pfizer: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Alexion: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding; Incyte: Research Funding; AstraZeneca: Honoraria; Lutheran Hospital, Fort Wayne, Indiana: Membership on an entity's Board of Directors or advisory committees. Li:Roche: Equity Ownership; Genentech: Employment. Mun:Genentech: Employment, Equity Ownership. Danilov:Curis: Consultancy; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; Abbvie: Consultancy; Bristol-Meyers Squibb: Research Funding; MEI: Research Funding; Seattle Genetics: Consultancy; Janssen: Consultancy; Aptose Biosciences: Research Funding; Takeda Oncology: Research Funding; AstraZeneca: Consultancy, Research Funding; Pharmacyclics: Consultancy; Gilead Sciences: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; Bayer Oncology: Consultancy, Research Funding; Celgene: Consultancy. OffLabel Disclosure: Yes, this was an investigational clinical study of the combination therapy of obinutuzumab and bendamustine in previously untreated patients with chronic lymphocytic leukemia.

Background: DARA, a human IgGκ monoclonal antibody targeting CD38, is approved in combination with bortezomib, melphalan, and prednisone (VMP) and bortezomib and dexamethasone (Vd) for newly diagnosed MM (NDMM) and relapsed MM (RMM), respectively. CyBorD is a commonly used immunomodulatory drug-sparing regimen for MM. In the LYRA (NCT02951819) study, DARA plus CyBorD (DARA-CyBorD) demonstrated efficacy and a tolerable safety profile at the end of induction. Here, we present updated findings examining the effect of monthly DARA maintenance on the efficacy and safety of DARA-CyBorD in NDMM and RMM. Methods: LYRA is an ongoing, single-arm, open-label, phase 2 study conducted at US community oncology centers. Patients (pts) were aged ≥18 years with documented MM per IMWG criteria, an ECOG performance score (PS) of 0-2, and ≤1 prior line of therapy. Pts received 4-8 induction cycles of DARA-CyBorD (cyclophosphamide 300 mg/m2 PO on Days 1, 8, 15, and 22; bortezomib 1.5 mg/m2 SC on Days 1, 8, and 15; and dexamethasone 40 mg PO or IV weekly [qw]) every 28 days. DARA was given at 8 mg/kg IV on Days 1 and 2 of C1, 16 mg/kg qw from C1D8 through C2, 16 mg/kg q2w for C3-6, and 16 mg/kg q4w for C7-8. After induction, eligible pts could undergo autologous stem cell transplantation (ASCT). All pts received up to 12 maintenance cycles with DARA 16 mg/kg IV q4w. Results: A total of 101 (87 NDMM, 14 RMM) pts were enrolled; 100 (86 NDMM, 14 RMM) pts received ≥1 treatment dose. Median age was 63 years; most pts were white (81%), male (64%), had ECOG PS 0-1 (94%) and had IgG (57%) MM; 36% of pts had high cytogenetic risk, defined as a del(17p), t(4:14) or t(14;16) abnormality. NDMM and RMM pts received a median of 6 and 8 cycles, respectively, of induction therapy. Thirty-nine NDMM pts and 1 RMM pt underwent ASCT. Fifty percent of pts received plerixafor; median stem cell yield for NDMM pts was 6.2 x 106 (range 2-15 x 106) CD34+ cells/kg. A total of 85 (75 NDMM, 10 RMM) pts received ≥1 dose of maintenance treatment; 63 (56 NDMM, 7 RMM) pts have received all 12 maintenance cycles. In NDMM pts, ORR was 87%, with 64% ≥VGPR and 12% ≥CR, by the end of induction. By the end of maintenance, ORR, ≥VGPR and ≥CR rates were 97%, 82% and 51% in NDMM pts who underwent ASCT and 83%, 70% and 30% in NDMM pts who did not receive ASCT. In RMM pts, ORR, ≥VGPR and ≥CR rates were 79%, 71% and 29% by the end of induction and 86%, 71% and 64% by the end of maintenance. At a median follow up of 24.8 mo in NDMM pts and 26.6 mo in RMM pts, median duration of response was not reached (NR). Median PFS (Figure) was NR in NDMM pts, regardless of transplant status, and was 21.7 mo in RMM pts; median OS was NR in NDMM pts and was 30.1 mo in RMM pts. In NDMM pts the 24-mo PFS rate was 89% in pts who underwent ASCT and 72% in pts who did not receive ASCT. The 24-mo OS rate was 90% for NDMM pts. In RMM pts, the 24-mo PFS and OS rates were 48% and 64%, respectively. All treated pts had ≥1 TEAE. Common TEAEs (≥25%) included fatigue, nausea, cough, diarrhea, upper respiratory tract infection, back pain, vomiting, insomnia, dyspnea, constipation, and headache. Grade 3/4 TEAEs were reported in 62% of pts; the most common (≥10%) was neutropenia (14%). Serious TEAEs occurred in 33% of pts; the most common (>2%) were pneumonia, atrial fibrillation and pulmonary embolism. TEAEs led to permanent treatment discontinuation in 7% of pts, with 2% related to treatment. TEAEs resulted in death in 2 pts (nephrotic syndrome, sudden death); both unrelated to treatment. Infusion reactions (IRs) occurred in 56% of pts including grades 1-2 in 52% of pts, grade 3 in 3% of pts and grade 4 in 1% of pts. Most common (>5%) IRs were chills, cough, dyspnea, nausea, pruritus, flushing and nasal congestion. Conclusion: Maintenance with DARA monotherapy for 12 mo increased the >CR rate in NDMM and RMM pts, consistent with observations in prior studies that longer DARA treatment improves depth of response. Importantly, the increase in ≥CR rate was associated with durable PFS and OS. The 24-mo PFS rates in NDMM and RMM pts compare favorably with results for DARA-VMP and DARA-Vd in NDMM and RRMM, respectively. Safety profile was consistent with previous reports of DARA, with no new safety concerns observed with longer follow-up. These data indicate that DARA-CyBorD is a safe, effective MM treatment and that DARA maintenance increases depth of response and achieves durable remissions. Disclosures Rifkin: Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Melear:Texas Oncology: Employment; DARA: Speakers Bureau. Faber:Cardinal Health: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Bensinger:Amgen, Celgene: Other: Personal Fees, Research Funding, Speakers Bureau; Takeda, Janssen: Speakers Bureau; Sanofi, Seattle Genetics, Merck, Karyopharm: Other: Grant. Burke:Gilead: Consultancy; Celgene: Consultancy; Roche/Genentech: Consultancy. Narang:Celgene: Speakers Bureau. Stevens:Astellas: Consultancy. Gunawardena:Janssen: Employment, Equity Ownership. Lutska:Janssen: Employment. Qi:Janssen: Employment. Ukropec:Janssen: Employment, Equity Ownership. Qi:Janssen: Employment. Lin:Janssen: Employment, Equity Ownership. Yimer:Amgen: Consultancy; Clovis Oncology: Equity Ownership; Puma Biotechnology: Equity Ownership; Celgene: Honoraria; Seattle Genetics: Honoraria; Janssen: Speakers Bureau; AstraZeneca: Speakers Bureau.

BACKGROUND: Venetoclax is an effective oral agent for frontline treatment of patients with chronic lymphocytic leukemia (CLL). Due to the rapid induction of cell death caused by the targeted activity of venetoclax, some patients require inpatient monitoring for tumor lysis syndrome (TLS) at initiation of therapy. In the recent CLL14 study, 64% and 22% of venetoclax-treated patients were medium and high risk for TLS, respectively. This study used disease re-staging every two cycles to explore the efficacy of using of obinutuzumab, with or without bendamustine prior to initiation of venetoclax, to reduce tumor burden and thus eliminate the need for hospitalizations, as well as reduce the risk for TLS at the initiation of venetoclax therapy. METHODS: This is a single arm open-label, phase 3b trial (NCT03406156). Patients had previously untreated CLL/SLL (excluding those with 17p deletion), an Eastern Cooperative Oncology Group (ECOG) performance score of ≤1, and a medium (any lymph node 5 - RESULTS: A majority of patients were 10 cm were debulked to 30%) were infusion-related reactions (71%; all grade 1-2), nausea (39%), headache (35%) and fatigue (32%). Neutropenia (28%) and thrombocytopenia (10%) were the most frequently reported Grade 3+ AEs. AEs of TLS were reported in the debulking phase in 7% (5/69) of patients. A retrospective analysis using Howard criteria for TLS identified three additional patients with laboratory TLS: two occurred during the debulking phase and one during the venetoclax phase, all driven by phosphate and uric acid. Uric acid levels were below the institutional upper limit of normal for the patient with TLS during venetoclax treatment and did not require management. No patients were hospitalized during venetoclax ramp up. CONCLUSIONS: Two cycles of obinutuzumab prior to initiation of venetoclax was an effective debulking strategy for patients with ALC >25 × 109 /L and lymph nodes 5 cm treated with obinutuzumab or >10 cm treated with obinutuzumab plus bendamustine may need >2 cycles to achieve low tumor burden. Debulking via obinutuzumab, with or without bendamustine, may allow more patients to be administered venetoclax in the outpatient setting, eliminating the need for hospitalization during venetoclax initiation. Figure Disclosures Sharman: AstraZeneca: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Andorsky:Genetech: Research Funding; Gilead: Research Funding; Celgene: Research Funding; AstraZeneca: Consultancy; CTI: Research Funding. Melear:Texas Oncology: Employment; DARA: Speakers Bureau. Kolibaba:Atara Bio: Consultancy; AbbVie, Acerta, Celgene, Genentech, Gilead, Janssen, Novartis, Pharmacyclics, Seattle Genetics, TG Therapeutics: Research Funding; Verastem: Honoraria. Yimer:Clovis Oncology: Equity Ownership; Celgene: Honoraria; Seattle Genetics: Honoraria; Janssen: Speakers Bureau; AstraZeneca: Speakers Bureau; Amgen: Consultancy; Puma Biotechnology: Equity Ownership. Burke:Celgene: Consultancy; Roche/Genentech: Consultancy; Gilead: Consultancy. Fanning:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Masud:AbbVie: Employment, Other: Stock/stock options. Zimmerman:AbbVie: Employment, Other: stock or options. Nielsen:AbbVie: Employment, Other: and may hold stock or stock options. Vizkelety:AbbVie: Employment, Other: stock or options. Jiang:AbbVie: Employment, Other: stock or options. Flinn:AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding.

Background PI-based therapy is a standard of care for non-transplant NDMM pts. However, long-term treatment, which is associated with improved outcomes, is often challenging in the RW. This may be due to a number of factors, including the burden of repeated intravenous (IV)/subcutaneous (SC) administration, distance from treatment center, comorbidities, and toxicity (e.g. peripheral neuropathy [PN] with btz). With the aim of increasing PI-based treatment adherence and duration while maintaining quality of life (QoL), the US MM-6 RW, community-based study (NCT03173092) investigates a transition from IV/SC btz-based induction to all-oral ixazomib-based therapy (ixazomib-lenalidomide-dexamethasone, IRd). We report efficacy and safety, plus adherence and electronic pt-reported outcomes (ePRO) compliance data, for the first 55 pts. Methods Non-transplant NDMM pts (transplant-ineligible or transplant delayed >24 mos) with ≥stable disease (SD) after 3 cycles of a btz-based induction are being enrolled at 23 community sites to receive IRd (ixazomib 4 mg, d 1, 8, 15; lenalidomide 25 mg, d 1-21; dexamethasone 40 mg [20 mg in pts aged >75 yrs], d 1, 8, 15, 22) for up to 26 x 28-d cycles or until progression/toxicity. Pts complete ePROs every cycle to assess QoL/treatment satisfaction, and a monthly medication adherence survey via a wearable device/smartphone. The primary endpoint is progression-free survival (PFS); key secondary endpoints include partial (PR), very good partial (VGPR), and complete (CR) response rates, and duration of therapy. Results As of April 1 2019, 55 pts had been enrolled at 16 sites. Median age was 72 (range 49-90) yrs, with 76% classified as elderly (≥65 yrs); 47% were male. Key characteristics of this RW population are summarized in Table 1. Comorbidities/concurrent medical conditions at the start of IRd therapy were extensive and included hypertension (51%), anemia (44%), fatigue (42%), renal and urinary disorders (36%), gastroesophageal reflux disease (31%), cardiac disorders (27%), constipation (27%), nausea (24%), and PN (16%); 91% of pts were receiving concomitant medications. At data cutoff, with 40 (73%) pts remaining on therapy, median duration of PI therapy, including prior btz-based induction, was 6.9 mos (mean 8.4 mos) (Table 2). Median duration of IRd treatment was 4.0 mos (median 5 cycles; mean 5.6 mos, 6.6 cycles), with pts having received up to 17.3 mos (18 cycles) of therapy to date. After 3 cycles of btz-based induction, the ≥VGPR rate was 27%, with 4% ≥CR; overall response rate (ORR) was 62%. With IRd therapy, the ≥VGPR rate was 40%, with 22% ≥CR; ORR was 65% (15% not evaluable). Following transition from btz-based induction to IRd, 21 pts (36%) had deepened responses (18% increase in ≥CR rate), including 3 VGPR to CR, 3 PR to CR, 1 MR to CR, 4 SD to CR, 3 PR to VGPR, 1 SD to VGPR, 5 SD to PR, and 1 SD to MR (Figure). With limited follow-up, and enrollment ongoing, 3 pts had progressed and one had died at data cutoff. The preliminary 6-mo PFS rate (95% CI) was 91% (74-97%) from start of IRd and 96% (84-99%) from start of btz-based induction. Average compliance with completing issued ePRO questionnaires during IRd treatment was 96% (61 pts; data cutoff July 8, 2019). Patients recorded their monthly medication adherence for the previous 4 weeks; 81% of evaluable pts (n=32) in cycle 1, 81% in cycle 2 (n=27), 77% in cycle 3 (n=22), 96% in cycle 4 (n=24), and 94% in cycle 5 (n=18) (n2 pts. AEs led to study drug modification in 47% and discontinuation in 4% of pts; 29% had serious AEs. PN occurred in 25% (4% grade 3) and led to dose modification in 13% of pts. There were no on-study deaths (i.e. occurring Conclusions These preliminary data in mostly elderly, comorbid, NDMM pts treated in the RW, community setting indicate the feasibility, tolerability, and efficacy of transitioning to IRd after 3 cycles of btz-based induction. Toxicities appeared similar to previous ixazomib studies. With 73% of pts remaining on therapy and enrollment continuing, duration of therapy is promising, substantial improvements in response have been seen, and ePRO compliance/ medication adherence is high, indicating the feasibility and value of these evaluations. Disclosures Rifkin: Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Noga:Takeda: Employment. Yimer:Amgen: Consultancy; Puma Biotechnology: Equity Ownership; Clovis Oncology: Equity Ownership; Celgene: Honoraria; Seattle Genetics: Honoraria; Janssen: Speakers Bureau; AstraZeneca: Speakers Bureau. Girnius:Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Birhiray:Puma: Consultancy, Research Funding, Speakers Bureau; Alexion: Consultancy; Kite Pharma: Honoraria; Bayer: Honoraria; Helsin: Honoraria; Incyte: Research Funding, Speakers Bureau; Seattle Genetics: Honoraria; Pfizer: Speakers Bureau; Abbvie: Consultancy, Honoraria; Celgene: Honoraria; AstraZeneca: Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Sanofi Oncology: Speakers Bureau; Lilly: Speakers Bureau; Genomic Health: Speakers Bureau; Amgen: Honoraria, Speakers Bureau; BMS: Speakers Bureau; Tessaro: Speakers Bureau; Exelexis: Speakers Bureau; Clovis Oncology: Speakers Bureau; Jansen Bioncology: Consultancy, Speakers Bureau; Coheris: Honoraria; Takeda: Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau. Yasenchak:Seattle Genetics: Consultancy; BMS: Consultancy. Lyons:Texas Oncology: Equity Ownership; Amgen: Consultancy; McKesson: Other: Leadership. Whidden:Takeda: Employment. Schlossman:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Wang:Millennium Pharmaceuticals, Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Boccia:DSI: Speakers Bureau; AstraZeneca: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau; Genentech: Speakers Bureau; AMAG: Consultancy.

Background: Patients on systemic therapy for cancer are at varying risk for venous thromboembolism (VTE) and its consequences. Thromboprophylaxis is recommended in hospitalized medical and surgical cancer patients, but most VTE occurs in ambulatory cancer patients where risk can be estimated with a validated score. However, the benefit of extended outpatient thromboprophylaxis is uncertain with heparins and has not been tested with direct oral anticoagulants. Methods: We conducted a double-blind, randomized, placebo-controlled, parallel-group, multicenter study in adult ambulatory patients with various cancers initiating a new systemic regimen and at increased risk for VTE (defined as Khorana score ≥ 2). Enrolled subjects were screened for deep-vein thrombosis (DVT) and if none found randomized 1:1 to rivaroxaban 10 mg once daily or placebo up to day 180. Subjects were screened with lower extremity ultrasounds every 8 weeks on study. Primary efficacy endpoint was a composite of objectively confirmed symptomatic or asymptomatic lower-extremity proximal DVT, symptomatic upper- or lower-extremity distal DVT, symptomatic or incidental pulmonary embolism and VTE-related death. ISTH-defined major bleeding was the primary safety endpoint. All endpoints were adjudicated by blinded independent committees. Analyses for efficacy endpoints were conducted for intent-to-treat (ITT) population (all randomized patients) for the up-to-day 180 observation period (primary) and the on-treatment period (supportive). Safety analyses were conducted for on-treatment period only for patients who received at least one dose of study drug. Results: Of 1,080 patients who provided consent, 49 (4.53%) had DVT on baseline screening and another 190 screen-failed due to other reasons. Of 841 randomized patients, 274 (32.6%) had pancreatic cancer; 698 (83%) were white and 428 (50.9%) were male. The primary efficacy endpoint occurred in 25 of 420 patients (5.95%) and 37 of 421 patients (8.79%) (HR, 0.66; 95% CI, 0.40 to 1.09; p=0.101) in the rivaroxaban and placebo groups respectively (number needed to treat, NNT=35) in the up-to-day 180 observation period (Figure 1A). Of all patients with VTE, 38.70% experienced events after discontinuing study drug. In a pre-specified analysis of all randomized patients during the on-treatment period, the primary endpoint occurred in 11 of 420 patients (2.62%) and 27 of 421 (6.41%) in rivaroxaban and placebo groups respectively (HR 0.40, 95% CI 0.20 to 0.80, p=0.007) (NNT=26) (Figure 1B). Major bleeding occurred in 8 of 405 (1.98%) in the rivaroxaban group and in 4 of 404 (0.99%) patients in the placebo group (hazard ratio, 1.96; 95% CI, 0.59 to 6.49; p=0.265) (number needed to harm, NNH=101). Clinically relevant non-major bleeding occurred in 2.72% and 1.98% of rivaroxaban and placebo groups, respectively (HR, 1.34; 95% CI, 0.54 to 3.32; p=0.53) (NNH=135). Adverse events were comparable between groups. For secondary efficacy endpoints, a pre-specified analysis of the composite of primary endpoint with addition of arterial and visceral thromboembolic events in the up-to-day 180 observation period showed significantly fewer events in rivaroxaban versus placebo group (6.90% versus 10.70% respectively; HR, 0.62; 95% CI: 0.39, 0.99; p=0.04). All-cause mortality occurred in 20.0% of patients in rivaroxaban group and 23.8% in placebo group (HR=0.83, 95% CI 0.62, 1.11; p=0.213). A pre-specified composite of the primary endpoint with all-cause mortality occurred in 23.1% of patients in rivaroxaban group and 29.5% in placebo group (HR 0.75; 95% CI 0.57 to 0.97; p=0.03) (Figure 1C). Conclusions: Rivaroxaban significantly reduced VTE and VTE-related death during the on-treatment period but not during the full study period; over one-third of events occurred post discontinuation of study drug. The incidence of major bleeding was low. The Khorana risk score cut-off of ≥2 identified cancer patients at high risk of thrombotic events both at baseline (4.53%) and during study (8.79% with additional 1.66% arterial events in placebo group). These results should inform future recommendations regarding thromboprophylaxis in at-risk ambulatory cancer patients. (Funded by Janssen; ClinicalTrials.gov number, NCT02555878) Figure 1 Figure 1. Disclosures Khorana: Parexel: Other: Personal fees and non-financial support for travel; Sanofi: Consultancy, Other: Personal fees and non-financial support for travel; Pfizer: Consultancy, Other: Personal fees and non-financial support for travel; Janssen: Consultancy, Other: Personal fees, Research Funding; TriSalus: Other: Personal fees; Halozyme: Other: Personal fees and non-financial support for travel; Seattle Genetics: Other: Personal fees and non-financial support for travel; AngioDynamics: Other: Personal fees and non-financial support for travel; LEO Pharma: Other: Personal fees and non-financial support for travel; Medscape/WebMD: Other: Personal fees and non-financial support for travel; Pharmacyclics: Other: Personal fees; PharmaCyte: Other: Personal fees; Bayer: Consultancy, Other: Personal fees and non-financial support for travel. Soff:Janssen: Research Funding; Amgen: Research Funding. Kakkar:Bayer AG: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy; Daiichi Sankyo Europe: Consultancy; Janssen Pharmaceuticals: Consultancy; Pfizer: Consultancy; Sanofi S.A.: Consultancy; Verseon: Consultancy. Vadhan-Raj:AMAG Pharmaceuticals, Inc: Other: received funding from Amag to support clinical trial; Janssen: Consultancy, Research Funding. Riess:Janssen Scientific Affairs: Other: Travel reimbursement; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees. Wun:Eli Lilly, Inc.: Research Funding; Emmaus, Inc.: Membership on an entity's Board of Directors or advisory committees; Glycomimetics, Inc.: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Pfizer, Inc.: Membership on an entity's Board of Directors or advisory committees. Streiff:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Other: outcome adjudication committee; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Research Funding; Roche: Research Funding; Portola: Consultancy, Research Funding. Garcia:Shingoi: Consultancy; Portola: Research Funding; Pfizer: Consultancy; Janssen: Consultancy, Research Funding; Incyte: Research Funding; Daiichi Sankyo: Research Funding; Bristol Meyers Squibb: Consultancy; Boehringer Ingelheim: Consultancy; Retham Technologies LLC: Consultancy; Genzyme Corporation: Consultancy; Alexion: Consultancy. Liebman:Janssen (Johnson & Johnson): Other: steering committee of the CASSINI trial during the conduct of the study. Belani:Janssen: Consultancy. O'Reilly:3DMed, Agios, AlignMed, Amgen, Antengene, Aptus, ASLAN, Astellas, AstraZeneca, Bayer, BeiGene, Bioline, BMS, Boston Scientific, Bridgebio, CARsgen, Celgene, CASI, Cipla, CytomX, Daiichi, Debio, Delcath, Eisai, Exelixis, Genoscience, Gilead, Halozyme: Consultancy; Hengrui, Incyte, Inovio, Ipsen, Jazz, Janssen, Kyowa Kirin, LAM, Lilly, Loxo, Merck, Mina, NewLink Genetics, Novella, Onxeo, PCI Biotech, Pfizer, PharmaCyte, Pharmacyclics, Pieris, QED, RedHill, Sanofi, Servier, Silenseed, Sillajen, Sobi, Targovax: Consultancy; Janssen: Research Funding; Acta Biologica, Agios, Array, AstraZeneca, Bayer, BeiGene, BMS, CASI, Celgene, Exelixis, Genentech, Halozyme, Incyte, Lilly, MabVax, Novartis, OncoQuest, Polaris Puma, QED, and Roche: Research Funding; Tekmira, twoXAR, Vicus, Yakult, and Yiviva: Consultancy. Patel:Janssen Pharmaceuticals: Research Funding. Yimer:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Speakers Bureau; AstraZeneca: Speakers Bureau; Epizyme: Equity Ownership; Clovis Oncology: Equity Ownership; Puma Biotechnology: Equity Ownership. Wildgoose:Janssen Scientific Affairs: Employment; Johnson & Johnson: Equity Ownership. Burton:Janssen Pharmaceuticals: Employment; Johnson & Johnson: Equity Ownership. Vijapurkar:Janssen Pharmaceuticals, Inc.: Employment; Johnson & Johnson: Equity Ownership. Kaul:Janssen Pharmaceuticals, Inc.: Employment; Johnson & Johnson: Equity Ownership. Eikelboom:AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, GlaxoSmithKline, Janssen, sanofi-aventis, and Eli Lilly: Honoraria, Research Funding; Heart and Stroke Foundation: Other: Personnel award. Bauer:Janssen: Consultancy. Kuderer:Celldex: Consultancy; Mylan: Consultancy, Other: Travel, Accommodations, Expenses; Myriad Genetics: Consultancy; Halozyme: Consultancy; Coherus Biosciences: Consultancy, Other: Travel, Accommodations, Expenses; Janssen Scientific Affairs, LLC: Consultancy, Other: Travel, Accommodations, Expenses; Pfizer: Consultancy; Bayer: Consultancy. Lyman:Halozyme; G1 Therapeutics; Coherus Biosciences: Consultancy; Generex Biotechnology: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Research support.

Background: Dara, a human IgGκ monoclonal antibody that targets CD38, is approved in combination with bortezomib, melphalan, and prednisone (VMP) for the treatment of newly diagnosed (ND) MM. CyBorD is another commonly used immunomodulatory drug-sparing regimen for MM. We evaluated the safety and efficacy of dara-CyBorD and administered the first dara infusion as a split dose over 2 days in pts with NDMM or relapsed MM (RMM) after 1 prior line of therapy. Methods: This is an ongoing, multicenter, single-arm, open-label, phase 2 study conducted at US community oncology centers in pts aged ≥18 years with documented MM per IMWG criteria; measurable disease; ECOG performance score (PS) of 0-2; and ≤1 prior line of therapy. Pts received 4-8 cycles (C) of dara-CyBorD (oral cyclophosphamide 300 mg/m2 on Days 1, 8, 15, and 22; subcutaneous bortezomib 1.5 mg/m2 on Days 1, 8, and 15; and oral or IV dexamethasone 40 mg weekly) every 28 days. Dara was administered at 8 mg/kg IV in 500 ml on Days 1 and 2 of C1, 16 mg/kg weekly from C1D8 through C2, 16 mg/kg every 2 weeks (q2w) for C3-6, and 16 mg/kg q4w for C7-8. After induction, pts could undergo autologous stem cell transplantation (ASCT). All pts receive 12 cycles of maintenance dara 16 mg/kg IV q4w. The primary endpoint was the proportion of pts achieving very good partial response or better (VGPR+) after 4 induction cycles using a computer algorithm based upon IMWG response criteria. Results: A total of 101 (87 ND, 14 RMM) pts were enrolled; 100 (86 ND, 14 RMM) pts received at least 1 dose of study treatment. Median age was 63 years (63 ND, 68 RMM); most pts were white (81%), male (64%), had ECOG PS 0-1 (94%), and had IgG (57%) or IgA (17%) MM; 35% of pts had high-risk cytogenetics defined as del(17p), t(4:14), or t(14;16). Eighty-two ND pts completed at least 4 induction cycles, 55 at least 6 cycles, and 26 the maximum of 8 cycles; 28 ND pts underwent ASCT by the data cutoff date. After 4 induction cycles, 44% of ND pts achieved VGPR+ (5% CR) with an overall response rate (ORR) of 79%. The VGPR+ rate (57%), CR rate (14%), and ORR (71%) were similar in RMM pts. At the end of induction (median 6 cycles), the VGPR+ rate, CR rate, and ORR in ND pts were 56%, 9%, and 81%, respectively. With a median follow up of 7.9 months, median PFS and OS were not reached; the 12-month PFS and OS rates were 87% and 99%, respectively, in ND pts. All 100 evaluable pts experienced ≥1 treatment-emergent adverse event (AE). AEs with incidence ≥20% included fatigue, nausea, diarrhea, cough, insomnia, vomiting, constipation, upper respiratory tract infection, dyspnea, headache, and back pain. Grade ≥3 AEs were reported for 56% of pts; the most common (≥10%) was neutropenia. Serious AEs (SAEs) occurred in 21% of pts; the most common (≥2%) were atrial fibrillation, bacteremia, pulmonary embolism, and mental status changes. AEs led to permanent treatment discontinuation in 3% of pts. Infusion reactions (IRs) occurred in 54% of pts, including 49% at C1D1 and 4% at C1D2; 2 Grade 3 IRs (hypertension, anaphylactic reaction) occurred at C1D1; no Grade ≥4 IRs occurred. The most common (≥5%) IRs were chills, cough, dyspnea, nausea, pruritus, and flushing. Median infusion time was 4.5 hours for C1D1, 3.8 hours for C1D2, and 3.5 hours for subsequent doses. Conclusion: Dara-CyBorD was active and well tolerated in pts with ND and RMM, including pts with high-risk cytogenetics. ORR, VGPR+, and CR rates improved with cycles 5-8 of induction, indicating that longer therapy with dara results in deeper response. Preliminary PFS and OS data in ND pts in the first year are comparable to dara-VMP. The safety profile was consistent with that previously reported for dara, with no new safety signals observed. Split first daratumumab dosing was feasible, reduced Day 1 infusion time, and resulted in a similar IR rate as previously described for single-dose administration. These findings indicate that dara-CyBorD, using a split-dose first infusion, can be safely administered in the community setting and may be an effective treatment option for pts with MM. www.clinicaltrials.gov identifier: NCT02951819 Figure 1. Kaplan-Meier estimate of progression-free survival (PFS) among patients with newly diagnosed multiple myeloma. Disclosures Yimer: AstraZeneca: Speakers Bureau; Puma Biotechnology: Equity Ownership; Clovis Oncology: Equity Ownership; Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Equity Ownership; Janssen: Speakers Bureau. Melear:Janssen: Speakers Bureau. Faber:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cardinal Health: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bensinger:celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Speakers Bureau; amgen: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Burke:Gilead: Consultancy; Genentech: Consultancy; Celgene: Consultancy; Abbvie: Consultancy; Bayer: Consultancy; Seattle Genetics: Consultancy, Speakers Bureau; Tempus Labs: Consultancy. Narang:Janssen: Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Stevens:Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Gunawardena:Janssen/ Johnson & Johnson: Employment, Equity Ownership. Lutska:Janssen/ Johnson & Johnson: Employment, Equity Ownership. Qi:Janssen/ Johnson & Johnson: Employment, Equity Ownership. Ukropec:Janssen Scientific Affairs, LLC: Employment. Qi:Janssen Research & Development, LLC: Employment. Lin:Janssen/ Johnson & Johnson: Employment, Equity Ownership. Rifkin:Amgen: Consultancy; McKesson: Equity Ownership; Boehringer Ingelheim: Consultancy; Celgene: Consultancy; EMD Serono: Consultancy; Takeda: Consultancy; Sandoz: Consultancy.

Introduction DLBCL is the most common lymphoid neoplasm in adults (Swerdlow 2016). While durable CRs are achieved in approximately 70% of patients (pts) with frontline RCHOP therapy (Pfreundschuh 2008), pts with high-risk features often experience disease resistance or relapse. In Part 1 of an ongoing study, pts with high-intermediate or high risk DLBCL by international prognostic index (IPI) scores, regardless of CD30 expression by IHC, were treated with 1.2 or 1.8 mg/kg brentuximab vedotin (BV) combined with RCHOP. After 3 of the first 10 pts treated at 1.8 mg/kg BV+RCHOP developed Grade 3 peripheral neuropathy (per Standardized MedDRA Query [SMQ]), all pts enrolled subsequently received treatment with 1.2 mg/kg BV+RCHOP. Following completion of enrollment in Part 1, the protocol was amended to enroll a non-randomized portion of the study (Part 2) evaluating the safety and efficacy of 1.8 mg/kg BV+RCHP (Yasenchak 2015), followed by an open-label, randomized portion comparing BV+RCHP to RCHOP (Part 3). Initial results from Part 2 and updated results from Part 1 are reported here. Methods For Part 2 of the study, pts with CD30-expressing high-intermediate and high-risk DLBCL were treated with up to 6 cycles of 1.8 mg/kg BV+RCHP (NCT01925612). Key inclusion criteria were CD30 expression by IHC performed by a local pathology lab and standard IPI scores of 3-5 or age-adjusted IPI (aaIPI) scores of 2-3 (high-intermediate/high risk). CD30 expression was confirmed by a central pathology lab, although CD30 expression by local pathology lab was required for eligibility. Disease response was evaluated with PET/CT per Cheson 2007. Results At the time of analysis for this ongoing study, 11 pts in Part 2 were treated with BV+RCHP (7 male, 4 female; 22-78 yrs). Of these pts, 9 had high-intermediate risk (IPI 3, aaIPI 2) and 2 had high risk disease (IPI 4-5, aaIPI 3), 6 had Stage IV disease, and 6 had an ECOG score of 2. At the end of treatment, the overall response rate was 91% (9 CR, 1 PR); 1 pt had PD after Cycle 4. The most frequent (>20%) treatment-emergent adverse events (AEs) were alopecia and nausea (73% each); fatigue (64%); constipation and peripheral sensory neuropathy (55% each); neutropenia and throat irritation (36% each); and chills, diarrhea, headache, and stomatitis (27% each). Grade 3 or 4 AEs occurred in 8 pts and 5 pts had serious AEs, which included febrile neutropenia, bacteremia, nausea, pneumocystis jiroveci pneumonia, pulmonary embolism, and vomiting. Peripheral sensory neuropathy occurred in 6 pts and all were Grade 1 or 2 events; no peripheral motor neuropathy AEs were reported. No AEs were fatal or led to discontinuation. One pt discontinued treatment after Cycle 4 due to disease progression. For the first 51 pts in Part 1, the progression-free survival (PFS) at 18 months for pts with CD30 expression (25 pts) or without detectable CD30 expression (24 pts) by IHC was 79% (95% CI: 57%, 91%) versus 58% (95% CI: 36%, 75%), respectively. Overall survival for pts was 92% (95% CI: 71%, 98%) versus 71% (95% CI: 48%, 85%), respectively. Ten pts had pre-existing peripheral neuropathy (per SMQ) at study entry. Treatment-emergent peripheral neuropathy (per SMQ) was observed in 75% of pts (38/51) who received BV+RCHOP; 55% of these pts (21/38) had resolution of all or some peripheral neuropathy events. Conclusions 1.8 mg/kg BV+RCHP is active as frontline treatment in CD30-expressing, high-intermediate/high risk DLBCL. When combined with RCHP, 1.8 mg/kg BV appears to be well-tolerated. The PFS and OS for pts with CD30-expression who received BV+RCHOP appear promising. The study is currently ongoing in pts with CD30-expressing high-intermediate/high risk DLBCL to assess the safety and activity of 1.8 mg/kg BV+RCHP versus standard RCHOP. Disclosures Halwani: Bristol Myers-Squibb: Research Funding; Kyowa Hakko Kirin: Research Funding; Takeda: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Other: Travel Expenses, Research Funding; Seattle Genetics: Consultancy, Research Funding; Immune Design: Research Funding; Miragen: Research Funding; Pharmacyclics: Consultancy; Amgen: Research Funding. Yasenchak:Seattle Genetics: Research Funding. Farber:Seattle Genetics: Research Funding. Burke:Pfizer: Consultancy; Janssen: Consultancy; Incyte: Consultancy; TG Therapeutics: Other: Travel Expenses; Millenium: Consultancy. Fayad:Seattle Genetics: Consultancy, Research Funding. Holkova:Seattle Genetics: Research Funding. Knapp:Insys Therapeutics, Inc.: Consultancy, Other: Travel, Accommodations, Expenses; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding. Kolibaba:Gilead: Consultancy, Research Funding; Celgene: Research Funding; TG Therapeutics: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; janssen: Research Funding; GSK: Research Funding; Genentech: Research Funding; Acerta: Research Funding. Patel-Donnelly:Seattle Genetics: Research Funding. Yimer:Ariad Pharmaceuticals: Consultancy; Biotheranostics: Consultancy; Bluebird Bio: Equity Ownership; Kite Pharma: Equity Ownership; Clovis Oncology: Equity Ownership; Juno Therpeutics: Equity Ownership; Seattle Genetics: Research Funding. Smith:Celgene: Consultancy, Speakers Bureau; Seattle Genetics: Research Funding. Levy:Janssen: Speakers Bureau; Amgen: Speakers Bureau; Takeda Pharmaceuticals International Co.: Speakers Bureau; Seattle Genetics: Research Funding; Actinium Pharmaceuticals, Inc.: Research Funding. Seetharam:Seattle Genetics: Research Funding. Belada:Seattle Genetics: Research Funding. Brooks:Seattle Genetics: Research Funding. Kingsley:Gilead: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Equity Ownership. Wagner-Johnston:Seattle Genetics: Research Funding. Ruffner:Forma Therapeutics: Consultancy; Sydnax: Consultancy; Seattle Genetics: Employment, Equity Ownership; Array Biopharma: Employment; Medivation: Employment. Bartlett:Gilead: Consultancy.

Introduction RCHOP is the standard frontline treatment for patients with DLBCL. However, for patients with high-intermediate or high-risk disease (IPI 3-5), outcomes are suboptimal, with an estimated 3-year PFS of about 55%. In addition to IPI, an additional factor associated with an increased risk include non-GCB cell of origin. Brentuximab vedotin, an ADC targeting CD30, has demonstrated single-agent activity in relapsed/refractory DLBCL patients. Of note, higher ORR and CR, as well as longer duration of PFS, were observed in those patients with CD30 detected on tumor cells by routine IHC. Methods This phase 2 study was designed to evaluate combination therapy using brentuximab vedotin (BV) and standard RCHOP chemotherapy as frontline treatment in patients with high-intermediate/high risk (standard IPI score 3-5 or age-adjusted IPI [aaIPI] score 2-3) DLBCL, regardless of CD30 expression (ClinicalTrials.gov NCT01925612). Patients were randomized to receive either 1.2 mg/kg BV+RCHOP or 1.8 mg/kg BV+RCHOP for up to 6 cycles of treatment. BV was given on Day 1 of every 21-day cycle. Response was assessed per investigator using Cheson 2007. AEs, physical examination findings, and laboratory testing were utilized to characterize safety. Tumor cell CD30 expression was measured by IHC and gene expression analysis; soluble CD30 was measured in plasma. Tumor microenvironment was also evaluated for frequency of immune-infiltrating cells. The primary endpoints for this study were the tolerability of each regimen and the CR rate at the end of treatment (EOT). Key secondary endpoints included progression-free survival (PFS). Additional exploratory endpoints included CD30 expression on tumor specimens (CD30- defined as Results Twenty-nine patients were treated with 1.2 mg/kg BV+RCHOP and 22 patients were treated with 1.8 mg/kg BV+RCHOP. Over half (63%) were high-intermediate risk (IPI 3, aaIPI 2) and 37% were high risk (IPI 4-5, aaIPI 3). Most had Stage IV disease (71%) and 27% had an ECOG score of 2. AEs in ≥50% of patients included peripheral sensory neuropathy (63%), fatigue (61%), nausea (55%), and diarrhea (53%). Grade 3 or higher events occurred in 76% of patients; the most frequent were neutropenia (33%) and febrile neutropenia (31%). The PET-negative CR rate was 69% overall; CD30+ patients had a CR rate of 76% (19/25) compared with 63% (12/19) in CD30- patients by IHC. Although PFS data are still immature (median follow up of 8 months), the estimated PFS rate at 12 months was 82% (95% CI: 58, 93) in CD30+ patients and 56% (95% CI: 32, 75) in CD30- patients. 60% (3/5) of patients with CD30- ABC-DLBCL progressed versus 27% (3/11) of CD30+ ABC-DLBCL patients. Four patients with EBV+ DLBCL were treated and all achieved CR; 3 EBV+ patients remain in remission after a median follow-up of 12 months. Within the microenvironment, a higher percentage of CD3+ T-cells was observed in patients with CR (23%; range, 4-80%) than in those with PR (14%; range, 10-15%) or PD (11%; range, 5-15%). Of the 32 patients who have not yet progressed, 50% had ≥20% CD3+ cells compared to 18% of patients with PD (2/11). Other factors, including soluble CD30 levels and infiltrating CD68+ cells, were not associated with clinical outcomes. Conclusions Interim results demonstrate that adding BV to RCHOP results in a high rate of CR in this population of IPI 3-5 DLBCL. Patients with CD30-expression in the tumor appear to have a higher CR rate and fewer early progression events than patients with CD30- DLBCL. Furthermore, subsets of patients who have a particularly poor prognosis (CD30+ ABC subtype and EBV+ DLBCL) appeared to have a favorable outcome with BV+RCHOP. Evaluation of the tumor microenvironment showed that higher frequencies of infiltrating CD3+ cells were observed in the CR group, suggesting possible immunologic correlates of response. However, CD30 expression appears to have greater prognostic significance in this study despite the relatively small sample size. These results are intriguing and merit further testing in a randomized trial. Disclosures Yasenchak: Seattle Genetics, Inc.: Research Funding. Off Label Use: Brentuximab vedotin is indicated in the US for treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates and for the treatment of patients with systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. The drug is being evaluated in this study for use as frontline treatment in patients with high-intermediate/high risk DLBCL in combination with multiagent chemotherapy. . Halwani:Abbvie: Research Funding; Pharmacyclics: Other: Travel expenses, Research Funding; Takeda/Millenium: Research Funding; BMS: Research Funding; Seattle Genetics, Inc.: Other: Travel expenses, Research Funding; Roche/Genentech: Research Funding; Kyowa Hakko Kirin: Research Funding; Amgen: Research Funding. Advani:Seattle Genetics, Inc.: Research Funding; Genetech: Consultancy. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Budde:Merck: Research Funding; Ikara Inc: Patents & Royalties; Atara Biotherapeutics: Consultancy; Seattle Genetics, Inc.: Research Funding. Burke:Millenium/Takeda: Consultancy; Incyte: Consultancy; TG Therapeutics: Other: Travel expenses; Gilead: Consultancy; Janssen: Consultancy; Seattle Genetics, Inc.: Research Funding. Farber:Seattle Genetics, Inc.: Research Funding. Holkova:Seattle Genetics, Inc.: Research Funding. Kolibaba:GSK: Research Funding; Seattle Genetics, Inc.: Research Funding; Acerta: Research Funding; Celgene: Research Funding; Gilead: Consultancy, Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; TG Therapeutics: Research Funding. Knapp:Celgene: Research Funding; Heron Pharmaceuticals: Other: Travel expenses, Research Funding; Merck: Research Funding; Seattle Genetics, Inc.: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Brystol-Myers Squibb: Research Funding; Genentech: Honoraria, Other: Travel expenses, Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; EMD Serono: Research Funding. Li:Seattle Genetics, Inc.: Employment, Equity Ownership. Manley:Seattle Genetics, Inc.: Employment, Equity Ownership. Patel-Donnelly:Seattle Genetics, Inc.: Research Funding. Seetharam:Seattle Genetics, Inc.: Research Funding. Yimer:Seattle Genetics, Inc.: Research Funding. Bartlett:Gilead: Consultancy, Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Millennium: Research Funding; Colgene: Research Funding; Medimmune: Research Funding; Kite: Research Funding; Insight: Research Funding; Seattle Genetics: Consultancy, Research Funding; MERC: Research Funding; Dynavax: Research Funding; Idera: Research Funding; Portola: Research Funding; Bristol Meyers Squibb: Research Funding; Infinity: Research Funding; LAM Theapeutics: Research Funding.