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356154 Background: Combinations of immune checkpoint inhibitors (CPI) blocking PD-1 and CTLA-4 or BRAF/MEK inhibitors have both shown significant antitumor efficacy and overall survival (OS) benefit in patients (pts) with BRAFV600-mutant metastatic melanoma (MM), leading to broad regulatory approval. Little prospective data exists to guide the choice of one over the other as initial therapy or the preferred treatment sequence in this population. The DREAMseq Trial was designed to compare the efficacy and toxicity of the sequence of nivolumab/ipilimumab (N/I) followed by dabrafenib/trametinib (D/T) to the converse sequence.Methods: Eligible pts with treatment-naive BRAFV600-mutant MM were stratified by ECOG Performance Status (PS) 0 or 1 and LDH level and randomized 1:1 to receive Step 1 with either N/I (Arm A) or D/T (Arm B) and at disease progression (PD) were enrolled in Step 2 receiving the alternate therapy, D/T (Arm C) or N/I (Arm D), respectively. Pts received N (1mg/kg)/I (3 mg/kg) q3 wks x 4 doses followed by N 240 IV q2 wks for up to 72 wks (Arms A and D) or D 150 mg po BID and T 2 mg po qD until PD (Arms B and C). In 2019, investigators were given the option to use alternate induction dosing of N (3mg/kg)/I (1 mg/kg) q3 wks x 4 doses for Arms A and D. Cycles were every 6 wks and imaging was obtained at baseline and q12 wks on each arm. Primary endpoint was 2-year OS. At the 4th Interim Analysis with 59% of pts being 2 yrs from enrollment, the DSMC and NCI CTEP recommended halting accrual and releasing the data.Results: Beginning 7/2015, 265 out of a proposed 300 pts were enrolled (133 Arm A and 132 Arm B). Median age was 61 (25-85) and 63% were male. Demographics for Arm A and B were balanced with 67% PS 0 and 60% with normal LDH. As of 7/16/21, at a median follow-up of 27.7 mos, 27 pts had switched to Arm C and 46 to Arm D. Overall Grade 3+ toxicity was 60% in Arm A and 52% in Arm B. Grade 5 treatment-related AEs included 2 on Arm A and 1 on Arm C. ORR to date is: Arm A 46% (52/113), Arm B 43% (49/114), Arm C 48% (11/23) and Arm D 30% (8/27). 37/42 assessed pts in Arm A and 19/37 in Arm B remain in response. Median DOR: Arm A- Not reached; Arm B-12.7 mos (95% CI: 8.2, -) (p

7531 Background: PI3Kδ inhibitors have been shown to have important roles in blocking mitogenic and survival signaling within the tumor cell and the tumor microenvironment and activate antilymphoma immune responses. Linperlisib is an oral highly selective small molecule inhibitor of PI3Kδ and has been demonstrated to be well-tolerated with a favorable PK profile in patients with lymphomas at the RP2D. This phase Ib study is evaluating the efficacy and safety of Linperlisib in relapsed or refractory peripheral T-cell lymphoma (PTCL), a highly aggressive malignancy with few treatment options for patients. Methods: Eligible PTCL patients who must have received at least 1 prior systemic conventional therapy were administrated Linperlisib 80mg orally once daily (RP2D) in 28 days cycle until disease progression, unacceptable toxicity, or withdrawal from the study. Tumor response was assessed by IWG 2007 criteria with CT performed every 2 cycles. The primary endpoint was the overall response rate (ORR), and the secondary endpoint was toxicity assessed by NCI-CTCAE5.0. Results: As of February 2, 2021, 36 PTCL patients were enrolled in this exploratory trial. Most patients were stage III (38.2%) or IV (50%). Of the 27 evaluable patients to date, the PTCL histologies were PTCL-NOS (n=12), AITL (n=10), ALCL (n=3), NKTCL (n=1) and MEITL (n=1). 19 of the 27 evaluable patients had Investigator confirmed responses for a 70.4% ORR including 25.9% CR (7pt) and 44.4% PR (12pt). In the major subtypes, ORR was 50% (6/12) PTCL-NOS and 80% (8/10) AITL, respectively. A disease control rate of 100% was observed, and most responses occurred by first assessment at C2D28. One subject who had a CR at C2D28 is currently in cycle 9 and continuing on Linperlisib. 36 patients experienced at least 1 AE in the trial, with 95% of AEs ≤ grade 2. Consistent with previously treated lymphoma patients, no unexpected toxicities were observed. The most common TRAEs (≥10%) were neutrophil count decreased (55.6%), leukocyte count decreased (33.3%), hypertriglyceridemia (22.2%), aspartate aminotransferase increased (16.7%), hypercholesterolemia (16.7%), alanine aminotransferase increased (11.1%), creatinine increased (11.1%), rash (11.1%), thrombocyte count decreased (11.1%) and electrocardiogram T wave abnormal (11.1%). No AE grade 4 was observed. 6 patients (16.7%) experienced at least one SAE, in which 4 (11.1%) SAEs were considered to be drug-related, including neutrophil count and leukocyte count decreased (2.8%), gastritis (2.8%), and pneumonia (5.6%). Conclusions: The oral PI3Kd inhibitor Linperlisib had significant activity in patients with relapsed or refractory PTCL. Toxicities with Linperlisib therapy were generally tolerable and manageable. Further efficacy and safety is being evaluated. Clinical trial information: NCT04108325.

1063 Background: Rintodestrant, a potent, oral selective estrogen receptor degrader, competitively binds and degrades the estrogen receptor (ER), thus blocking ER signaling in tumors resistant to other endocrine therapies (ET). Results from parts 1 and 2 dose-escalation/expansion indicate that once-daily (QD) rintodestrant has a favorable safety profile and antitumor activity in patients (pts) with heavily pretreated ER+/HER2– advanced breast cancer (ABC), including those with ESR1 variants (Aftimos et al. SABCS 2020 [PS12-04, PD8-07]). The optimal dose of rintodestrant was 800 mg. Here, we present part 3, combining rintodestrant with the CDK4/6 inhibitor palbociclib. Methods: This open-label study evaluated rintodestrant in pts with ER+/HER2– ABC after progression on ET (NCT03455270). Part 3 assessed rintodestrant 800 mg QD + palbociclib 125 mg QD for 21 days every 28 days. Key eligibility criteria included ≤1 line of chemotherapy and/or ≤1 line of ET in the advanced setting, with ≥6 months of ET in the advanced setting and/or ≥24 months in the adjuvant setting. Prior CDK4/6 inhibitor therapy was not allowed. Primary objectives included safety and efficacy. Secondary objectives included pharmacokinetics and antitumor activity (RECIST v1.1). Exploratory objectives included mutation profiling (cell-free DNA) at baseline and cycle 1 day 15. Results: Enrollment occurred Jul–Oct 2020. As of Dec 9, 2020, 40 pts were treated, with a median age of 58 years (35–76) and ECOG PS of 0 (70%) or 1 (30%); 20% had de novo stage 4 disease, 10% bone-only, and 68% visceral metastases. Median number of visceral sites was 1 (0–3): 30% of pts with lung and 40% with liver involvement. Median number of prior lines in the advanced setting was 1 (0–2), including chemotherapy (48%), fulvestrant (15%), and aromatase inhibitors (50%). Most recent ET was given in the adjuvant and metastatic settings in 28% and 73% of pts, respectively. Rintodestrant-related adverse events (AEs) were reported in 8% of pts—all nonserious and grade 2—and included nausea (3%), vomiting (3%), and neutropenia (3%). The most common (≥10%) treatment-related AEs (rintodestrant and/or palbociclib) were neutropenia (88%), leukopenia (45%), anemia (10%), and thrombocytopenia (10%); grade 3/4 neutropenia was 38%/15%, in line with the safety profile of palbociclib. No deaths or treatment discontinuations due to AEs were reported. At data cutoff (median treatment duration of 3 months [1.5–4.6]), 28 pts (70%) remained on study treatment, 2 (5%) had a confirmed partial response, and 27 (68%) had stable disease. Additional efficacy and pharmacodynamic data will be presented. Conclusions: Rintodestrant, as monotherapy or combined with palbociclib, continues to demonstrate an excellent safety/tolerability profile with promising antitumor activity in pts with ER+/HER2– ABC, including those with ESR1 variants. Clinical trial information: NCT03455270 .

e14048 Background: Glioblastoma (GBM) is the most aggressive and most common primary central nervous system cancer in adults. Blocking the interaction between Programmed Cell Death Protein-1 (PD-1) and its ligand (PD-L1) has shown remarkable success in the treatment of several cancers. However, many challenges remain in improving the efficacy of using monoclonal antibodies (Ab) against the receptor PD-1 in GBM, mainly due to the “non-immunogenic” tumor characteristics of GBM. PD-L1 has been found to be overexpressed on the surface of human GBM tumor cells and tumor-associated macrophages (TAM). Radiotherapy (RT), as one of the standard therapy of GBM, could alter the tumor microenvironment and promote an antitumor immune response. We hypothesize that anti-PD-L1 therapy can enhance the RT effects and improve the outcome of treatment when combined. Methods: Using a preclinical orthotropic syngeneic CT-2A mouse GBM tumor model, we studied the efficacy of combined therapy with anti-PD-L1 and RT. Mice were stratified into four treatment groups: control, RT, anti-PD-L1 Ab, and anti-PD-L1 Ab plus RT. RT(8 Gy) was given one time simultaneously with the first dose of anti-PD-L1, followed by systemic anti-PD-L1 maintenance treatment to the mice. Overall survival and tumor growth were monitored. Immunohistochemistry on resected tumors during treatment was performed to characterize the immune response. Single-cell RNA sequencing (scRNA-seq) was also performed to further study the immunologic parameters in the mouse brain. Results: Our results showed that anti-PD-L1 Ab in combination with RT provided a remarkable antitumor immune response and improved overall survival, with 25.5, 34, and 30 days of median survival in control (no-treatment), RT, and anti-PD-L1 groups, respectively, and achieving long-term survival and complete tumor response in 80% of the mice in the anti-PD-L1+RT treatment group (median survival not reached) in GBM tumor-bearing mice. The combined therapy promoted the recruitment of tumor-infiltrating immune cells, reversed the hostile tumor immune environment with a higher M1/TAM ratio, CD8+ /CD4+ T cell ratio, and CD8+ T cell /Treg cell ratio in the tumor area comparing with those parameters in single modality treatment groups. Furthermore, scRNA-seq data demonstrated that anti-PD-L1 combined with RT resulted in robust higher CD8 effector T cells, while lower CD4 and CD8 exhausted T cells in the tumor region compared to other groups. Increased CD4 central memory T cells and CD8 central memory T cells were seen only in tumors treated with anti-PD-L1+RT providing immunologic explanations on the durable control of GBM achieved only by the combined therapy. Conclusions: The anti-PD-L1 therapy synergizes with RT by reversing the hostile tumor immune environment resulting in improved tumor control and long-term survival in the syngeneic mouse GBM model.

e14019 Background: High-grade glioma (HGG) is the most common malignant brain tumor and lacks effective treatment regimen. Anlotinib is a multikinase inhibitor blocking angiogenesis and tumor cell proliferation simultaneously. This study was performed to evaluate the efficacy and safety of anlotinib alone or in combination with temozolomide (TMZ) in the treatment of recurrent HGG. Methods: This is a single-center, retrospective study. Eligible patients (pts) were diagnosed with pathologically confirmed high grades (WHO III/IV) glioma and had recurrent or progressive disease on or after prior treatment. Other key eligibility criteria included Karnofsky Performance Status (KPS) ≥ 40, aged 16 ̃75 years and having at least one measurable lesion (RANO criteria). Pts were administrated with anlotinib once daily for 14 days every 3 weeks till disease progression, intolerable toxicities or death. The initial dose was 12mg for younger pts ( < 40 years old) with KPS ≥ 60 and 10 mg for others. Combination treatment was allowed if previous TMZ was effective and tolerable. TMZ was administered on dose-dense schedule (150mg/m2, QD, d1-d7 and d15-d21 every 28 days) or metronomic schedule (25-50mg/m2 QD). The primary endpoint was progression-free survival at 6 months (PFS6m) accessed according to RANO criteria. The second endpoints included overall survival (OS), objective response rate (ORR) and disease control rate (DCR). Results: Between August 2019 and June 2020, 23 pts with HGG (15 grade IV; 8 grade III; 12 males, 11 females) were enrolled. The median age and median KPS was 42 years and 60. 16 pts have multifocal or disseminated disease. 18 pts received ≥2 lines previous treatment. At the data cutoff date on September 2020, the median duration of treatment was 9 weeks (range: 3-33). The PFS6m was 39.1% and the median PFS was 4.2 months (95% CI: 2.8, 5.6). The median OS was not reached (95% CI: NE, NE) and the OS at 12 months (OS12m) was 54.8%. 8 pts observed tumor response and 9 pts had stable disease. The ORR and DCR were 34.8% and 73.9% respectively. The results of survival analysis for subgroups were summarized in table below. Grade 1 or 2 treatment-related adverse events (TRAEs) occurred in 65.2% pts. No ≥ grade 3 TRAE was found. All hematological TRAEs occurred in patients received combination regimen. No TRAE-induced treatment termination occurred. The lower incidence of TRAE may partly attributed to that most pts (18/23) received lower initial dose (10mg) of anlotinib and the relatively shorter treatment duration. Conclusions: This study showed treatment with anlotinib alone or in combination with TMZ had promising efficacy and favorable tolerability in patients with recurrent HGG.[Table: see text]

9 Background: Dostarlimab is a humanized anti–PD-1 monoclonal antibody that binds the PD-1 receptor, blocking interaction with ligands PD-L1 and PD-L2. The ongoing phase 1 GARNET study (NCT02715284) is evaluating dostarlimab in pts with advanced solid tumors. Here we present safety and efficacy data from cohort F. Methods: Cohort F of the GARNET trial enrolled pts with dMMR or POLEmut non-endometrial solid tumors; the majority were gastrointestinal (GI) in origin. Pts must have progressed per blinded independent central review (BICR) following prior systemic therapy for advanced disease and had dMMR status by local immunohistochemistry. Pts received 500 mg dostarlimab Q3W for 4 cycles and 1000 mg Q6W until discontinuation. Objective response rate (ORR) and duration of response (DOR) were assessed by BICR per RECIST v1.1. Pts were included in the efficacy analysis if they received ≥1 dose of dostarlimab, had measurable disease at baseline, and 6 mo of follow up. All pts who received ≥1 dose were included in the safety analysis. Results: 144 pts were included in the safety analysis, with 106 dMMR pts in the efficacy analysis (1 POLEmut pt with a confirmed PR was not included in this population). Of the 106 pts, 99 (93.4%) had GI tumors. Confirmed ORR in dMMR pts was 38.7% (95% CI: 29.4, 48.6), with a complete response rate of 7.5%. ORR was consistent across tumor type (Table). At the data cutoff, median duration of follow-up (n = 107; dMMR and POLEmut pts) was 12.4 months and median DOR was not reached. The Kaplan–Meier estimated probability of maintaining response at 12 and 18 months was 91.0% and 80.9% respectively. Treatment-related adverse events (TRAEs) were reported in 68.8% of pts; 8.3% of pts experienced at least 1 grade ≥3 TRAE. The most common was lipase increased in 2 (1.4%) pts. Treatment-related serious AEs (SAEs) were reported in 6 (5.5%) pts, and 2 pts (1.8%) discontinued dostarlimab due to a TRAE. No deaths were attributed to dostarlimab. Conclusions: Dostarlimab demonstrated durable antitumor activity in a cohort of dMMR solid tumor pts, the majority of whom had GI cancers. The safety profile was consistent with other cohorts in GARNET, with immune-related TRAEs infrequent and low grade. Clinical trial information: NCT02715284. [Table: see text]

TPS152 Background: Combining anti-programmed cell death protein 1 (PD-1) antibodies with other immuno-modulatory or targeted therapies may improve outcomes. NCT03697304 is an open-label, Phase II, platform trial assessing BI 754091, an anti-PD-1 antibody, combined with other agents. Here, we describe Module C in which BI 754091 will be combined with BI 836880, a humanized bispecific nanobody, that targets vascular endothelial growth factor (VEGF) and angiopoietin2 (Ang2). VEGF and Ang2 play key roles in tumor angiogenesis and have an immunosuppressive effect in the tumor microenvironment. Combining anti-VEGF/Ang2 with an anti-PD-1 therapy promotes an immunopermissive state supportive of T-cell-mediated tumor cell death. Methods: Patients are being enrolled in 5 cohorts: 1) locally advanced/metastatic gastric or gastroesophageal adenocarcinoma with ≥1 prior treatment (anti-PD-[L]1 naïve); 2) any advanced/metastatic solid tumor (excluding NSCLC and melanoma) with prior anti-PD-(L)1 treatment, which progressed after achieving at least stable disease (SD) for 4 months; 3) advanced/metastatic solid tumors with no benefit from prior anti-PD-(L)1 treatment (SD

1015 Background: As monotherapies, both ERI (a chemotherapeutic microtubule inhibitor) and PEMBRO (a programmed death [PD]-1 blocking immunotherapy) have shown promising antitumor activity in mTNBC. Emerging data suggest that the addition of immunotherapy to traditional chemotherapy holds promise for mTNBC. This open-label, single-arm, phase 1b/2 study evaluated the safety and efficacy of ERI + PEMBRO in mTNBC. Methods: Patients (pts) with mTNBC and ≤2 prior systemic anticancer therapies for metastatic disease were enrolled and stratified by prior number of therapy (Stratum 1, 0; Stratum 2, 1–2). Pts received IV ERI 1.4 mg/m2 on day (d)1 and d8 and IV PEMBRO 200 mg on d1 of a 21-d cycle. The primary objectives were safety and objective response rate (ORR per RECIST 1.1 by independent imaging review). Assessments also included efficacy outcomes by PD ligand-1 (PD-L1) expression status; PD-L1+ was defined as a combined positive score ≥1 using the PD-L1 IHC 22C3 pharmDx. Results: As of data cutoff (July 31, 2019), 167 pts (Stratum 1, n=66; Stratum 2, n=101) were enrolled and treated. No dose-limiting toxicities were observed. The most common treatment-emergent adverse events were fatigue (66%), nausea (57%), peripheral sensory neuropathy (41%), alopecia (40%), and constipation (37%). No deaths were considered treatment related. The overall ORR was 23.4% (95% CI: 17.2–30.5). Efficacy outcomes by PD-L1 status (PD-L1+, n=74; PD-L1-, n=75) and stratum are presented (table). Conclusions: ERI + PEMBRO has activity in pts with mTNBC. There was a trend toward more robust activity for the combination among patients with PD-L1+ tumors compared to PD-L1- tumors in the first-line setting (Stratum 1); whereas, in the later-line setting (Stratum 2) similar survival outcomes were observed among the PD-L1+ and PD-L1- pts. ERI + PEMBRO shows promise for mTNBC with efficacy that appears greater than historical reports of either agent alone. Clinical trial information: NCT02513472 . [Table: see text]

1037 Background: MCLA-128 (zenocutuzumab) is an ADCC-enhanced humanized bispecific antibody targeting HER2 and HER3 and potently blocking HER3-ligand induced receptor dimerization. Upregulation of Her2:Her 3 pathway is a means of resistance to ET in HR+ breast cancer, indicating a potential role for MCLA-128. In preclinical studies, the combination of MCLA-128 with ET in breast cancer xenografts outperformed single drug treatments. The current study explores the use of MCLA-128 to rescue pts with ET-resistant MBC who have progressed on a CDK4/6i. Methods: This phase II, open-label trial planned for up to 40 evaluable women with HR+, HER2 low (IHC 1+/IHC 2+ with negative FISH) MBC, who had progressed on a CDK4/6i and up to 3 lines of ET, who had received ≤ 2 chemotherapy regimens in the metastatic setting. Pts received MCLA-128 (750 mg, 2h IV, flat dose) q3w combined with last ET on which the pt had previously progressed immediately prior to study entry. Disease control rate (DCR; RECIST 1.1, per investigator), best overall response (BOR), overall response rate (ORR), safety, and PK, are evaluated. Data cut off was 14Nov2019. Results: 48 pts were treated, all of whom had progressed on a CDK4/6i. Pts had received a median 2 prior ET lines (range 1-5) and 1 line (range 1-3) of chemotherapy. Pts had a median number of 3 metastatic sites (range 1-6) and 42 (88%) had visceral involvement. Among 42 pts evaluable for efficacy, DCR was 45% (90% CI 32-59) with 2 pts having unconfirmed PR and 19 pts SD as BOR. Common related AEs (all grades; G3-4) were asthenia/fatigue (27%; 2%), diarrhea (25%; 0), nausea (21%; 0). No clinically significant LVEF decline was seen. At the end of cycle 1, mean trough level of MCLA-128 was 15.5 µg/mL, and mean terminal half-live was 102 h (n = 19-21). Data on the primary endpoint, clinical benefit rate at 24 weeks, and biomarkers will be provided. Conclusions: The addition of MCLA-128 to the last line of ET showed clinical activity after ET+CDK4/6i failure and a favorable safety profile. Clinical trial information: NCT03321981 .

e18007 Background: Pembrolizumab is a monoclonal antibody that binds to the PD1 receptor blocking its interaction with PDL1 and PDL2, releasing PD1 pathway-mediated inhibition of the immune response. Pembrolizumab is not currently licensed for use in cervical cancer anywhere in Europe. Pembrolizumab was granted approval by the FDA in 2018 for treatment of patients with recurrent or metastatic cervical cancer with progression on or after chemotherapy whose tumours express PDL1 CPS ≥1, based on the interim results from Keynote 158. This showed an ORR of 14.6% in PDL1+ population. The aim of this project was to assess our experience with pembrolizumab in patients with advanced cervical cancer in an Irish Healthcare Setting. Methods: Patients with advanced cervical cancer treated with pembrolizumab at 3 hospitals in Ireland were included. Patients’ clinical data was collected from hard copy and electronic medical records. All patients had recurrent or metastatic cervical cancer. Patients received Pembrolizumab 200mg IV once every three weeks. To enable us to compare our results with the reported outcomes from Keynote 158 we analysed PFS, OS and ORR. Results: Data collection was between April 2018 and December 2019. Patient baseline characteristics include: median age 41 (27-77yrs), 95% FIGO stage IVB, 5% stage IIIB. Histology: 70% SCC, 20% adenocarcinoma, 5% mixed large/small cell, 5% unknown. PDL1 status: 50% positive, 30% unknown, 20% negative. 90% had received previous systemic treatment in the metastatic setting. The ORR was 25% with a DCR of 30%. All responses were in patients with PDL1+ or of unknown PDL1 status. mOS was 8.9months in total population (11.2months in PDL1+), and mPFS was 6.4months (8.3months in PDL1+). 45% of patients experienced all grade toxicity with 10% experiencing grade 3-4. At the time of our analysis 70% had discontinued treatment and 65% of patients had died. Conclusions: The observed activity in our patient population is superior to the interim results from Keynote 158. There are limited therapeutic options in these symptomatic and often terminally ill patients. Additionally all of these alternate treatments create a significant toxicity profile impacting hugely on the patients’ quality of life. Therefore, in our real life experience, pembrolizumab provides an effective and much improved toxicity profile alternative in this patient population. We believe, based on our findings, pembrolizumab should be considered as a standard option for those with advanced PDL1+ cervical cancer.

e13096 Background: Breast cancers remain the most lethal malignancies amongst women worldwide and the second leading cause of cancer-related mortalities in the US. Subtype heterogeneity and aggressive invasive potential are believed to be the major contributors of these outcomes. Triple-negative breast cancer (TNBC) are notoriously aggressive, difficult-to-treat, and metastatic. Inflammation-driven tumorigenesis has been shown to correlate with cell-free DNA (cfDNA) and other damage-associated molecular patterns (DAMPs) in cancer patient sera. We showed that nucleic-acid scavengers (NAS) can block pro-inflammatory signals elicited by DAMP-activation of innate immune sensors (e.g. toll-like receptors). Treatment with the NAS PAMAM-G3 drastically reduced liver metastatic burden in an immunocompetent murine model of pancreatic cancer. Methods: TNBC cells lines were treated with a cocktail of standard-of-care chemotherapeutic agents and the conditioned media (CM) from these cells served as an in vitro DAMP source. Downstream function of TLR activation was tested via a HEK293-TLR reporter cell line measuring absorbance at 655nm. The in vitro invasive phenotype was tested and quantified using a Transwell-Matrigel invasion assay. Cytokine secretion was measured using a BioLegend cytokine array. Results: TNBC CM greatly increased TNBC cell invasion in vitro and that treatment with the NAS PAMAM-G3 significantly inhibits this effect. Treatment of human monocytes (THP-1) with TNBC CM elicited a strong pro-inflammatory response with elevated levels of IL-8, IL-6, CCL2, and IL-1β. Other biologically immune responders including human PBMCs will be tested to determine the potential impact on the tumor immune microenvironment during tumorigenesis and treatment. Conclusions: To elucidate the mechanism by which this NAS works in these tumor settings, our lab has developed several PAMAM-G3 derivatives, including biotin, IR-, and near-IR fluorophore labeled molecules. These molecules will allow us to capture and characterize DAMPs and do in vivo live imaging experiments to gain insight into NAS PK/PD properties. This insight into NAS capabilities will enhance our understanding of metastatic progression and its interplay with the immune system. Moreover, these principles will aid in the development of novel of anti-metastatic therapies to improve TNBC patient outcomes.

TPS23 Background: COM701 is a novel 1st-in-class monoclonal antibody that binds with high affinity to poliovirus receptor related immunoglobulin domain containing (PVRIG) blocking its interaction with its ligand, PVRL2. In preclinical experiments inhibition of PVRIG alone and in combination with a PD-1 inhibitor leads to activation of T cells in the tumor microenvironment generating an anti-tumor immune response leading to tumor growth inhibition. Novel checkpoint therapies are needed for the treatment of patients with advanced malignancies. We hypothesized that COM701 monotherapy and in combination with nivolumab will be safe and tolerable and demonstrate preliminary antitumor activity in pts with advanced solid malignancies. Methods: This ongoing phase 1 study (NCT03667716) is evaluating the safety and tolerability of escalating doses of COM701 monotherapy IV Q3 or Q4 weekly and in combination with nivolumab 360 mg IV Q3 weekly or 480 mg IV Q4 weekly. Key Inclusion Criteria: Age ≥18 yrs, histologically or cytologically confirmed advanced solid malignancy and has exhausted all available standard therapy, ECOG performance status 0-1, prior ICI permissible. Key Exclusion Criteria: Symptomatic interstitial lung disease or inflammatory pneumonitis, untreated or symptomatic central nervous system metastases. Primary outcome measures are the incidence of adverse events and dose-limiting toxicities (21-day or 28-day DLT window), pharmacokinetics of COM701 and to identify the maximum tolerated dose and/or the recommended dose for expansion. Key secondary outcome measures are to characterize the immunogenicity and preliminary antitumor activity of COM701 as monotherapy and in combination with nivolumab. Study Design: Hybrid accelerated titration and 3+3 study design. Statistical Considerations: Adverse events graded as per CTCAE v4.03, responses as per RECIST v1.1. Analyses of all study objectives are descriptive and hypothesis generating. As of the date of this submission dose level 8 of COM701 monotherapy and dose level 3 of the combination arm are open to enrollment. Updated data will be presented at the conference. Clinical trial information: NCT03667716.

218 Background: Dostarlimab (TSR-042) is an investigational humanized anti-PD-1 monoclonal antibody that binds the PD-1 receptor, blocking the interaction with ligands PD-L1 and PD-L2. The ongoing GARNET trial (NCT02715284) is evaluating dostarlimab in pts with advanced solid tumors. Here we present safety and efficacy data from cohort F. Methods: Cohort F in the GARNET trial enrolled pts with dMMR or microsatellite instability high (MSI-H) non-endometrial solid tumors, the majority of which were GI in origin. Pts must have progressed following prior systemic therapy for advanced disease, assessed by independent central review (ICR). Pts received 500 mg dostarlimab Q3W for 4 cycles and 1000 mg Q6W thereafter. Objective response rate (ORR) and duration of response (DOR) were assessed by ICR per RECIST v1.1. Pts were included in the efficacy analysis if they received ≥1 dose of dostarlimab, had measurable disease at baseline, and ≥24 weeks of follow up. All pts who received ≥1 dose were included in the safety analysis. Results: 109 pts were included in the safety analysis, with 48 dMMR pts in the efficacy analysis. Of the 48 pts, 42 (88%) had GI tumors. Confirmed ORR in dMMR pts was 43.8% (95% CI: 29.5, 58.8), with a complete response rate of 8.3%. ORR was consistent across tumor type (Table). Median DOR was not reached. The probability of maintaining response at 12 months was 85.9%. Treatment-related adverse events (TRAEs) were reported in 55% of pts; 7.3% of pts experienced grade ≥3 TRAEs, including 1 each of adrenal insufficiency, rash, diarrhea, and fatigue. Treatment-related serious AEs (SAEs) were reported in 6 (5.5%) pts, and 2 pts (1.8%) discontinued dostarlimab due to a TRAE. No treatment-related deaths were reported. Conclusions: Dostarlimab demonstrated robust, durable antitumor activity in a cohort of dMMR solid tumor pts, the majority of whom had GI cancers, with an acceptable safety profile. Clinical trial information: NCT02715284. [Table: see text]

1063 Background: Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising targeted therapies for BRCA-mutated cancers by blocking repair of DNA double-strand breaks. However, resistance to PARP inhibitors have been described in some patients lowering overall response rates. The mechanisms underlying PARP inhibitor (PARPi) resistance are an area of active investigation. Methods: PARPi adaptive resistant clones (MDA-MB-468, MDA-MB-231, HCC1806) were generated in triple-negative breast cancer cell lines. Through morphologic observation and functional analysis, we evaluated epithelial-mesenchymal transition (EMT) and changes in immune checkpoint programmed death-ligand 1 (PD-L1). We also downregulated the expression of PD-L1 by shRNA to study the role of PD-L1 in PARPi resistance. We evaluated the immunology sensitivity to cytotoxic T cell upon PD-L1 change using a murine ex-vivo CD8+ T cell killing assay and a comparison of total killing cells percentage per well. Results: We demonstrated that inhibition of PARP enhances EMT, which induces phosphorylation of Akt at S473. This in turn upregulates the expression of PD-L1 by 2-3 fold in triple-negative breast cancer cells. In addition, PARPi–induced EMT occurred independent of PD-L1 upregulation in triple-negative breast cancer cells. Metformin administration (10µM) was found to reverse EMT by blocking the p-Akt S473 axis through activation of AMPK, resulting in downregulation of PD-L1 expression and sensitizing PARPi-resistant cancer cells to T cell killing. Conclusions: In summary, we identified that induction of EMT is a new mechanism for PARP inhibitor resistance. Metformin was able to reverse EMT and therefore a combination of metformin and PARP inhibitors may be a promising therapeutic strategy to increase the efficacy of PARP inhibitors and tumor sensitivity to T cells.

9547 Background: Cemiplimab, a PD-1-axis blocking agent, has recently been approved for unresectable cSCCs. We report results of the CARSKIN study evaluating pembrolizumab in the first-line setting. Methods: Chemotherapy naive patients (pts) with unresectable cSCCs, either locally or regionally advanced or metastatic, and ECOG PS ≤1 were accrued to this multi-institutional phase II trial to assess tumor response rate (RR) and safety of pembrolizumab administered IV (200 mg Q3W) for a period up to 24 months (mo). Baseline PD-L1 expression was centrally assessed on tumor. The primary endpoint was the RR at 15 weeks (wks) per RECIST v1.1 (independent review). A Simon two-stage design was used. Results: From 03/2017 to 01/2018, 39 pts (79% males, median age 79 years) were enrolled. Disease was local (18%), regional (62%) or metastatic (21%); 38% of pts were PS 0. The median number of infusions was 8. The median follow-up was 10.2 mo; 15 pts are still on pembrolizumab. Thirty-four pts were evaluable for tumor response, and 39 for toxicity. The RR at 15 wks was 38.5 % (95% CI: 24–55%) in the ITT population corresponding to 2 CR and 13 PR. The best responses were 3 CR and 12 PR. The DCR was 51% (20/39 including 5 SD) at 15 wks. The median PFS was 8.4 mo and the median OS was not reached. No responder has progressed to date including 2 pts who discontinued pembrolizumab for 6 to 12 mo. Treatment-related AEs (TRAEs) occurred in 67% of pts, including 8% with severe TRAEs (1 gr 3 cholestasis, 1 gr 3 colitis and 1 death due to recurrence of a non-related head and neck cancer) and 10% who discontinued because of a TRAE. Centrally assessed baseline PD-L1 expression was positive in 77% of patients (1% tumor staining threshold), but it failed to predict response at 15 wks with a median PD-L1 expression of 10% in responders and non-responders at 15 wks (P = .55). Conclusions: In this series of 39 elderly pts with unresectable cSCCs, the safety profile was consistent with previous pembrolizumab studies. First-line pembrolizumab provided robust antitumor activity regardless of PD-L1 expression levels. Clinical trial information: NCT02883556.

3086 Background: Immunotherapies blocking the interaction of CTLA-4 or Programmed Death 1 (PD-1) with their ligands are the standard of care for advanced MEL although many pts fail to benefit from immunotherapy. Herein, we seek to identify epigenetic and genetic signatures associated with lack of response in patients treated with immunotherapy . Methods: We performed whole exome sequencing of 580 cancer-related genes and whole-genome DNA methylation arrays targeting > 850k CpG sites covering promoters, enhancers, and transcription factor sites in 28 MEL samples from patients treated with PD-1 +/- CTLA-4 inhibitors. Findings were correlated with collected clinical history. Results: Findings are summarized in the table . Unsupervised clustering and multi-parametric analysis showed a distinct methylation signature independent of age, sex, stage, site of metastasis, or type of treatment (adj. p

6048 Background: The potential for durvalumab, a PD-L1 blocking monoclonal antibody, to treat head and neck squamous cell carcinoma (HNSCC) is being evaluated in multiple clinical trials. We assessed circulating protein biomarkers in HNSCC patients prior to treatment to better understand pathways related to clinical outcomes and potentially relevant for targeting in combination with durvalumab. Methods: Sixty-six selected serum proteins were measured by multiplex immunoassay at baseline in HNSCC patients receiving durvalumab treatment: 106 patients with high PD-L1 (≥25% tumor cells; SP263 assay) in phase II HAWK trial and 52 patients with low/no PD-L1 in phase II CONDOR trial. Results: Multivariate Cox modeling demonstrated that higher baseline concentrations of angiogenic, pro-inflammatory, and myeloid-associated proteins (ANGPT2, CRP, IL6, S100A12) were associated with shorter overall survival (OS), while higher concentration of a bone formation marker and immunostimulatory hormone (BGLAP) correlated with longer OS in 158 durvalumab-treated HNSCC patients ( P< 0.05). These 4 proteins also showed higher baseline levels in patients with progressive disease (PD) compared to stable disease (SD) and partial or complete responses (PR/CR), while BGLAP had lower levels in PD compared to SD or PR/CR (Mann-Whitney P< 0.05). The 5 proteins remained significantly associated with OS in a multivariate model including PD-L1, ECOG, tumor size, and neutrophil count. Bone metastasis status had no impact on the association of BGLAP with OS, which has not been reported before in HNSCC. Interestingly, ANGPT2 level above median showed the highest hazard ratio (HR = 2.2, P

e14299 Background: Antibodies blocking the immune checkpoint pathways represent an important milestone in the treatment of patients with metastatic melanoma. However, individuals presenting cold tumors do usually not show a clinical benefit. New cancer vaccine approaches are needed to cover this gap. Methods: A novel replication attenuated vaccine vector based on lymphocytic choriomeningitis virus expressing full length melanocyte differentiation antigens is evaluated in mouse melanoma models and in PBMCs and T cell cultures from melanoma patients. Results: Here, we demonstrate that intratumoral but not intravenous injection of a recombinant propagating LCMV vector expressing the melanoma-associated antigen TRP2 leads to T cell-dependent eradication of established s.c. melanoma. Importantly, intratumoral vaccination shows an abscopal effect on distant lung metastasis and protects from a rechallenge with melanoma. Confocal microscopy and flow cytometry reveal that intratumoral injection of rLCMV vectors reprograms the tumor microenvironment resulting in sustained T cell fitness. In addition, we demonstrate that rLCMV vectors can efficiently transduce human antigen presenting cells. Moreover, in vitro data confirm that rLCMV efficiently induces T cells against various melanoma-associated antigens in PBMCs from melanoma patients. Conclusions: Preclinical assessment of propagating rLCMV vectors shows unique features of this cancer vaccine resulting in a profound and multistep activation of the cancer immunity cycle resulting in eradication of established melanomas in the B16F10 mouse model after one single immunization. Positive proof of principle experiments using PBMCs from melanoma patients suggest a rapid evaluation in clinical trials.

97 Background: Immunotherapy with the CTLA-4 blocking mAb ipilimumab (IPI) has improved the long-term (>3 y) survival of a subpopulation (15-20%) of patients (pts) with metastatic melanoma. Little is known about the psychosocial outcome and the long-term effects of immune-related adverse events in these survivors. Methods: Pts with advanced melanoma (AJCC stages IIIC or IV) who were in complete remission for at least 2 y after treatment initiation, were eligible for this ongoing study. Data on health related quality of life (HRQOL), psychosocial outcome and neurocognitive function (NCF) were collected using 5 validated questionnaires, a semi-structured psychiatric examination (SSPE), and computer-based NCF testing. Results: Test results from 17 pts (5 F/12 M), median age 57 y (range 33-86) were analyzed. Median time since start of IPI was 5.5 y (range 2-7). Seven pts (41%) had elevated scores on the Cognitive Failure Questionnaire (CFQ). Nine pts (53%) had elevated scores on the Hospitalization Depression Scale (HADS) indicating moderate anxiety (4 pts), severe anxiety (2 pts), and moderate depression (3 pts). The SSPE revealed that all 10 pts who were professionally active at the time of diagnosis, had to change or stop work due to their illness. Nine pts (53%) reported persisting emotional distress: anxiety, existential problems, survivor guilt, post-traumatic stress symptoms or daily worrying about the disease. Three pts were referred for suicidal ideation in relation with their disease. Four pts (24%) developed hypophysitis and suffered from comorbid depression (1 pt), adjustment disorder (2 pt), or post-traumatic stress disorder related to the symptoms of hypopituitarism (1 pt). Five years after the incidence of hypophysitis, all pts had elevated scores on the Fatigue Severity Scale, the HADS; and 3 pts on the CFQ. All cases of skin toxicity (8 pts), hepatitis (2 pts), colitis (2 pts), sarcoidosis (2 pts), and Guillain-Barre syndrome (1 pt) resolved without long-term impact on HRQOL. Conclusions: A majority of melanoma survivors treated with IPI continues to suffer from emotional distress and cognitive problems impacting their HRQOL. Timely detection and providing adaptive care is imperative.

TPS330 Background: VERU-111 is a novel oral small molecule (NCE) that targets α and β-tubulin subunits of microtubules resulting in the inhibition of tubulin polymerization. Agents that target microtubules are among the most effective for the treatment of metastatic cancers. However, these currently available agents target only the β-tubulin subunit and are administered IV. VERU-111 has high oral bioavailability and does not interact with MDR proteins. In nonclinical models, VERU-111 has high activity against many tumor types as well as against prostate cancers that have become resistant to taxanes and novel androgen blocking agents (abiraterone and enzalutamide). In 28-day dog and rat toxicity studies, no neutropenia, myelosuppression, or liver function test changes were observed at oral daily doses in blood concentrations that resulted in antitumor activity in preclinical models. Based on these unique properties, VERU-111 has advanced into a Phase1b/2 clinical trial. Methods: V1011101 is a Phase 1b/2 study, being conducted in at least three sites in the US, evaluating the safety and preliminary efficacy of VERU-111 in men with metastatic castration and androgen blocking agent resistant prostate cancer (mCARPC). The Phase 1b portion of the study consists of 21-day cycles where VERU-111 is taken daily, orally for 7-days followed by a 14-day hiatus (dose cycle). Safety/tolerability of VERU-111 and MTD of VERU-111 will be determined. The Phase 2 will use the selected dose cycle from the Phase 1b and the primary endpoint will be the PSA50 response rate, defined as a decline in PSA to > 50% of baseline level, confirmed with a second measurement at least 3 weeks apart (PCWG3) and determine the pharmacokinetic profile of VERU-111. The secondary endpoints include determining the safety/tolerability of VERU-111 as defined as incidence of CTCAE v5.0 grade ≥3 toxicities; estimating the median PSA progression-free survival (PCWG3); estimating the median progression-free survival (PCWG3); and estimating the objective response rate. It is anticipated that based upon the Phase 1b/2 clinical findings VERU-111 will also be expanded into other cancer types.

TPS473 Background: The Axl pathway coordinately mediates immune evasion and drug resistance in pancreatic cancer. Systemic Axl inhibition can enhance the efficacy of cancer therapy by blocking tumor cell proliferation, survival and drug resistance associated with epithelial-mesenchymal transition (EMT), and targeting innate immune suppression in the tumor microenvironment. Bemcentinib (BGB324) is a first in class, selective oral inhibitor of Axl. Our group has shown that bemcentinib therapy, in combination with gemcitabine, improved survival in multiple preclinical models of pancreatic cancer. Methods: This is a multicenter, randomized, phase 1b/2 clinical trial of nab-paclitaxel/gemcitabine/cisplatin with or without bemcentinib. Patients with metastatic pancreatic cancer, good performance status and preserved liver, kidney and hematologic function are eligible. The treatment schedule is as follows: Bemcentinib 100 or 200 mg daily, nab-paclitaxel 125 mg/m2, gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 intravenously on D1, 8 every 21 days. 3 -12 patients will be recruited in part 1 following a modified 3+3 dose finding scheme. Part 2 of the study is a 1:1 randomized phase 2 design enrolling 62 patients. The primary objective is to determine complete response rate. Secondary end points are overall response rate, PFS and adverse events. A parallel biomarker study will accompany the trial analyzing blood and tissue samples to determine the effect of chemotherapy and bemcentinib on 1) Axl pathway activity in tumor tissue, 2) changes in immune landscape including upregulation of immune cytokines, and immune cell infiltration into the tumor, 3) apoptosis and decreased proliferation of tumor and 4) to identify predictive biomarkers of response. Clinical trial information: NCT03649321.

7027Background: Outcomes are poor for older patients with AML and MDS who progress on HMAs. Blocking the CXCL12/CXCR4 axis may be therapeutic as this is essential for retention of malignant stem ce...

12024Background: VEGF and Ang-2 inhibitors have demonstrated clinical activity in various tumor types. Given the overlap of the VEGF/VEGFR2 and Ang-2/Tie-2 signaling pathways there is a rationale f...

2523Background: BI 836880 (q3w or qw, iv) was evaluated in two first-in-human, Phase I trials in pts with advanced/metastatic solid tumors. We report exploratory PK/PD analysis of these studies to ...

e23546Background: Capsule and pseudocapsule are correlated with higher complete tumor excision rate and lower incidence of recurrence by restricting tumor’s growth and block its invasion. Based on ...

2016Background: The BBB limits the efficacy of many chemotherapies in GBM patients by blocking the passage of drugs to the brain. Two to four minutes of LIPU in combination with injection of micron...

2550Background: PLX51107 is an orally active small molecule inhibitor that exhibits low nanomolar potency in blocking interactions mediated by the four BET family proteins and a unique pharmacokine...

3069 Background: DUR is a human IgG1 monoclonal antibody (mAb) that blocks PD-L1. TRE is a human IgG2 mAb inhibitor of CTLA-4. Blocking these checkpoints can result in antitumor activity in some solid tumors. The targets for DUR and TRE are non-redundant, providing sound rationale for clinical testing of the combination. Methods: This is an ongoing Phase 1, multicenter, open label study (NCT01975831) with a dose escalation (3+3 design) and subsequent expansion phase. Patients (pts) with renal cell carcinoma (RCC), cervical (CC), colorectal (CRC), non-triple-negative breast (NTNBC), ovarian (OC), non-small cell lung, or head and neck cancer are eligible. Primary endpoints are safety/tolerability and identification of maximum tolerated dose (MTD) of the combination. Secondary objectives include tumor response and progression-free/overall survival. Results: As of 16 Dec 2016, 105 pts were treated. DUR 1500 mg every 4 weeks (Q4W) and TRE 75 mg Q4W X 4 was the regimen used for opening the expansion phase. Dose-limiting toxicities were reported in 4 pts: diarrhea, colitis, abnormal liver function tests (abn LFTs), and hyponatremia. The majority of treatment-related AEs (TRAEs) were Grades (Gr) 1 and 2. TRAEs ≥ Gr 3 were reported in 12 pts; the majority were diarrhea/colitis (n = 5) and abn LFTs (n = 4) and responded to established treatment algorithms. There was 1 Gr 5 TRAE: multi organ failure. No new toxicities were identified. The preliminary responses by tumor type with n ≥ 10 pts are shown in the table below. Responses were seen in OC and RCC at the Cohort 2 dose escalation level (DUR 1/TRE 3 mg/kg). There were 4 cases of SD > 24 weeks: CC, n=2; CRC, n=1; OC, n=1. PD-L1 status was not tested. Conclusions: The DUR + TRE combination has a manageable safety profile, with preliminary evidence of clinical activity. These data support continued study of the combination therapy; the study is ongoing. Clinical trial information: NCT01975831. [Table: see text]

7026 Background: Blocking PD-1/PD-L1 pathways enhances anti-leukemia responses in murine AML (Zhang et al, Blood 2009). PD-1 positive CD8 T-cells are increased in bone marrow (BM) of pts with AML (Daver et al, ASH 2016). AZA up-regulates PD-1 in AML (Yang et al., Leukemia 2013). Methods: Pts were eligible if they had AML and failed prior therapy, had adequate performance status (ECOG ≤ 2), and organ function. AZA 75mg/m2Days 1-7 with nivolumab 3mg/kg on Day 1 and 14 was established as the recommended phase II dose. Courses were repeated every 4-5 weeks indefinitely. Responses were evaluated at the end of 3 courses. Results: 53 pts with med age 68 years (range, 44 – 90), secondary AML (43%), poor risk cytogenetics (43%), med prior regimens 2 (range, 1-7) have been enrolled. Common mutations included DNMT3A (n = 11), TP53 (n = 11), TET2 (N = 8), CEBPA (n = 8), ASXL1(n = 8). All 53 pts are evaluable for response: 11 (21%) achieved CR/CRi and 7 (14%) had hematologic improvement (HI) for an overall response rate of 35%. Additionally, 14 (26%) had ≥50% BM blast reduction, 3 (6%) had stable disease > 6 months, and 12 (23%) had progression. The CR/CRi have been durable with 9 of 11 (82%) pts with CR/CRi alive at 1 year, after censoring for SCT. Med survival for the 53 evaluable pts was 5.7 months (range, 0.9 – 16.2) and in the 27 salvage 1 pts was 9.3 months (range, 1.6 – 16.2). These compare favorably to historical survival with AZA-based salvage protocols at MDACC. Grade 3/4 and Grade 2 immune toxicities were observed in 7 (14%) and 6 (12%) pts, respectively. These responded rapidly to steroids and 12 of 13 pts were successfully rechallenged with nivolumab. Multicolor flow-cytometry data were available on pretherapy, end of cycle 1, and end of cycle 2 BM aspirates in 9 CR/CRi and 22 non-responders. Pts who achieved CR/CRi had higher pre-therapy total CD3 (P = 0.02) and higher CD8+ T-cells (P = 0.07) infiltrate in the BM. Responders demonstrated progressive increase in BM CD8+ and CD4+ infiltrate. Both responders and non-responders had increase in CTLA4+ CD8+ cells on therapy. Conclusions: Full dose AZA and nivolumab are tolerable and may produce durable responses in relapsed AML. Up-regulation of CTLA4 may be a mechanism of resistance to PD1 based therapies in AML. Clinical trial information: NCT02397720.

e19518 Background: Multiple myeloma (MM) is still an incurable disease. There are many different treatment options and most patients in the early treatment will have a good effect, but some patients will relapse due to acquired drug resistance. The purpose of this study is to investigate the existence of MM stem cells and its relationship with drug resistence. Methods: A total of 53 patients were recruited who underwent MM between 2010 and 2012. We analysed the expression of stem cell markers (Nanog, Oct4 and Sox2) and their relationship with clinical characteristics and 3– year disease free survival (DFS) or overall survival (OS). Then we chose MM cell line RPMI 8226 for the study, explored the possible mechanism of chemotherapy tolerance. Results: We found that that expression levels of Nanog, Oct4 and Sox2 were 11.3% (6/53), 17.0% (9/53) and 20.8% (11/53), respectively. Only positive expression of Sox2 had relationship with ISS stage ( p= 0.049). Furthermore, positive expression of Sox2 ( p= 0.039) was significantly associated with poor DFS. And after induced treatments, RPMI 8226 cells changed, including cell morphology, cell cycle, apoptosis, stem cell markers and changes in signal transduction pathways. Inhibiting PI3K/AKT/mTOR pathway can improve sensitivity to chemotherapy and radiotherapy. Conclusions: These findings demonstated stem cells markers had significant meanings in MM patients’ prognosis. There may be stem-like cells in MM, which is insensitivity to radiotherapy or chemotherapy, and blocking PI3K/AKT/mTOR pathway can reverse it.

e21049Background: PEMBRO, a PD-1 blocking mAb, is approved for the treatment of patients (pts) with advanced melanoma. Outcome of pts treated outside a clinical trial is not established. Detection ...

e21058Background: the PD-1 blocking mAb PEMBRO is approved for the treatment of patients (pts) with advanced melanoma. The correlation between baseline clinical characteristics and outcome of pts t...

e21023Background: The advent of agents blocking programmed death 1/ligand (PD-1/PD-L1) has transformed the treatment of melanoma and other malignancies. A recent study suggested that suppression of...

Randomization and blocking have the potential to prevent the negative impacts of nonbiologic effects on molecular biomarker discovery. Their use in practice, however, has been scarce. To demonstrate the logistic feasibility and scientific benefits of randomization and blocking, we conducted a microRNA study of endometrial tumors (n = 96) and ovarian tumors (n = 96) using a blocked randomization design to control for nonbiologic effects; we profiled the same set of tumors for a second time using no blocking or randomization. We assessed empirical evidence of differential expression in the two studies. We performed simulations through virtual rehybridizations to further evaluate the effects of blocking and randomization. There was moderate and asymmetric differential expression (351/3,523, 10%) between endometrial and ovarian tumors in the randomized dataset. Nonbiologic effects were observed in the nonrandomized dataset, and 1,934 markers (55%) were called differentially expressed. Among them, 185 were deemed differentially expressed (185/351, 53%) and 1,749 not differentially expressed (1,749/3,172, 55%) in the randomized dataset. In simulations, when randomization was applied to all samples at once or within batches of samples balanced in tumor groups, blocking improved the true-positive rate from 0.95 to 0.97 and the false-positive rate from 0.02 to 0.002; when sample batches were unbalanced, randomization was associated with the true-positive rate (0.92) and the false-positive rate (0.10) regardless of blocking. Normalization improved the detection of true-positive markers but still retained sizeable false-positive markers. Randomization and blocking should be used in practice to more fully reap the benefits of genomics technologies. Clin Cancer Res; 20(13); 3371–8. ©2014 AACR.

3092 Background: Analogs of rapamycin (rapalogs) targeting mammalian target of rapamycin complex 1 (mTORC1) have shown clinical activity in several cancers. Nonetheless, preclinical and clinical data suggest that there may be intrinsic resistance to rapalogs through a feedback loop which activates upstream signaling when mTORC1 is blocked. BI 836845 is a fully human antibody, currently in phase I clinical trials, which potently neutralizes both IGF-1 and IGF-2. We tested whether BI 836845 is able to improve the efficacy of rapamycin by inhibiting upstream signaling in preclinical models. Methods: Cancer cell lines were profiled in vitro and in vivo for sensitivity to BI 836845 and rapamycin, alone or in combination. Mitogenic signaling was examined by measuring levels of phosphorylated AKT (pAKT) using Western blot analysis. IGF bioactivity was determined using a cellular IGF-1R phosphorylation ELISA. Results: The combination of BI 836845 and rapamycin was more effective than either agent alone at inhibiting the proliferation of Ewing’s sarcoma cells cultured in vitro as well as in a nude mouse xenograft model in vivo. Analysis of cell signaling upstream of mTOR demonstrated that treatment with rapamycin alone resulted in elevated pAKT, indicating feedback loop activation. BI 836845 treatment alone or in combination with rapamycin inhibited AKT phosphorylation, demonstrating that the rapamycin-induced increase in pAKT was due to elevated IGF bioactivity. Consistent with this we demonstrated that rapamycin increased IGF bioactivity in mice and that this could be inhibited by BI 836845. We extended these studies to include other cancer cell lines and profiled the correlation between improved efficacy of the combination with BI 836845 inhibition of rapamycin-induced feedback. A correlation has been observed for cancer cells derived from several indications. Conclusions: Rapamycin treatment increases AKT activation via elevated IGF ligand bioactivity. This effect can be inhibited by BI 836845, thus explaining the improved pre-clinical efficacy seen when both agents are combined. These data provide a rationale for the clinical combination of rapalogs and BI 836845.

TPS2622 Background: BMS-936558 is a fully human IgG4 monoclonal antibody targeted against human Programed Death-1 (PD1) receptor on activated T and B lymphocytes. Blocking of PD-1 prevents these activated cells from becoming anergic, thereby maintaining anti-tumor immunologic activity. Methods: The PK of BMS-936558 was characterized with data from a single ascending dose (SAD) and a multiple ascending dose (MAD) study in subjects with advanced solid malignancies. Subjects received a single IV infusion of 0.3 to 10 mg/kg BMS-936558 in the SAD study (MDX-1106-01 Study) and 0.1 to 10 mg/kg BMS-936558 every two weeks in the MAD study (MDX-1106-03/CA209003 Study). The PK of BMS-936558 was characterized by non-compartmental analysis of intensively sampled PK data from a SAD study, as well as by population PK analysis of available intensive and sparse PK data from the SAD and MAD studies, respectively. Results: The PK of BMS-936558 is linear in the studied dose range with dose-proportional increase in Cmax and AUC with low to moderate (20-44%) inter-subject variability. Geometric mean clearance ranged from 0.13 - 0.19 mL/h/kg, whereas mean volume of distribution ranged from 83 -113 mL/kg. The range of mean terminal elimination half-life of BMS-936558 is 17 to 25 days which is consistent with half-life of endogenous IgG4. BMS-936558 PK was adequately described by a linear two-compartment model, and there was no evidence of a contribution of target mediated drug disposition to drug elimination within tested dose range. Body weight and gender are potentially clinically significant covariate for both clearance and volume of distribution (> 20% effect); and baseline CRP, LDH, and albumin are potentially clinically significant covariates for CL. The body weight normalized dosing employed produces trough concentrations that are approximately constant over a wide range of body weights. Conclusions: The pharmacokinetics of BMS-936558 is dose-proportional and body weight normalized dosing is appropriate to ensure consistent exposure over a wide range of body weights.

8583 Background: Ipilimumab (ipi), a monoclonal antibody blocking CTLA-4, demonstrated survival benefit in metastatic melanoma in two randomized controlled trials. With its approval by the FDA, the use of this immunotherapy is increasing. The surgical safety of ipi has not been reported. Methods: From our prospective database, we identified patients undergoing surgery within 30 days of receiving a dose of ipi or on maintenance ipi between October 2007 and August 2011. Surgical toxicity was graded 1-5 by the Clavien classification. In 10 patients matched blood and tumor infiltrating lymphocytes were harvested. Phenotype of T cell subsets were analyzed by flow cytometry. Results: 23 patients were identified who underwent 34 operations a median of 27 weeks after initiation of ipi (1-123 weeks). Indications for surgery were symptomatic, progressive, or isolated persistent disease in 52%, 39% and 9% respectively. Subcutaneous resections were the most frequent, followed by intra-abdominal and nodal procedures (Table). Grade 1 wound complications were seen in 17% of patients. One patient had a Grade 2 wound complication. No Grade 3-5 complications were seen. With a median follow up from starting ipi of 86 weeks, 3 patients have no evidence of disease, 10 are alive with disease and 10 have died of disease. Analysis of the T cell infiltrate and peripheral blood from 10 patients with progressive or symptomatic disease shows an elevated % of CD4+FOXP3+ T regulatory cells and a 2.8 fold reduction in CD8+/ CD4+FOXP3+ T regulatory ratio in the tumor compared to blood (p=0.02). Conclusions: Results from this single-center experience suggest that surgery is safe in patients receiving ipi. Immune modulation caused by CTLA-4 blockade does not appear to impact wound healing, even in the bowel. In carefully selected patients metastectomy may be appropriate for breakthrough metastases. The high percentage of T regulatory cells and low T effector cells in the progressive tumors suggests a mechanism of immune escape. [Table: see text]

TPS149 Background: Co-selective inhibition of VEGFRs and FGFR has the potential benefit of blocking the two most relevant players in tumor angiogenesis and simultaneously targeting proliferation in...

8110 Background: Bortezomib is an effective treatment for both multiple myeloma (MM) and Waldenstrom Macroglobulinemia (WM), whose activity is attributed to blocking elimination of ubiquitin tagged...

e14544 Background: BEV is potent inhibitor of VEGF-mediated tumor angiogenesis. VEGF is also crucial in antineoplastic immunortolerance by blocking the generation of dendritic cells (DC). VEGF inhibition may thus result in an improved anti-cancer immune response which may be further augmented by GM-CSF, a powerful stimulator of DC generation. In a previous study, GM-CSF was able to produce clinical responses in patients (pts) suffering from refractory carcinomas (Kurbacher et al., Oncology 2005). In this trial, we investigated BEV+GM-CSF in pts with advanced solid neoplasms. Methods: 26 pts have been enrolled: epithelial ovarian cancer, n=12; breast cancer, n= 6; primary peritoneal carcinoma, n=3; hormone-refractory prostate cancer, n=2; miscellaneous, n=3. All pts have been considered refractory to or non-treatable by chemotherapy due to their baseline bone marrow and/or organ functions. Fourteen pts had previously received BEV as part of other antineoplastic regimens. BEV was applied at a fixed dose of 6 mg/kg q2w. The starting dose of GM-CSF (sargramostim) was 125 μg/d. In cases not responding and/or not achieving moderate leukocytosis (< 20 G/L), GM-CSF was increased every 4 weeks at 25 μg increments up to a maximum of 250 μg/d. Toxicity was documented according to the NCI-CTC score, responses were recorded according to the RECIST or Rustin criteria. Results: Grade (G) 3–4 hypertension was seen in 3 pts, with 1 pt experiencing cerebral stroke 6 weeks after cessation of BEV+GM-CSF. Other G3–4 toxicities were fatigue in two pts, and fever, pain, myalgia, and central nervous symptoms in either one pt. Other side-effects like injection-site reactions, proteinuria, anemia, thrombocytopenia, and constipation did not exceed G1–2. The objective response rate was 31% (1 CR, 7 PR, 10 SD, and 8 PD); the rate of pts benefiting was 69%. Eight pts failing prior BEV benefited from BEV+GM-CSF. Until today, 13 pts have died. The median time to progression is 92 days and the median overall survival is 302 days. Conclusions: BEV+GM-CSF is an active and generally well tolerated non-cytotoxic regimen in pts with advanced solid tumors. Thus, large-scaled studies of this promising treatment are warranted. No significant financial relationships to disclose.

3048 Background: The antitumor activity of a homolog of ipilimumab, a CTLA-4 blocking agent, was investigated in combination with ixabepilone, the first in a new class of microtubule-stabilizing dr...

13515 Background: CP-675,206 is a fully human, cytotoxic T lymphocyte-associated antigen 4 (CTLA4) blocking mAb with immune stimulating properties under development for the treatment of metastatic melanoma. The pharmacokinetics of CP-675,206 is similar to endogenous IgG, with a long plasma half-life (22 days). We explored the use of TPE in two patients (pts) receiving CP-675,206, postulating that TPE could be used to remove mAb in cases where toxicities are thought to result from persistence of mAb in circulation. Methods: For both pts, five TPEs were performed over 7 days using a Cobe Spectra blood cell separator (TPE daily x 3, 2 days rest, and TPE daily x 2). One plasma volume was processed per TPE and replaced with a 60%/40% albumin/saline solution. Plasma CP-675,206 concentration was measured at baseline and after the 3rd and 5th TPE. Results: Patient 1 was a 62 year-old with metastatic melanoma who received 8 monthly doses of CP-675,206 (10 mg/kg). Six days after the last dose, the pt was found to have elevated ALT and bilirubin and detectable anti- smooth muscle and anti-microsomal antibodies. Based on a suspicion of therapy-related autoimmune hepatitis, the pt underwent TPE. Plasma CP-675,206 concentration declined by 96% following the 5th TPE, and ALT and bilirubin normalized over the 4 weeks following TPE with no other evidence of clinical hepatitis. Patient 2 was a 78 year-old with in-transit melanoma who received 3 monthly doses of CP-675,206 (10 mg/kg) and was responding to therapy. Two weeks after the last dose the pt developed diffuse bilateral arthralgias. The pt was diagnosed with rheumatoid factor-negative rheumatoid arthritis, presumably related to therapy with CP-675,206, and underwent TPE. Pre- and post-TPE plasma CP-675,206 concentrations are pending. The arthralgias persisted, and the pt subsequently received oral methotrexate with slow improvement in symptoms over the next 6 months. Conclusions: TPE is highly effective for reducing the plasma concentration of CP-675,206 and may be useful to avert the progression of drug-related adverse events. Clinical benefit from TPE may vary depending on the interval from dosing and may be limited by slow reversibility of T-cell immunostimulation. [Table: see text]

18185 Fatty acid synthase (FAS) is highly expressed in many human cancers, including lung cancers. Previous work has shown that blocking FAS activity by cerulenin, a natural antibiotic, or C75, a first-generation synthetic small molecule, leads to apoptosis in cells that overexpress this enzyme. However, the use of C75 is limited by the dose-dependent anorexia that appears to be associated with stimulation of fatty acid oxidation. Pharmacokinetics studies show that the activity of C75 peaks within hours of administration and by 24 hours, approximately 80% of activity is lost. Thus, the effectiveness of C75 is limited by this short duration of anti-neoplastic activity and the prolonged anorexic effects.Several second-generation novel FAS-inhibitory compounds have been synthesized that show significant inhibition of FAS, without parallel stimulation of fatty acid oxidation. Among the most promising of the compounds is C93, which inhibits FAS at nearly equal potency as C75, but has significantly less stimulation of fatty acid oxidation. We treated mice with xenografts (orthotopic and subcutaneous) developed from 3 different human lung cancer cell lines (H460, A549, and LX-7) with daily intraperitoneal injections of C93 (5 days/week) at 50 mg/kg for 4 weeks and observed significant (up to 70%) inhibition of tumor growth in all xenograft models tested. Furthermore, no significant weight loss and no organ-specific toxicity were recognized in treated animals. These results suggest that it is possible to pharmacologically uncouple inhibition of FAS from stimulation of fatty acid oxidation, and thus achieve anti-neoplastic activity by inhibition of FAS without significant drug-induced anorexia. Finally, we tested an oral formulation of C93 with the intent of developing a dosing protocol suitable for clinical applications. Similar levels of drug in tumor tissue, and similar inhibition of fatty acid synthase enzyme activity, were seen after oral and intraperitoneal administrations of drug. Furthermore, repeated oral administration of C93 to animals with subcutaneous H460 lung cancer xenografts inhibited tumor growth to a similar level observed after intraperitoneal administration. Thus, fatty acid synthase appears to be a promising target for lung cancer treatment. No significant financial relationships to disclose.

14124 Background: PTK787, an aminophthalazine, is an orally active angiogenesis inhibitor blocking all known vascular endothelial growth factor receptors (VEGFR)- and platelet-derived growth factor receptor (PDGFR)-tyrosine kinases . The majority of metastatic neuroendocrine malignancies express VEGF and PDGF receptors. Since both growth factors have been implicated in tumor-induced angiogenesis, PTK787 offers a novel approach for inhibiting tumor growth. Methods: In a phase II trial, we investigated the safety and antitumor activity of PTK787 in patients who had biopsy-proven metastatic neuroendocrine cancer, such as carcinoid, and had shown evidence of progression on somatosatin analog therapy. Eligible patients had measurable lesions other than bone, a Karnofsky performance status >60 and normal hematologic, renal and hepatic functions. Patients on octreotide therapy were required to be on a stable dose not exceeding 30 mg monthly of the LAR formulation. Initial dosing of PTK787 was 1,250 mg daily. Results: Six patients (4 males) were enrolled between 5/20/05 to 8/09/05. Median age was 61 years (range, 48 to 65). There was 1 withdrawal of consent. The remaining 5 patients continue on treatment as of January 2006. One patient required a 10 day discontinuation for rising SGOT/SGPT and alkaline phosphatase. Resumption of PTK787 at 1,000 mg daily was well tolerated in this patient. Radiographically and scintigraphically, all 5 patients have demonstrated stable disease by CT and OctreoScan, respectively. Recruitment to this trial continues. Conclusions: PTK787 is generally well tolerated in patients with metastatic neuroendocrine cancer and may be effective in controlling somatostatin analog resistant disease though partial radiographic responses have not been observed. No significant financial relationships to disclose.

3690 Background: Epidermal growth factor receptor (EGFR) is overexpressed in many types of cancers, especially in colorectal cancer (CRC). Blocking EGFR activation represents an innovative strategy...