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Purpose New immuno-oncology therapies targeting programmed cell death receptor 1 (PD-1) have improved patient outcomes in a broad range of cancers. The objective of this analysis was to evaluate the PK, pharmacodynamics (PDy), and safety of dostarlimab monotherapy in adult patients with previously-treated advanced solid tumors who participated in parts 1 and 2A of the phase 1 GARNET study. Methods Part 1 featured a 3 + 3 weight-based dose–escalation study, in which 21 patients received dostarlimab 1, 3, or 10 mg/kg intravenously every 2 weeks. The 2 fixed-dose nonweight-based dosing regimens of dostarlimab 500 mg every 3 weeks (Q3W) and 1000 mg every 6 weeks (Q6W) were evaluated using a modified 6 + 6 design in part 2A (n = 13). In parts 1 and 2A, treatment with dostarlimab could continue for up to 2 years or until progression, unacceptable toxicity, patient withdrawal, investigator’s decision, or death. Results The dostarlimab PK profile was dose proportional, and maximal achievable receptor occupancy (RO) was observed at all dose levels in the weight-based and fixed-dose cohorts. Trough dostarlimab concentration after administration of dostarlimab 500 mg Q3W was similar to that after dostarlimab 1000 mg Q6W, the values of which (≈40 µg/mL) projected well above the lowest dostarlimab concentration required for full peripheral RO. No dose-limiting toxicities were observed. Conclusions Dostarlimab demonstrated consistent and predictable PK and associated PDy. The observed safety profile was acceptable and characteristic of the anti-PD-1 drug class. Trial registration: ClinicalTrials.gov, NCT02715284. Registration date: March 9, 2016.

Introduction/Background* Dostarlimab is a humanized programmed death-1 (PD-1) receptor monoclonal antibody that blocks interaction with the PD-1 ligands. GARNET (NCT02715284) is a phase 1 study assessing antitumor activity and safety of dostarlimab monotherapy in patients with solid tumors. Dostarlimab has shown antitumor activity in patients with mismatch repair deficient (dMMR) and mismatch repair proficient (MMRp) advanced and recurrent endometrial cancer (EC). Here we report on the time of onset of treatment-related adverse events (TRAEs) and immune-related (ir) TRAEs over the course of dostarlimab treatment in patients with dMMR (cohort A1) and MMRp (cohort A2) EC in the GARNET trial. Methodology Patients with advanced or recurrent dMMR or MMRp EC that progressed on or after a platinum regimen received 500 mg of dostarlimab every 3 weeks for 4 cycles, then 1000 mg every 6 weeks (Q6W) until disease progression or discontinuation. Result(s)* A total of 126 patients with dMMR EC and 145 patients with MMRp EC were included in the safety population. Few TRAEs were seen in ≥10% of patients: fatigue (17.3%), diarrhea (14.4%), nausea (13.7%), and asthenia (11.1%). The majority of cases occurred during cycles 1–3, with a peak occurrence at cycle 1 for all 4 TRAEs. Hypothyroidism was the only irTRAE seen in ≥5% of patients, and 94% of cases occurred between cycles 2 and 8, with a peak occurrence seen at cycle 4. irTRAEs that were seen in ≥1% of patients included diarrhea (4.1%), amylase increased (2.2%), aspartate aminotransferase increased (2.2%), alanine aminotransferase increased (1.8%), colitis (1.5%), hyperglycemia (1.5%), lipase increased (1.5%), adrenal insufficiency (1.1%), and hyperthyroidism (1.1%). Conclusion* When analyzed over the dMMR and MMRp EC safety population of the GARNET trial, dostarlimab has an acceptable safety profile with manageable adverse events. irTRAEs and TRAEs were seen in a low percentage of patients and were seen more frequently earlier in the time course of dostarlimab treatment. No increase in the rate of TRAEs or irTRAEs was seen when changing to the 1000-mg Q6W dose. C, cycle; dMMR, mismatch mutation repair deficient; ir, immune-related; MMRp, mismatch mutation repair proficient; TRAE, treatment-related adverse event; W, weeks

Introduction/Background* Dostarlimab is a humanised programmed death (PD-1) receptor monoclonal antibody approved for patients with mismatch mutation repair-deficient/microsatellite instability-high (dMMR/MSI-H) recurrent or advanced endometrial cancer (EC) that progressed on or after a platinum-based chemotherapy regimen. GARNET is a phase 1 study assessing the antitumour activity and safety of dostarlimab monotherapy in patients with advanced solid tumours. Methodology GARNET is a multicentre, open-label, single-arm study. Here we report on 2 independent expansion cohorts of patients with recurrent or advanced EC that progressed on or after a platinum-based chemotherapy regimen. Patients were assigned to cohort A1 (dMMR/MSI-H EC) or cohort A2 (mismatch mutation repair-proficient/microsatellite-stable [MMRp/MSS] EC) based on immunohistochemistry testing. Patients received 500 mg of dostarlimab intravenously once every 3 weeks for 4 cycles, then 1000 mg once every 6 weeks until disease progression, discontinuation or withdrawal. The primary endpoints are objective response rate (ORR) and duration of response by blinded independent central review using RECIST version 1.1. Result(s)* In total, 129 dMMR/MSI-H and 161 MMRp/MSS patients were enrolled and dosed. Of these, 108 dMMR/MSI-H and 156 MMRp/MSS patients who had measurable disease at baseline and ≥6 months of follow-up were included for efficacy analyses. ORR and disease control rate (DCR) for dMMR/MSI-H EC was 43.5% and 55.6%, respectively; ORR and DCR for MMRp/MSS EC was 14.1% and 34.6%, respectively (table 1). Overall, 16 patients (5.5%) discontinued treatment due to a treatment-related adverse event (5 dMMR/MSI-H, 11 MMRp/MSS). Table 2 shows safety by cohort and overall. No deaths were attributed to dostarlimab. Conclusion* Dostarlimab demonstrated durable antitumour activity in both dMMR/MSI-H and MMRp/MSS advanced/recurrent EC. dMMR/MSI-H status was associated with a higher response rate. DCR achieved in MMRp/MSS EC was noteworthy, considering MMRp/MSS tumours are historically associated with a poor prognosis. The dostarlimab safety profile was manageable. Clinical trial registration NCT02715284

Monoclonal antibodies that block the interaction between programmed cell death 1 (PD-1) and its ligand (PD-L1) have revolutionized cancer immunotherapy. However, immunogenic responses to these new therapies—such as the development of antidrug antibodies (ADAs) and neutralizing antibodies (NAbs)—may represent a significant challenge to both efficacy and safety in some patients. Dostarlimab (TSR-042) is an approved, humanized, anti-PD-1 monoclonal antibody that has shown efficacy in multiple solid tumor types. Here, we report the results of an immunogenicity analysis of dostarlimab monotherapy in patients enrolled in the GARNET trial, a multicenter, open-label, single-arm phase 1 study. Overall, 477 of 478 patients (99.8%) were included in the analysis of dostarlimab antibody prevalence, and 349 out of 478 enrolled patients (73.0%) were evaluable for treatment-emergent antibodies to dostarlimab. The incidence of treatment-emergent ADAs was 2.5% at the recommended therapeutic dose (500 mg Q3W for the first 4 doses, 1000 mg Q6W until discontinuation), which is comparable to other anti-PD-(L)1 drugs. NAbs were detected in only 1.3% of patients. In the small percentage of patients who developed ADAs, there was no evidence of altered efficacy or safety of dostarlimab at the recommended dosing regimen. These findings demonstrated that treatment with dostarlimab was associated with a low risk of eliciting clinically meaningful ADAs over the course of this study, and dostarlimab is already approved by health authorities. Supplementary Information The online version contains supplementary material available at 10.1208/s12248-021-00624-7.

Belantamab mafodotin (belamaf) is a BCMA-targeted antibody–drug conjugate recently approved as monotherapy for adults with relapsed/refractory multiple myeloma who have received ≥4 prior therapies. Belamaf binds to BCMA and eliminates myeloma cells by multimodal mechanisms of action. The cytotoxic and potential immunomodulatory properties of belamaf have led to novel combination studies with other anticancer therapies. Here, we describe the rationale and design of DREAMM-5, an ongoing Phase I/II platform study evaluating the safety and efficacy of belamaf combined with novel agents, including GSK3174998 (OX40 agonist), feladilimab (an ICOS; GSK3359609), nirogacestat (a gamma-secretase inhibitor; PF-03084014) and dostarlimab (a PD-1 blocker) versus belamaf monotherapy for patients with relapsed/refractory multiple myeloma.Clinical trial registration: NCT04126200 (ClinicalTrials.gov).

Introduction/Background Dostarlimab is a humanised programmed death (PD)-1 receptor monoclonal antibody that blocks interaction with the PD-1 ligands, PD-L1 and –L2. GARNET is a phase 1 study assessing antitumour activity and safety of dostarlimab monotherapy in patients with advanced solid tumours. Methodology This multicentre, open-label, single-arm study is being conducted in 2 parts, dose escalation and expansion. Here we report on 2 independent expansion cohorts of patients with recurrent or advanced endometrial cancer (EC) that progressed on or after a platinum-based chemotherapy regimen. Assignment to cohort A1 (mismatch mutation repair deficient [dMMR] EC) or cohort A2 (mismatch mutation repair proficient [MMRp] EC) was determined by immunohistochemistry (IHC) testing. Patients received 500 mg dostarlimab intravenously once every 3 weeks for 4 cycles, then 1000 mg once every 6 weeks until disease progression, discontinuation or withdrawal. The primary endpoints are objective response rate (ORR) and duration of response (DOR) by blinded independent central review using RECIST version 1.1. Results In total, 126 dMMR and 145 MMRp pts identified by IHC were enrolled and dosed. Of these, 103 dMMR and 142 MMRp pts had measurable disease as baseline and sufficient follow-up time (6 months) for efficacy analyses, respectively. Patients that progressed prior to 6 months were included in the evaluable population. ORR for dMMR EC was 44.7%; ORR for MMRp EC was 13.4% (table 1). Median DOR and OS were not reached in either cohort. Overall, 15 pts (5.5%) discontinued treatment due a TRAE (5 dMMR, 10 MMRp). Safety by cohort and overall are shown in table 2. There were no deaths attributed to dostarlimab. Conclusion Dostarlimab demonstrated durable antitumour activity in both dMMR and MMRp advanced/recurrent EC. dMMR status by IHC was associated with a higher response rate. Dostarlimab demonstrated a notable disease control rate (35.2%; 2.1% complete response, 11.3% partial response, 21.8% stable disease) in patients with MMRp EC, which comprised a higher percentage of patients with Type II EC and is historically associated with a worse prognosis. No new safety signals were detected. These cohorts are the largest prospective evaluation of a PD-(L)1 therapy in EC to date. Disclosures Clinical trial registration: NCT02715284 This study was sponsored by GlaxoSmithKline, Waltham, MA, USA. Dr. Oaknin reports consulting and honoraria from AstraZeneca, Tesaro, Clovis, PharmaMar, and Roche. Dr. Gilbert reports honoraria from Meck, AstraZeneca, and Pfizer. Dr. Tinker reports grants and personal fees from AstraZeneca. Dr. Sabatier reports grants from EISAI and AstraZeneca; personal fees from Roche, Pfizer, Tesaro, Novartis and AstraZeneca; and non-financial support from Roche, Pfizer, AstraZeneca, and Amgen. Dr. O’Malley reports personal fees from Immunogen, Eisai, Agenus, GSK : Consultant/Advisory Board for Clovis, Ambry, Abbvie, Janssen/JJ Steering committee for Genentech/Roche and Merck; Institutional funding from Ajinomoto Inc, Ludwig Cancer Research, Stemcentrx, Inc, CERULEAN PHARMA, GOG Foundation, BMS, Serono Inc, TRACON Pharmaceuticals, Yale University, New Mexico Cancer Care Alliance, INC Research, Inc., Inventiv Health Clinical, Iovance Biotherapeutics, Inc, and PRA International. Dr. Ghamande reports consulting fees from Seattle Genetics; speakers’ bureau fees from GSK; and institutional grants from GSK, Merck, Roche, Genentech, Takeda, Seattle Genetics, Advaxis, BMS, Clovis, Abbvie, and Tesaro. Dr. Pothuri reports grants, personal fees and non-financial support from GSK; Advisory Board fees from AstraZeneca and Clovis Oncology. Dr. Boni has nothing to disclose. Drs. Guo and Im are employees of GlaxoSmithKline.

Introduction/Background PROs enable direct measurement of the experiences of pts with cancer related to an intervention. Regulators increasingly use PROs to inform the risks and benefits of new drug candidates, focusing on 3 core concepts: physical functioning (PF), disease-related symptoms (DRS), and symptomatic adverse events (AEs). Dostarlimab is an investigational anti–programmed death-1 monoclonal antibody that has shown activity in pts with advanced dMMR EC (objective response rate, 42%; disease control rate, 58%) and an acceptable safety profile. Here, we report on PROs in pts treated with dostarlimab in the single-arm GARNET trial. Methodology Pts with recurrent or advanced dMMR/MSI-H EC that progressed on a platinum regimen received 500 mg Q3W*4 of dostarlimab, then 1000 mg Q6W until disease progression or discontinuation (DC). PRO assessment, an exploratory endpoint, was measured using the EORTC-QLQ-C30. PROs were collected at baseline (BL), each dose cycle, and after DC. For PF and DRS (pain and fatigue), we conducted multi-item descriptive analyses, including change from BL. For symptomatic AEs and tolerability (nausea, vomiting, constipation, diarrhoea, tiredness/fatigue), we conducted item-level analyses to understand response distribution and change in response categories from BL: improved, stable, and 1-, 2-, or 3-category worsening. Results PRO data were available for 66/104 pts who received ≥1 dose of dostarlimab. Questionnaire compliance was consistent across domains, ranging from 100% at BL to 45% at cycle 7. Pain, fatigue, and PF were maintained above BL starting at cycles 1, 3, and 4, respectively. Symptomatic AEs were experienced by a minority of pts, with Conclusions PROs from the GARNET trial showed that dostarlimab was generally well tolerated and disease-related symptoms were improved or maintained while on treatment. These data, along with the efficacy and safety profile of dostarlimab, support use of dostarlimab in pts with dMMR/MSI-H advanced EC. Disclosures Clinical trial registration: NCT02715284 Funding: GlaxoSmithKline, Waltham, MA, USA Encore statement: This data is presented on behalf of the original authors with their permission. Presented at European Society for Medical Oncology (ESMO) annual meeting, September 19–21, 2020, Virtual. Dr. Kristeleit reports personal fees from Tesaro. Dr. Mathews reports institutional grants from Tesaro. Dr. Redondo reports institutional research funding from PharmaMar, Roche, and Eisai; and advisory roles at PharmaMar, AstraZeneca, Tesaro, Roche, and Eisai. Dr. Brown reports honoraria from Olympus; consulting or advisory role at Caris, Tesaro, Clovis, AstraZeneca, and Genentech; and speakers’ bureau at Clovis. Drs. Huang, Eliason, and Im are employees of GlaxoSmithKline.

Background Carboplatin-paclitaxel is standard systemic anticancer therapy for recurrent or advanced EC for which surgery and/or radiation are not curative. Dostarlimab (TSR-042) is an anti-programmed cell death (PD)-1 humanised monoclonal antibody that has demonstrated antitumour activity and an acceptable safety profile in patients (pts) with recurrent or advanced EC in the GARNET trial. The RUBY trial will evaluate the efficacy and safety of dostarlimab in combination with carboplatin-paclitaxel in recurrent or primary advanced EC compared with carboplatin-paclitaxel alone. Trial Design This is a global, randomised, double-blind, multicenter, placebo-controlled study. Eligible pts must have first recurrent or primary stage III or stage IV EC with a low potential for cure by radiation therapy or surgery alone or in combination. Pts with carcinosarcoma are eligible for enrolment. 470 pts will be enrolled from approximately 160 sites in the ENGOT countries, United States, and Canada. Stratification factors are DNA mismatch repair status (proficient [p], or deficient [d] MMR), prior external pelvic radiotherapy (yes or no), and disease status (recurrent, primary stage III or primary stage IV). Pts will be randomised 1:1 to receive combination dostarlimab 500 mg or placebo + carboplatin AUC 5 + paclitaxel 175 mg/m2 every 3 weeks for 6 cycles followed by dostarlimab 1000 mg or placebo monotherapy every 6 weeks for up to 3 years in the absence of progressive disease, death, unacceptable toxicity, or patient/physician decision to withdraw from the study. The primary endpoint is progression-free survival (PFS) as assessed by the investigator in the all-comers population and the dMMR population per RECIST version 1.1. Secondary efficacy endpoints are PFS assessed by blinded independent central review per RECIST version 1.1, overall survival, objective response rate, duration of response, disease control rate, safety and tolerability, and patient-reported outcomes. Disclosures Sponsor: GlaxoSmithKline, Waltham, MA, USA NCT number: NCT03981796 Encore statement: This data is presented on behalf of the original authors with their permission. Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, May 29–31, 2020, Virtual. Dr. Mirza reports personal fees and other from Karyopharm Therapeutics; Personal fees and other from Sera Prognostics and Roche; Grants and Personal fees from AstraZeneca, Clovis Oncology, Pfizer, GSK, Genmab, BioCad, Sotio, Boehringer Ingelheim, Geneos Therapeutics, Merck, Oncology Venture, Seattle Genetics, Sera Prognostics,Takeda Pharmaceutical Company Ltd, and Zailab. Dr. Coleman reports consulting fees from Merck, Reoche/Genentech, AstraZeneca, Oncomed/Mateo, Novocure, Oncosec, Janssen, Clovis, Tesaro/GSK, Abbvie, Eisai, Arrivive, and Oncoquest; grants from Merck, Roche/Genentech, V-Foundation, AstraZeneca, Janssen, Clovis, Genmab and Abbvie; and honoraria/reimbursement from Merck, Roche/Genentech, AstraZeneca, Oncomed/Mateo, Novocure, Oncosec, Janssen, Clovis, Tesaro/GSK, Eisai, Arrivive and OncoQuest. Dr. Slomovitz reports consulting/advisory fees from GlaxoSmithKline. Dr. Powell reports consulting/advisory fees from Roche/Genentech, AstraZeneca, Tesaro, and Clovis Oncology; and speakers’ bureau at Genentech/Roche, AstraZeneca, Tesaro and Clovis Oncology. Drs. Hanker and Valabrega have nothing to disclose. Drs. Im, Walker, and Guo are employees of GlaxoSmithKline.

Background Single-agent belamaf, a B-cell maturation antigen-targeting antibody-drug conjugate, induced durable responses with a manageable safety profile in patients with RRMM at 13 months of follow-up (DREAMM-2; NCT03525678). The unique multimodal mechanisms of action (MoAs) of belamaf, in combination with MoAs of selected agents, have the potential to achieve synergistic effects in RRMM to further enhance the benefit-risk profile. Belamaf is being evaluated in DREAMM-5 in various lines of treatment, as monotherapy or in combination with other agents. Methods DREAMM-5 (NCT04126200) is a phase 1/2 platform study that utilizes a master protocol with separate sub-studies comprised of sequential dose-exploration (DE) and cohort-expansion (CE) phases to identify effective belamaf combinations compared with a shared single-agent belamaf control arm (CE phase only). In the DE phase, patients will be assigned to one of the multiple belamaf dosing combination cohorts by a predetermined algorithm (N≤10 per cohort). A recommended phase 2 dose (RP2D) for each combination will be identified based on safety and preliminary efficacy in the DE phase. An interim analysis of safety, pharmacokinetic, biomarker, and efficacy data will be performed for each combination to determine if it should move forward to the CE phase. Patients in the CE phase (N≥35 per cohort) will be randomized to a sub-study, and within a sub-study, to either the combination arm or belamaf control arm. Patients will also be stratified by number of prior therapies; eligible patients will have received ≥3 prior lines, including an immunomodulatory agent, proteasome inhibitor, and anti-CD38 antibody. All patients will provide informed consent for participation. Primary objectives of the study are to identify the RP2D (DE phase), the overall response rate (≥partial response, CE phase), and safety and tolerability for each combination. Sub-study 1 (combination with GSK3174998, OX40 agonist antibody) is no longer open to enrollment. Sub-studies 2 (combination with GSK3359609, feladilimab, anti-ICOS agonist), 3 (combination with nirogacestat [PF-03084014; SpringWorks Therapeutics], gamma-secretase inhibitor), and 4 (combination with dostarlimab, PD-1 antagonist antibody) are currently open to enrollment. Sub-study 5 (combination with isatuximab [Sanofi], CD38 antagonist antibody) will be open to enrollment soon. Additional sub-studies will be explored based on scientific rationale and/or available preclinical combination data. Funding GSK (208887; NCT04126200). Belamaf drug linker technology licensed from Seagen Inc.; mAb produced using POTELLIGENT Technology licensed from BioWa. Nirogacestat and isatuximab produced by and used in collaboration with SpringWorks Therapeutics and Sanofi, respectively Encore Statement ©2021 European Hematology Association, Inc. Reused with permission. This abstract was accepted and previously presented at the 2021 EHA Annual Meeting. All rights reserved.

PurposeCombining the mTOR inhibitor ridaforolimus and the anti-IGFR antibody dalotuzumab demonstrated antitumor activity, including partial responses, in estrogen receptor (ER)-positive advanced breast cancer, especially in high proliferation tumors (Ki67>15%).MethodsThis randomized, multicenter, international, phase II study enrolled postmenopausal women with advanced ER-positive breast cancer previously treated with a nonsteroidal aromatase inhibitor (NCT01234857). Patients were randomized to either oral ridaforolimus 30mg daily for 5 of 7days (once daily [qd]×5days/week) plus intravenous dalotuzumab 10mg/kg/week or oral exemestane 25mg/day, and stratified by Ki67 status. Due to a high incidence of stomatitis in the ridaforolimus-dalotuzumab group, two sequential, nonrandomized, reduced-dose cohorts were explored with ridaforolimus 20 and 10mg qd×5days/week. The primary endpoint was progression-free survival (PFS).ResultsMedian PFS was 21.4weeks for ridaforolimus 30mg qd×5days/week plus dalotuzumab 10mg/kg (n=29) and 24.3weeks for exemestane (n=33; hazard ratio=1.00; P=0.5). Overall survival and objective response rates were similar between treatment arms. The incidence of drug-related, nonserious, and serious adverse events was higher with ridaforolimus/dalotuzumab (any ridaforolimus dose) than with exemestane. Lowering the ridaforolimus dose reduced the incidence of grade 3 stomatitis, but overall toxicity remained higher than acceptable at all doses without improved efficacy.ConclusionsThe combination of ridaforolimus plus dalotuzumab was no more effective than exemestane in patients with advanced ER-positive breast cancer, and the incidence of adverse events was higher. Therefore, the combination is not being further pursued.

Introduction: Single-agent belamaf (GSK2857916), a B-cell maturation antigen-targeting antibody-drug conjugate, induced deep and durable responses in patients with RRMM, with a manageable safety profile with 13 months of follow-up (DREAMM-2; NCT03525678; Lonial et al, ASCO 2020, Poster 436). A platform trial design allows efficient evaluation of belamaf in combination with other anti-myeloma agents, such as a humanized wild-type IgG1 anti-OX40 agonist, an IgG4-inducible T-cell co-stimulator (ICOS) agonist, a gamma-secretase inhibitor, and a humanized programmed cell death (PD)-1 antagonist. The unique, multimodal mechanisms of action (MoAs) of belamaf, in combination with MoAs of these agents, has the potential to achieve synergistic effects in RRMM to further enhance anti-myeloma activity without compromising safety. Methods: DREAMM-5 (NCT04126200) is a Phase I/II study that utilizes a master protocol with separate substudies comprised of sequential dose-exploration (DE) and cohort-expansion (CE) phases, to identify promising, effective belamaf combinations when compared with a shared single-agent belamaf control arm (CE phase only). The DE phase consists of multiple dosing cohorts with belamaf combinations in which patients are assigned to treatment slots by a predetermined algorithmic approach (N≤10 per cohort). A recommended Phase II dose (RP2D) for each combination treatment will be identified based on the safety and preliminary efficacy in the DE phase. At the end of the DE phase, an interim analysis of safety, pharmacokinetic, and efficacy data will also be performed for each substudy treatment combination to determine whether the combination should move forward at the RP2D to the CE phase. Patients in the CE phase (N≥35 per cohort) will be randomized to a substudy and within a substudy to either combination treatment or the belamaf monotherapy control arm; patients will also be stratified by number of prior therapies). Eligible patients will have RRMM and will have received ≥3 prior therapy lines, which includes a prior immunomodulatory agent, proteasome inhibitor, and anti-CD38 antibody; all patients will provide informed consent for participation. The primary objectives of the study are to identify the RP2D (DE phase) and the overall response rate (≥partial response, CE phase), along with safety and tolerability, for each combination treatment. Substudies 1 (combination with GSK3174998, OX40 agonist antibody), 2 (combination with GSK3359609, ICOS agonist antibody), and 3 (combination with nirogacestat [PF-03084014; SpringWorks Therapeutics], gamma-secretase inhibitor) are currently open to enrollment. Substudy 4 (combination with dostarlimab; PD-1 antagonist antibody) is under review. Additional substudies will be explored based on scientific rationale and/or preclinical combination study results. Funding: GSK (Study 208887); belamaf drug linker technology licensed from Seattle Genetics; belamaf monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa; nirogacestat gamma-secretase inhibitor produced by and used in collaboration with SpringWorks Therapeutics. Figure: DREAMM-5 study design Figure 1 Disclosures Richardson: Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Nooka:GlaxoSmithKline: Consultancy, Honoraria, Other: Personal Fees: Travel/accomodations/expenses, Research Funding; Karyopharm Therapeutics, Adaptive technologies: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Spectrum Pharmaceuticals: Consultancy; Adaptive Technologies: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Quach:Amgen, sanofi, celgene, Karyopharm, GSK: Research Funding; Amgen, Celgene, karyopharm, GSK, Janssen Cilag, Sanofi.: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline, Karyopharm, Amgen, Celgene, Janssen Cilag: Consultancy; GlaxoSmithKline, Karyopharm, Amgen, Celgene, Janssen Cilag: Honoraria. Trudel:Celgene, Janssen, Takeda, Sanofi, Karyopharm, Amgen Canada: Honoraria; Celgene, Amgen, GSK: Consultancy, Research Funding; GSK, Celgene, Janssen, Amgen, Genentech: Research Funding. Routledge:Celgene, Sandoz: Consultancy; Amgen, BMS, Celgene, Sandoz: Honoraria. Song:Otsuka: Honoraria; Janssen: Honoraria, Research Funding; Amgen, Celgene,Takeda: Consultancy, Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Paul:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Khan:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Brouch:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Ferron-Brady:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Yeakey:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Shelton:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Montes de Oca:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Smith:SpringWorks: Current Employment, Current equity holder in publicly-traded company. Im:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Ahlers:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Paul:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Holkova:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Gupta:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company; Novartis: Current equity holder in publicly-traded company. Kremer:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Rodriguez-Otero:GlaxoSmithKline: Consultancy, Current Employment, Current equity holder in publicly-traded company, Honoraria; Kite: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Medscape: Membership on an entity's Board of Directors or advisory committees; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Sanofi: Consultancy, Honoraria.

Background Despite recent advances in the treatment of advanced non-small-cell lung cancer, there remains a need for effective treatments for progressive disease. We assessed the efficacy of pembrolizumab for patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer. Methods We did this randomised, open-label, phase 2/3 study at 202 academic medical centres in 24 countries. Patients with previously treated non-small-cell lung cancer with PD-L1 expression on at least 1% of tumour cells were randomly assigned (1:1:1) in blocks of six per stratum with an interactive voice-response system to receive pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, or docetaxel 75 mg/m(2) every 3 weeks. The primary endpoints were overall survival and progression-free survival both in the total population and in patients with PD-L1 expression on at least 50% of tumour cells. We used a threshold for significance of p

Importance Deficient mismatch mutation repair mechanisms may sensitize endometrial cancers to anti-programmed death 1 (PD-1) therapies. Dostarlimab (TSR-042) is an investigational anti-PD-1 antibody that binds with high affinity to the PD-1 receptor. Objective To assess the antitumor activity and safety of dostarlimab for patients with deficient mismatch repair endometrial cancer. Design, setting, and participants This ongoing, open-label, single-group, multicenter study began part 1 on March 7, 2016, and began enrolling patients with deficient mismatch mutation repair endometrial cancer on May 8, 2017. Median follow-up was 11.2 months (range, 0.03 [ongoing] to 22.11 [ongoing] months; based on radiological assessments). Statistical analysis was performed July 8 to August 9, 2019. Interventions Patients received 500 mg of dostarlimab intravenously every 3 weeks for 4 doses, then 1000 mg every 6 weeks until disease progression, treatment discontinuation, or withdrawal. Main outcomes and measures The primary end point was objective response rate and duration of response by blinded independent central review using Response Evaluation Criteria in Solid Tumors, version 1.1. Results As of the data cutoff, 104 women (median age, 64.0 years [range, 38-80 years]) with deficient mismatch mutation repair endometrial cancers were enrolled and treated with dostarlimab. Of these, 71 had measurable disease at baseline and at 6 months or more of follow-up and were included in the analysis. There was a confirmed response in 30 patients (objective response rate, 42.3%; 95% CI, 30.6%-54.6%); 9 patients (12.7%) had a confirmed complete response, and 21 patients (29.6%) had a confirmed partial response. Responses were durable; the median duration of response was not reached (median follow-up was 11.2 months). The estimated likelihood of maintaining a response was 96.4% at 6 months and 76.8% at 12 months. Anemia (3 of 104 [2.9%]), colitis (2 of 104 [1.9%]), and diarrhea (2 of 104 [1.9%]) were the most common grade 3 or higher treatment-related adverse events. Conclusions and relevance In this nonrandomized trial, dostarlimab was associated with clinically meaningful and durable antitumor activity with an acceptable safety profile for patients with deficient mismatch mutation repair endometrial cancers after prior platinum-based chemotherapy. Trial registration ClinicalTrials.gov identifier: NCT02715284.

275 Background: PRO enable direct measurement of the experiences of patients with cancer. Anti-programmed death 1 (PD-1) therapies have shown favorable PRO in lung cancer but a data gap remains in EC. Dostarlimab is an investigational anti-PD-1 monoclonal antibody which has shown promising activity in GARNET in advanced mismatch repair deficient (dMMR) EC pts and a low incidence of symptomatic grade ≥3 treatment-related adverse events. Here, we report on PRO measures collected from pts with dMMR/microsatellite instability high (MSI-H) EC in the single-arm GARNET trial. Methods: Pts with dMMR/MSI-H EC confirmed by local tests, with recurrent or advanced disease that progressed on a platinum regimen were enrolled. Pts received 500 mg Q3W of dostarlimab for 4 cycles, then 1000 mg Q6W until disease progression or discontinuation. PRO assessment was an exploratory endpoint and was measured by the EORTC Quality of Life Questionnaire (QLQ-C30), a validated instrument used evaluate quality of life (QOL), functioning, disease symptoms, and treatment-related side effects. PRO were collected at each dose administration, end of treatment, and follow-up. A mixed-model for repeated measures was used to assess change from baseline, accounting for time and baseline ECOG scores. The threshold to determine clinically meaningful group-level change was ±10 points. Results: PRO data were available for 43 pts. Compliance rates were 98%. Relative to baseline, pts reported meaningful improvements in pain, insomnia, and social and emotional functioning over the trial duration. Appetite, nausea, vomiting, constipation, diarrhea, and physical and role functioning were stable over the trial duration. QOL and global health status were also maintained. Conclusions: PRO from 43 pts enrolled in the GARNET trial show that disease- and treatment-related symptoms and QOL are improved or maintained while receiving treatment. These data, along with the efficacy and safety profile of dostarlimab, strongly support the use of dostarlimab in dMMR/MSI-H advanced EC. Funding: GlaxoSmithKline, Waltham, MA, USA. Clinical trial information: NCT02715284 .

TPS6107 Background: Carboplatin-paclitaxel is considered standard systemic anticancer therapy for recurrent or advanced EC for which surgery and/or radiation are not curative. Dostarlimab (TSR-042) is an anti-programmed cell death (PD)-1 humanized monoclonal antibody that has demonstrated antitumor activity and an acceptable safety profile in patients (pts) with recurrent or advanced EC in the GARNET trial. The RUBY trial was designed to evaluate the efficacy and safety of dostarlimab in combination with carboplatin-paclitaxel in recurrent or primary advanced EC compared with carboplatin-paclitaxel alone. Methods: This is a global, randomized, double-blind, multicenter, placebo-controlled study. Eligible pts must have first recurrent or primary stage III or stage IV EC with a low potential for cure by radiation therapy or surgery alone or in combination. Pts with carcinosarcoma are eligible for enrollment. 470 pts will be enrolled from approximately 160 sites in the ENGOT countries, United States, and Canada. Stratification factors are microsatellite instability (MSI) status (MSI-high [MSI-H] or microsatellite stable [MSS]), prior external pelvic radiotherapy (yes or no), and disease status (recurrent, primary stage III, or primary stage IV). Pts will be randomized 1:1 to receive combination dostarlimab 500 mg or placebo + carboplatin AUC 5 + paclitaxel 175 mg/m2 every 3 weeks for 6 cycles followed by dostarlimab 1000 mg or placebo monotherapy every 6 weeks for up to 3 years in the absence of progressive disease, death, unacceptable toxicity, or patient/physician decision to withdraw from the study. The primary endpoint is progression-free survival (PFS) as assessed by the investigator in the all-comers population and the MSI-H population per RECIST version 1.1. Secondary efficacy endpoints are PFS assessed by blinded independent central review per RECIST version 1.1, overall survival, objective response rate, duration of response, disease control rate, safety and tolerability, and patient-reported outcomes. Clinical trial information: NCT03981796.

e18032 Background: PRO enable direct measurement of the experiences of patients with cancer. Anti-programmed death 1 (PD-1) therapies have shown favorable PRO in lung cancer but a data gap remains in EC. Dostarlimab is an investigational anti-PD-1 monoclonal antibody which has shown promising activity in GARNET in advanced mismatch repair deficient (dMMR) EC pts (with an ORR of 42.9% and a disease control rate of 58.6%), and a low incidence of symptomatic grade ≥3 treatment-related adverse events (anemia [2·9%], colitis [1·9%], and diarrhea [1·9%]). Here, we report on PRO measures collected from pts with dMMR/microsattelite instability high (MSI-H) EC in the single-arm GARNET trial. Methods: Pts with dMMR/MSI-H EC confirmed by local tests, with recurrent or advanced disease that progressed on a platinum regimen were enrolled. Pts received 500 mg Q3W of dostarlimab for 4 cycles, then 1000 mg Q6W until disease progression or discontinuation. PRO assessment was an exploratory endpoint and was measured by the EORTC Quality of Life Questionnaire (QLQ-C30), a validated instrument used to evaluate quality of life, functioning, disease symptoms, and treatment-related side effects. PRO were collected at each dose administration, end of treatment, and follow-up. A mixed-model for repeated measures was used to assess change from baseline, accounting for time and baseline ECOG scores. The threshold to determine clinically meaningful group-level change was ±10 points. Results: PRO data were available for 43 pts. Compliance rates were high at 98%. Relative to baseline, pts reported meaningful improvements in pain, insomnia, and social and emotional functioning over the trial duration. Appetite, nausea, vomiting, constipation, diarrhea, and physical and role functioning were stable over the trial duration. Quality of life and global health status were also maintained. Conclusions: PRO from 43 pts enrolled in the GARNET trial show that disease- and treatment-related symptoms and quality of life are improved or maintained while receiving treatment. These data, along with with the efficacy and safety profile of dostarlimab, strongly support the use of dostarlimab in dMMR/MSI-H advanced EC. Clinical trial information: NCT02715284.

PurposeTo evaluate whether adding humanized monoclonal insulin growth factor-1 receptor (IGF-1R) antibody (dalotuzumab) to mammalian target of rapamycin (mTOR) inhibitor (ridaforolimus) plus aromatase inhibitor (exemestane) improves outcomes in patients with estrogen receptor (ER)-positive advanced/metastatic breast cancer.MethodsThis randomized, open-label, phase II trial enrolled 80 postmenopausal women with high-proliferation (Ki67 index staining≥15%), ER-positive breast cancer that progressed after a non-steroidal aromatase inhibitor (NCT01605396). Randomly assigned patients were given oral ridaforolimus 10mg QD 5×/week, intravenous dalotuzumab 10mg/kg/week, and oral exemestane 25mg/day (R/D/E, n=40), or ridaforolimus 30mg QD 5×/week and exemestane 25mg/day (R/E; n=40). Primary end point was progression-free survival (PFS).ResultsMedian PFS was 23.3weeks for R/D/E versus 31.9weeks for R/E (hazard ratio 1.18; 80% CI 0.81-1.72; P=0.565). Grade 3-5 adverse events were reported in 67.5% of patients in the R/E arm and 59.0% in the R/D/E arm. Stomatitis (95.0 vs. 76.9%; P=0.021) and pneumonitis (22.5 vs. 5.1%; P=0.027) occurred more frequently in the R/E than the R/D/E arm; hyperglycemia (27.5 vs. 28.2%) occurred at a similar rate.ConclusionsR/D/E did not improve PFS compared with R/E. Because the PFS reported for R/E was similar to that reported for everolimus plus exemestane in patients with advanced breast cancer, it is possible that lower-dose ridaforolimus in the R/D/E arm (from overlapping toxicities with IGF1R inhibitor) contributed to lack of improved PFS.

Background: Preclinical studies indicate that the dual inhibition of IGFR and mTOR may be additive or synergistic and abrogates the feedback activation of AKT due to rapamycin analog mTOR inhibitors. A phase 1 study of the mTOR inhibitor RIDA and the anti-IGFR antibody DALO demonstrated that the combination was feasible and well-tolerated at doses that were nearly those used for the two single agents. The dose limiting toxicity was stomatitis, similar to RIDA monotherapy. Preliminary signals of anti-tumor activity, including partial responses and prolonged progression free survival (PFS), were observed in ER+ advanced breast cancer (ABC), especially in high proliferation tumors (Ki67 ≥15%). Methods: The trial was a multi-center, international randomized study with PFS as the primary endpoint. Key eligibility included ABC with prior treatment with a non-steroidal aromatase inhibitor. The original phase 2 study design was a two-part, adaptive design intended to first test the combination of RIDA (30 mg by mouth daily for 5 out of every 7 days), -DALO (10 mg/kg IV weekly) against a standard agent, exemestane in Part A. Patients were stratified into high and low proliferation strata based on baseline Ki67. Following a demonstration of PFS benefit of the combination in Part A, Part B was intended to show the PFS benefit of the combination over each single agents by comparing RIDA-DALO to RIDA and DALO. Results: The study was initiated in October 2011. Accrual was suspended after the first 66 patients were randomized due to a higher than expected rate of stomatitis in the RIDA-DALO arm. Preliminary data indicated an overall incidence of any grade stomatitis was 68% (22/33 pts), and of grade 3 stomatitis was 35% (11/33 pts). In an effort to identify a more tolerable regimen, the study was amended to eliminate Part B and to evaluate two sequential reduced dose RIDA-DALO cohorts in a non-randomized design: 20mg and 10mg for 5 out of every 7 days. The dose of DALO was unchanged. Preliminary safety results of overall and grade 3 stomatitis in the 20 mg were 81.5% (22/27 pts) and 37% (10/27 pts), respectively. Although the incidence of overall stomatitis in the 10 mg cohort remained high, 88% (22/25 pts), grade 3 stomatitis was dramatically reduced to 8% (2/25 pts). Conclusion: Preliminary evaluation of safety from this phase 2 study demonstrates that the previously recommended phase 2 dose of RIDA-DALO was not tolerable. However lower doses of RIDA (10 mg) in combination with DALO appeared to be tolerable with markedly reduced rates of grade 3 stomatitis. Final results of efficacy, safety and RNA profiling analysis from the two RIDA-DALO dose cohorts as well as from the randomized portion of the study will be available at the time of the meeting. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-04.

Background: The clinical benefit of combination of mTOR inhibition and anti-hormonal therapy has been previously established and represents a new standard of care for patients with hormone receptor positive (HR+) advanced breast cancer (ABC). Preclinical evaluation of the mTOR pathway demonstrates that dual inhibition of IGFR and mTOR may be additive or synergistic and abrogates the feedback activation of AKT due to rapamycin analog mTOR inhibitors. A completed phase 1 study of the combination of the mTOR inhibitor, RIDA and the anti-IGFR antibody, DALO demonstrated preliminary signals of anti-tumor activity. This was further evaluated in a recently completed phase 2 study of RIDA-DALO compared to exemestane in ER+ ABC. Final safety and efficacy results from that phase 2 study will be reported at this meeting (see Baselga et al). Building upon the clinical synergies of mTOR and EX as well as the biologic relationship of the mTOR and IGFR pathways, a clinical study has been initiated to evaluate the triplet combination of RIDA-DALO-EX compared to RIDA-EX. Methods: This is a multicenter, international, randomized phase 2 study of the triplet combination of RIDA (10 mg by mouth daily for 5 out of every 7 days), DALO (10 mg/kg IV weekly), and EX (25 mg QD) compared to RIDA (30 mg by mouth daily for 5 out of every 7 days) and EX (25 mg QD) in high KI67 (≥15%) expressing ER+, ABC. Approximately 84 patients will be randomized 1:1 to either triplet or doublet therapy. Key eligibility criteria include: HR+ and HER-2 negative measurable ABC, prior therapy with a non-steroidal aromatase inhibitor, and KI67 labeling index ≥15%. The primary endpoint of the study is progression free survival (PFS). Key secondary endpoints include evaluation of percent (%) reduction from baseline in the sum of imaging measurements (target lesion diameters or volumes) at 16 weeks between the two arms, and overall response rates. The sample size is event driven with a target of 38 PFS events, which provides approximately 80% power, at 1-sided alpha of 0.1, to detect a HR of 0.5, corresponding to an approximate 100% improvement in median PFS, from 10.6 to 21.2 months. Safety parameters or adverse experiences of special interest include hyperglycemia, stomatitis, mucosal inflammation, pneumonitis and hearing loss. Accrual has been completed with results expected in May 2014. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-13.

Introduction: TSR-042 is a humanized monoclonal antibody targeting programmed death (PD)-1, effectively blocking interaction with its ligands PD-L1 and PD-L2. TSR-042 is being evaluated in patients (pts) with advanced solid tumors in the ongoing phase 1 GARNET trial (NCT02715284). Weight based dose escalation (Part 1) and fixed-dose safety studies (Part 2A) have been completed,1 and the study is currently enrolling pts with specific tumor types into expansion cohorts. Here, we present safety and efficacy data from the microsatellite instability-high (MSI-H) endometrial cancer (EC) and non-small cell lung cancer (NSCLC) cohorts, as well as pharmacokinetic (PK) and receptor occupancy (RO) characterization at the recommended phase 2 dose (RP2D). Methods/Procedures: 30 NSCLC pts and 19 MSI-H EC pts with previously treated recurrent or advanced disease were enrolled; median number of prior lines of therapy for metastatic disease was 1.0 for both cohorts. MSI status for EC pts was determined centrally using a next generation sequencing-based assay. Key exclusion criteria included prior therapy with agents targeting anti-PD-1, PD-L1, or PD-L2, and uncontrolled CNS metastases. Pts were treated at the R2PD of TSR-042: 500 mg Q3W for the first 4 cycles and 1000 mg Q6W thereafter. Serum and PBMCs were collected for PK and RO analyses, respectively. Antitumor activity was assessed by investigators using immune-related Response Evaluation Criteria in Solid Tumors (irRECIST). RO was assessed using a CD3+ binding assay (direct receptor occupancy).1 Results: Among the 30 NSCLC and 19 MSI-H EC pts, 42 (85.7%) pts reported ≥1 adverse event (AE), with grade ≥3 AEs reported in 13/49 (26.5%) pts. The most common AEs were diarrhea and nausea (11 pts each), arthralgia and fatigue (9 pts each), and cough, decreased appetite, and dyspnea (7 pts each). 25/49 (51.0%) pts reported treatment-related AEs; 11/49 (22.4%) pts had serious AEs; 1 case of grade 3 fatigue and 1 case of grade 3 leukopenia and grade 3 neutropenia were deemed treatment-related. 21 NSCLC and 11 MSI-H EC pts had at least 1 tumor assessment. Among NSCLC pts, 7/21 (33.3%) had a partial response (irPR; confirmed and unconfirmed), and 6/21 (28.6%) had stable disease (irSD); among MSI-H EC pts, 4/11 (36.4%) had irPR, and 2/11 (18.2%) had irSD. TSR-042 demonstrated dose-proportional PK. The maximal achievable RO was observed in pts treated at the RP2D, consistent with the results reported for Parts 1 and 2A.1 Conclusions: These results indicate clinical benefit of TSR-042 in previously treated NSCLC and MSI-H EC patients, with a safety profile similar to other PD-1 inhibitors. PK results were consistent across all patients evaluated and show that maximal achievable receptor occupancy was attained at the RP2D. 1. Sachdev JC et al. Ann Oncol. 2017(suppl 5):28:420;1185P Citation Format: Victor Moreno, Maria-Pilar Barretina-Ginesta, Wei Guo, Sharon Lu, David Jenkins, Kristen McEachern, Vienna Reichert, Steven Dunlap, Ellie Im, Lucy Gilbert, Ana Oaknin, Charles Leath, III, Janakiraman Subramanian. Preliminary safety, efficacy, and PK/PD characterization from GARNET, a phase 1 clinical trial of the anti-PD-1 monoclonal antibody, TSR-042, in patients with recurrent or advanced NSCLC and MSI-H endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT053.

Dinaciclib is a novel selective inhibitor of cyclin-dependent kinase (CDK)1, CDK2, CDK5, and CDK9. We conducted a phase I study to investigate the effects of dinaciclib when administered with rituximab. In this phase I nonrandomized dose-escalation 3 + 3 trial, patients with relapsed/refractory chronic lymphocytic leukemia (CLL) were treated with dinaciclib and rituximab. Dinaciclib was administered intravenously (IV) over 2 h on days 1, 8 and 15 in cycles 2–13 (28-day cycles). Rituximab 375 mg/m2 was administered IV on days 1, 8, 15 and 22 in cycle 1 (28-day cycle) and on day 1 during cycle 3–13. Rituximab was not administered in cycle 2. Rituximab and dinaciclib were given alone in cycles 1 and 2, respectively, and in combination in cycles 3–13. Primary objectives included determination of the recommended phase II dose of dinaciclib and evaluation of pharmacokinetics (PK) when administered with rituximab. Five patients completed the study due to early termination. All presented with drug-related adverse events (AEs), but no dose-limiting toxicities were observed. The most commonly observed toxicities included hematological, digestive and metabolic AEs. However, no tumor lysis syndrome has been reported in the study. Four patients achieved stable disease, and one patient achieved complete response according to 2008 iwCLL criteria at cycle 3. PK samples were collected from 5 patients, and no obvious interaction between dinaciclib and rituximab was observed. Limited data from this study shows dinaciclib in combination with rituximab was well tolerated and revealed encouraging clinical activity in relapsed/refractory CLL patients.

3030Background: In KEYNOTE-010 (NCT01905657), pembro was superior to doce for OS in patients (pts) with PD-L1–positive advanced NSCLC that progressed after ≥2 platinum-doublet chemotherapy cycles (...

9024Background: KEYNOTE-010 (NCT01905657) showed that the anti–PD-1 antibody pembrolizumab (pembro; MK-3475) at doses of 2 and 10 mg/kg Q3W provided superior OS over docetaxel in patients (pts) wit...

9015Background: In the phase III KEYNOTE-010 study (NCT01905657), pembrolizumab (pembro; MK-3475) provided superior OS over docetaxel (doce) in patients (pts) with previously treated, PD-L1–positiv...

8031 Background: As monotherapy, the anti–PD-1 antibody pembro has shown robust antitumor activity in advanced NSCLC patients (pts). KEYNOTE-021 evaluated the safety, tolerability, and clinical act...

8011 Background: Pembro is a potent anti–PD-1 monoclonal antibody. IPI, an anti–CTLA-4 antibody, has shown activity in advanced NSCLC. In melanoma, combined anti–PD-1 and anti–CTLA-4 treatment has shown robust efficacy and manageable toxicity. We report interim results from a phase 1 study evaluating pembro + IPI in patients (pts) with recurrent NSCLC. Methods: Pts with stage IIIB/IV NSCLC that recurred after ≤ 2 prior regimens received pembro + IPI every 3 wk for 4 cycles followed by maintenance pembro. Based on emerging data from the nivolumab + IPI advanced NSCLC study, doses were reduced from 10 mg/kg to 2 mg/kg for pembro and from 3 mg/kg to 1 mg/kg for IPI). Primary end point was safety and incidence of dose-limiting toxicities (DLTs) in the first 3 wk of dosing. Response was assessed every 6 wk per RECIST 1.1 by investigator review. Results: As of Dec 2014,17 pts were enrolled: 3 at pembro 10 mg/kg + IPI 3 mg/kg, 3 at pembro 10 mg/kg + IPI 1 mg/kg, and 11 at pembro 2 mg/kg + IPI 1 mg/kg. No DLTs or...

Introduction: The combination of a mammalian target of rapamycin (mTOR) inhibitor and an aromatase inhibitor has been shown to significantly increase progression-free survival (PFS) in patients with estrogen receptor-positive (ER+) advanced or metastatic breast cancer. Ridaforolimus is an alternative mTOR inhibitor with high potency and specificity. We hypothesized that triplet therapy with ridaforolimus, dalotuzumab (a humanized monoclonal antibody targeting the IGF-1 receptor [IGFR]), and exemestane (R/D/E) would be more effective than doublet therapy with ridaforolimus and exemestane (R/E). Methods: This phase 2, randomized, open-label trial enrolled 80 postmenopausal patients who had high-proliferation (KI67 staining) ER+ breast cancer that had progressed following treatment with a nonsteroidal aromatase inhibitor. Patients received either triplet therapy, at the previously determined maximum tolerated dose of oral ridaforolimus 10 mg QD×5, dalotuzumab 10 mg/kg/week IV, and oral exemestane 25 mg/day (R/D/E, n=40), or doublet therapy with R 30 mg QD×5 and E 25 mg/day (R/E, n=40). Dose increases of R to 20 or 40 mg QD×5 were permitted in the R/D/E or R/E arms, respectively, in the absence of grade ≥2 stomatitis after cycle 1. The R dose could be reduced in either arm for toxicity. The primary endpoint was PFS in the ITT population by central review. Adverse events (AE) of clinical interest (Tier 1) included stomatitis, pneumonitis, hearing loss, and hyperglycemia. Results: Baseline characteristics were balanced between treatment groups. The median PFS was 23.3 (95% CI, 8.71, 38.43) weeks for R/D/E versus 31.9 (95% CI, 16.00, 39.29) weeks in the R/E arm (hazard ratio, 1.18; 80% CI, 0.81-1.72; P=0.565). All patients experienced at least one AE. 5 (12.8%) and 3 (7.5%) patients in the R/D/E and R/E arms, respectively, discontinued the study because of AE. Serious drug-related AE occurred in 2.6% of the R/D/E arm and 15% of the R/E arm. Dose modifications due to AE occurred in 10.3% and 50% in the R/D/E and R/E arms, respectively (difference -39.7%; 95% CI, -56.7, -20.4). Tier 1 AE were primarily grade 1-2 in severity. Stomatitis occurred in 76.9% (30/39 patients) in the R/D/E arm vs 95.0% (38/40 patients) in the R/E arm (P=0.021), and grade 3-4 stomatitis was similar between arms (23.1% vs 25%). Pneumonitis occurred in 5.1% vs 22.5% (P=0.027) and hearing loss occurred in 1 patient in each treatment arm (2.6% vs 2.5%), all grade 1-2. Hyperglycemia occurred at a similar rate in both treatment arms (28.2% vs 27.5%), with grade 3-4 events in 4 (10.3%) and 3 (7.5%) patients in the R/D/E and R/E arms, respectively. Conclusions: The combination of R 10 mg QD×5, D, and E did not improve PFS when compared to R 30 mg QD×5 plus E. The incidence rates of AE were lower in the R/D/E arm than the R/E arm for most categories of adverse events, likely because of the higher dose of R in the R/E arm. The efficacy reported for R/E in this study is similar to that reported in previous studies evaluating mTOR inhibitors in combination with exemestane in ABC. Overlapping toxicities and lower doses likely contributed to the lack of improved PFS with the addition of the IGFR inhibitor to this combination. Citation Format: Hope S Rugo, Olivier Tredan, Jungsil Ro, Serafin Morales, Antonino Musolino, Noemia Afonso, Marta Ferreira, Kyong Hwa Park, Javier Cortes, Antoinette R Tan, Joanne L Blum, Lamar Eaton, Christine K Gause, Adelle (Zhen) Wang, Ellie Im, David J Mauro, José Baselga. Results from the phase 2 trial of ridaforolimus, dalotuzumab, and exemestane compared to ridaforolimus and exemestane in advanced breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr PD5-1.

Objectives: Dostarlimab is a humanized programmed death (PD)-1 receptor monoclonal antibody that blocks interaction with the PD-1 ligands. GARNET (NCT02715284) is a phase 1 study assessing antitumor activity and safety of dostarlimab monotherapy in patients (pts) with solid tumors. Here, we report efficacy endpoints by irRECIST based on investigator assessment (IA) for the endometrial cancer (EC) cohorts. Methods: This is a multicenter, open-label, single-arm, dose-escalation and cohort-expansion study. Here, we report on 2 independent expansion cohorts of pts with recurrent or advanced EC (dMMR EC and MMRp EC, determined by immunohistochemistry [IHC]) that progressed on or after a platinum-based chemotherapy regimen. Pts received 500 mg dostarlimab IV Q3W for 4 cycles, then 1000 mg Q6W until disease progression, discontinuation, or withdrawal. The primary endpoints of objective response rate (ORR) and duration of response (DOR) by blinded independent central review (BICR) using RECIST v1.1, and safety have been reported previously.1 Immune-related endpoints (irORR and irDOR by irRECIST) are based on IA, and are prespecified secondary endpoints. Results: In total, 126 dMMR and 145 MMRp pts identified by IHC were enrolled and dosed. Of these, 103 dMMR and 142 MMRp pts had measurable disease at baseline by BICR, and sufficient follow-up time (6 mo) for the primary efficacy analyses. 110 dMMR and 144 MMRp pts had measurable disease at baseline by IA and sufficient follow-up time (6 mo) and were included for efficacy analysis of irORR and irDOR; some additional pts were considered to have measurable disease at baseline by IA. Efficacy data based on irRECIST are shown in the table. irORR was 45.5% in dMMR pts, and 13.9% in MMRp pts. Download : Download high-res image (141KB) Download : Download full-size image Conclusions: Efficacy endpoints reported by RECIST v1.1 and irRECIST show similar results. irDCR was particularly of interest in the MMRp cohort, a group with a poorer prognosis. The potential benefit seen in this single-arm trial awaits confirmation in ongoing randomized controlled studies. Reference: [1] Oaknin, A, et al. Annals of Oncology (2020) 31 (suppl_4): S1142-S1215. 10.1016/annonc/annonc325. LBA36. Funding: GlaxoSmithKline.