Kuruvilla, John

Abstract Introduction: Nivolumab, a fully human IgG4 monoclonal antibody targeting programmed death receptor-1, has recently been FDA approved for classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous stem cell transplantation (ASCT) and post-transplantation brentuximab vedotin (BV). CheckMate 205 (NCT02181738) is a phase 2, international, multicohort study evaluating nivolumab monotherapy in patients with cHL after failure of ASCT. At minimum 6 months' follow-up of Cohort B (205B) which included patients who had received BV after disease recurrence following ASCT, objective response rate (ORR) per independent radiologic review committee (IRRC) was 66% and 6-month progression-free survival (PFS) was 77%, with an acceptable safety profile (Younes et al. Lancet Oncol 2016; Jul 20 [Epub ahead of print]). Here we report outcomes with longer follow-up (minimum 12-month follow-up) in 205B. Primary results from Cohort A, which enrolled patients who relapsed after ASCT but were BV-naïve, will also be presented for the first time as data were not available at time of abstract submission. Methods: CheckMate 205 was designed to evaluate the efficacy and safety of nivolumab monotherapy in patients with cHL who relapsed after ASCT in 3 cohorts: 205A (BV-naive patients; n = 63); 205B (BV after failed ASCT; n = 80); 205C (BV at any time prior to study drug; n = 100). Nivolumab was given at 3 mg/kg intravenously every 2 weeks until disease progression or unacceptable toxicity in 205A and 205B. The primary endpoint was IRRC-assessed ORR. Results: 80 patients were treated in Cohort 205B; the median age was 37 years (range 18-72). Patients had received a median of 4 prior regimens (range 3-15). At data cut-off (April 2016) with median duration of follow-up of 15.4 months (range 1.9-18.5), 43 patients (54%) still remained on therapy. IRRC-assessed ORR for patients in 205B was 68% (95% confidence interval [CI], 56%, 78%). CR and partial response (PR) rates per IRRC were 8% (3%, 16%) and 60% (48%, 71%), respectively. With longer follow-up, the median duration of response was prolonged to 13.1 months (95% CI, 8.7, not reached; range, 0.0+, 14.2+). The median duration of CR (DOCR) was not reached (95% CI, 4.6, not available [NA]; range, 0.7+, 10.4+) and the median duration of PR was 13.1 months (95% CI, 7.79, NA; range, 0.0+, 13.4+) (Table 1). IRRC median PFS was 14.8 months (95% CI, 11.3 months, NA); 12-month PFS was 54.6% (95% CI, 40.9%, 66.4%), and 12-month overall survival (OS) was 94.9% (median OS not reached). Of 37 patients (46%) who discontinued nivolumab, the most common reasons were disease progression (n = 19 [24%]), allogeneic stem cell transplant (n = 7 [9%]) and adverse events (n = 5 [6%]). Seventy-four patients (93%) had drug-related adverse events (AEs) of any grade. The most common drug-related AEs were fatigue (28%), infusion reaction (20%), arthralgia (15%), and rash (15%). 29% of patients had Grade 3-4 drug-related AEs; the most common were increased lipase (8%), neutropenia (5%), and increased aspartate aminotransferase (4%). The most common serious AEs were pyrexia, pneumonia, tumor progression, arrhythmia, infusion reaction, and meningitis (≤4% each). Conclusions: In this report with extended 12-month follow-up, longer remissions are noted following nivolumab monotherapy in relapsed cHL, including durable PRs in heavily pretreated patients. Nivolumab has an acceptable safety profile, similar to previously reported. Primary results following nivolumab monotherapy in BV-naïve patients with cHL who progressed after ASCT (Cohort 205A) will also be presented at the meeting. Study funding: Study funded by Bristol-Myers Squibb. Professional writing assistance was provided by K. Jesien of Caudex and funded by Bristol-Myers Squibb. Disclosures Timmerman: Seattle Genetics, Genmab, Celgene: Consultancy, Honoraria; Bristol-Myers Squibb, Kite Pharma, Valor Biopharmaceuticals, Janssen: Research Funding. Engert:Takeda, BMS: Consultancy, Honoraria, Research Funding. Armand:Bristol-Myers Squibb: Consultancy, Research Funding; Pfizer: Research Funding; Roche: Research Funding; Infinity Pharmaceuticals: Consultancy; Merck: Consultancy, Research Funding; Sequenta Inc: Research Funding. Collins:Takeda: Consultancy, Honoraria, Speakers Bureau. Kuruvilla:Roche Canada: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Honoraria; Merck: Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Lundbeck: Honoraria. Cohen:Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding. Trneny:Roche, Celgene, Takeda, Janssen, Gilead, Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche, Celgene: Research Funding. De Boer:NKI-AVL: Employment. Shipp:Cell Signaling: Honoraria; Merck, Gilead, Takeda: Other: Scientific Advisory Board; Bayer: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Rodig:Bristol-Myers Squibb: Honoraria, Research Funding; Perkin Elmer: Membership on an entity's Board of Directors or advisory committees. Kato:Bristol-Myers Squibb: Employment. Sumbul:Bristol-Myers Squibb: Employment. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding.

Background: In the SCHOLAR-1 study, the largest published retrospective analysis of outcomes in patients with refractory large B-cell lymphoma (LBCL), the objective response rate (ORR) was 26% and complete response (CR) rate was 7% with available salvage therapies in the pre-chimeric antigen receptor (CAR) T cell therapy era (Crump et al. Blood. 2017). These results served as a benchmark for assessing novel therapies. ZUMA-1 (NCT02348216) is the pivotal, multicenter, single-arm Phase 1/2 study evaluating axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 CAR T cell therapy, in patients with refractory LBCL that supported the approval of axi-cel in the United States and Europe. At a median follow-up of 27.1 months, the ORR in ZUMA-1 was 83% and the CR rate was 58% (Locke et al. Lancet Oncol. 2019). Here, we describe comparative analyses of outcomes in ZUMA-1 and SCHOLAR-1 after adjusting for potential imbalances in refractory status between the 2 studies. Methods: Patients in both studies had refractory LBCL defined as stable disease of ≤ 6 months with ≥ 4 cycles of frontline or ≥ 2 cycles of later-line therapy, progressive disease as best response, or relapse ≤ 12 months post autologous stem cell transplant (SCT). To address potential imbalances between studies in refractory status which could affect response and survival outcomes, standardized analyses were performed which equally weighted the proportions of patients by refractory categorization (primary refractory, refractory to ≥ second-line therapy, or relapse after SCT) and presence of post-refractory SCT in each study. Stratified Cochran-Mantel-Haenszel (CMH) tests and Cox models were used to compare the odds ratio for response and hazard ratio (HR) for survival between ZUMA-1 and SCHOLAR-1. P values were descriptive and were not adjusted for multiplicity. Results: Axi-cel was administered to 101 patients in the pivotal Phase 2 portion of ZUMA-1. In the SCHOLAR-1 analysis, 508 patients were evaluable for response and 497 were evaluable for survival. The median follow-up in ZUMA-1 was 2.3 years, and the median follow-up from the overall SCHOLAR-1 study ranged from 7.6 to 14.8 years across different cohorts. In general, ZUMA-1 patients were more heavily pretreated with more patients receiving ≥ 3 lines of therapy as compared with SCHOLAR-1 (69% vs 23%). ZUMA-1 also had more patients who were refractory to second- or later-line therapy compared with SCHOLAR-1 (76% vs 62%). Fewer patients in ZUMA-1, however, were classified as primary refractory vs those in SCHOLAR-1 (26% vs 45%), and a similar proportion of patients between studies relapsed within 1 year of SCT (21% vs 18%). After standardization, the ORR and CR rate in ZUMA-1 vs SCHOLAR-1 were 72% and 54% vs 22% and 7%, respectively. The odds ratios for ORR and CR rate were 7.2-fold and 11.5-fold higher, respectively in ZUMA-1 vs SCHOLAR-1 (CMH test; P < .0001 for both ORR and CR rate). The 2-year survival rate after standardization was 50% (95% CI, 40% - 59%) in ZUMA-1 and 12% (95% CI, 9% - 15%) in SCHOLAR-1, which translated to a 73% reduction in the risk of death in ZUMA-1 relative to SCHOLAR-1 (HR, 0.27; P < .0001). Conclusions: This standardized analysis of the ZUMA-1 and SCHOLAR-1 studies indicates that treatment with axi-cel in this selected population results in 11.5-fold higher odds of CR and a 73% reduction in the risk of death compared with standard salvage regimens in an unselected population. Although limited by retrospective evaluation and cross-study comparisons, these results support the previous literature indicating that axi-cel is a highly effective treatment option for patients with refractory LBCL. Disclosures Neelapu: Pfizer: Consultancy; BMS: Research Funding; Cellectis: Research Funding; Precision Biosciences: Consultancy; Allogene: Consultancy; Acerta: Research Funding; Cell Medica: Consultancy; Celgene: Consultancy, Research Funding; Karus: Research Funding; Novartis: Consultancy; Poseida: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Incyte: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Merck: Consultancy, Research Funding. Locke:Novartis: Other: Scientific Advisor; Kite: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy. Bartlett:Genentech, Inc.: Research Funding; Gilead: Research Funding; Autolus: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Affimed: Research Funding; Immune Design: Research Funding; Incyte: Research Funding; Janssen: Research Funding; Kite Pharma: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding. Reagan:Kite, A Gilead Company: Consultancy; Curis: Consultancy; Seattle Genetics: Research Funding. Miklos:Celgene-Juno: Consultancy; Novartis: Consultancy; Adaptive Biotechnologies: Consultancy, Research Funding; Janssen: Consultancy; Miltenyi: Consultancy, Research Funding; AlloGene: Consultancy; Kite, A Gilead Company: Consultancy, Research Funding; Pharmacyclics: Consultancy, Patents & Royalties, Research Funding; Becton Dickinson: Consultancy; Precision Bioscience: Consultancy. Jacobson:Pfizer: Research Funding; Celgene: Consultancy, Other: travel support; Humanigen: Consultancy, Other: travel support; Precision Biosciences: Consultancy, Other: travel support; Bayer: Consultancy, Other: travel support; Novartis: Consultancy, Honoraria, Other: travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: travel support. Oluwole:Pfizer: Consultancy; Spectrum: Consultancy; Gilead Sciences: Consultancy; Bayer: Consultancy. Siddiqi:BeiGene: Research Funding; Celgene: Research Funding; TG Therapeutics: Research Funding; Kite, A Gilead Company: Research Funding; Seattle Genetics: Speakers Bureau; Janssen: Speakers Bureau; Juno Therapeutics: Consultancy, Other: travel support, Research Funding; PCYC: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau. Crump:Kite/Gilead: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Servier: Consultancy. Kuruvilla:Seattle Genetics: Honoraria; Roche: Honoraria; Novartis: Honoraria; Merck: Honoraria; Karyopharm: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Celgene: Honoraria; BMS: Honoraria; Astra Zeneca: Honoraria; Amgen: Honoraria; Seattle Genetics: Consultancy; Roche: Consultancy; Merck: Consultancy; Karyopharm: Consultancy; Gilead: Consultancy; Abbvie: Consultancy; BMS: Consultancy; Janssen: Research Funding; Roche: Research Funding. Van Den Neste:Gilead: Other: travel support. Farooq:Celgene: Honoraria; Kite Pharma: Research Funding. Navale:Kite, A Gilead Company: Employment, Equity Ownership; Gilead: Equity Ownership; Allogene: Equity Ownership; Cellectis: Equity Ownership; Bluebird Bio: Equity Ownership; Amgen: Equity Ownership; Organesis: Equity Ownership; Jounce: Equity Ownership; Editas: Equity Ownership; Intellia: Equity Ownership. DePuy:Kite, A Gilead Company: Consultancy, Other: travel support. Kim:Kite, A Gilead Company: Employment.

Abstract Introduction: Genetic alterations at 9p24.1 resulting in overexpression of programmed death-1 (PD-1) ligands are near-universal in cHL (Roemer et al, J Clin Oncol 2016); cHL may thus be uniquely sensitive to PD-1 blockade. Nivolumab (nivo), an anti-PD-1 monoclonal antibody, was associated with an objective response rate (ORR) of 69% in relapsed/refractory (R/R) cHL after auto-HCT and irrespective of prior brentuximab vedotin (BV) in the phase 2 CheckMate 205 study (Armand et al, J Clin Oncol 2018; NCT02181738). Whether some patient (pts) can derive very long clinical benefit, whether depth of response predicts long-term outcome, whether treatment (Tx) can be interrupted in complete remission (CR), and whether the safety profile of nivo in R/R cHL changes with prolonged Tx all remain unclear. We therefore present an updated analysis of CheckMate 205, focusing on long-term efficacy and safety. Methods: This international, single-arm, multi-cohort study enrolled pts aged ≥18 y with R/R cHL after auto-HCT. Pts were BV naïve (Cohort A), had prior BV failure after auto-HCT (Cohort B), or had received BV before and/or after auto-HCT (Cohort C). Pts received nivo 3 mg/kg every 2 wk until disease progression (PD)/unacceptable toxicity. Pts in Cohort C discontinued nivo after 1 y in CR and could resume if they relapsed within 2 y of the last dose. Primary endpoint was ORR per independent radiology review committee (IRC); additional endpoints included duration of response (DOR) per IRC, progression-free survival (PFS) per IRC, overall survival (OS), and safety. Time to next Tx (TTNT: time from first dose to next systemic Tx or death) was an exploratory post-hoc analysis. Responses were assessed using International Working Group 2007 criteria. Results: In total, 243 pts were enrolled to Cohorts A (n=63), B (n=80), and C (n=100). Baseline characteristics have been previously described (Armand et al, J Clin Oncol 2018). At data cut-off, minimum follow-up was 31 mo and 49 pts (20%) were still on Tx; the most common reason for discontinuation was PD (35%). Median duration of Tx was 14 mo. ORR per IRC was 71% (65%, 71%, 75% in Cohorts A, B, C, respectively) with a best overall response (BOR) of CR in 21% (32%, 14%, 20% in Cohorts A, B, C, respectively). Among 51 pts who achieved CR, 20 had CR as the first response and 31 improved from partial remission (PR), mostly (n=28/31) within 1 year of first PR. Median time to response was 2 mo, and to CR was 4 mo. Within the first 6, 12, and 18 mo, 68%, 71%, and 71% of pts, respectively, achieved a response. Median DOR was 18 mo overall, and was 32 and 13 mo in pts with a BOR of CR and PR, respectively. Among responders, 64%, 44%, 31%, and 21% of pts had a DOR of at least 6, 12, 18, and 24 mo, respectively. Overall, 11 pts in Cohort C discontinued with persistent investigator-assessed CR; 2 reinitiated nivo due to PD. Median (95% CI) PFS per IRC among all pts was 15 (11-19) mo (Figure A), and was 17, 12 and 15 mo in Cohorts A, B, and C, respectively. Median OS was not reached in any cohort; 24-mo OS rates were 90%, 86%, and 86% in Cohorts A, B, and C, respectively, and were similar among pts in CR, PR, or with stable disease (SD; Figure B). Median TTNT was 29, 27, and 20 mo in Cohorts A, B, and C, respectively. The most common Tx-related adverse events (AEs) of any grade (G) were fatigue (24%), diarrhea (16%), and rash (12%), each <1% G3-4. Tx-related infections were reported in 15% of pts, 2% G3-4. Tx-related infusion related reactions were reported in 34 pts (14%), <1% G3-4. The most commonly reported immune-mediated AE category was rash, which was G3-4 in 4 pts (2%). In total, 26 pts (11%) experienced an AE of any cause leading to discontinuation. There were no Tx-related deaths. Conclusions: With the longest phase 2-3 study follow-up of a checkpoint inhibitor in R/R cHL to date, nivo was associated with frequent and durable responses regardless of BV Tx history. More than 1 in 5 responders remained in response ≥2 years later. With extended follow-up, additional pts achieved CR in all cohorts. Pts with CR had longer PFS than pts with PR or SD. However, pts with both PR and SD had prolonged OS, unlike pts with PD, which may suggest that clinical benefit duration is not well predicted by conventional response criteria. Nivo continued to be well tolerated, with no new safety signals. Characteristics of long-term responders will be presented. Study support: BMS. Medical writing: A Gill, Caudex, funded by BMS Figure. Figure. Disclosures Armand: Infinity: Consultancy; Affimed: Consultancy, Research Funding; Pfizer: Consultancy; Otsuka: Research Funding; Adaptive: Research Funding; Merck: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Roche: Research Funding; Tensha: Research Funding. Younes:Celgene: Honoraria; Genentech: Research Funding; Janssen: Honoraria, Research Funding; Bayer: Honoraria; Novartis: Research Funding; J&J: Research Funding; Astra Zeneca: Research Funding; BMS: Honoraria, Research Funding; Merck: Honoraria; Abbvie: Honoraria; Takeda: Honoraria; Seattle Genetics: Honoraria; Roche: Honoraria, Research Funding; Sanofi: Honoraria; Incyte: Honoraria; Curis: Research Funding; Pharmacyclics: Research Funding. Zinzani:PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Honoraria, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Collins:ADC Therapeutics: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Speakers Bureau; Celleron: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau; Celgene Corporation: Research Funding; BMS: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria; Amgen: Research Funding. Ramchandren:Merck: Research Funding; Bristol-Myers Squibb: Consultancy; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Cohen:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioInvent: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Takeda: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees. De Boer:Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees; EISA: Membership on an entity's Board of Directors or advisory committees. Kuruvilla:Lundbeck: Honoraria; Gilead: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Princess Margaret Cancer Foundation: Research Funding; Leukemia and Lymphoma Society Canada: Research Funding; Abbvie: Consultancy; Merck: Consultancy, Honoraria; Karyopharm: Honoraria; Roche: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Amgen: Honoraria; Celgene: Honoraria. Trněný:F. Hoffman-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board, Research Funding; Sandoz: Honoraria; Gilead: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Abbvie: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Morphosys: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board. Shipp:Merck: Research Funding; Bayer: Research Funding; AstraZeneca: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sacchi:Bristol-Myers Squibb: Employment, Equity Ownership. Sumbul:Bristol-Myers Squibb: Employment. Ansell:Trillium: Research Funding; Pfizer: Research Funding; Regeneron: Research Funding; Celldex: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Merck & Co: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Takeda: Research Funding.

Abstract Background: The pivotal phase 3 ECHELON-1 study demonstrated superior efficacy of brentuximab vedotin plus doxorubicin, vinblastine and dacarbazine (A+AVD) versus doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) in patients with previously untreated advanced stage classical Hodgkin lymphoma (cHL) with a 2-year modified progression-free survival (mPFS) of 82.1% in the A+AVD group versus 77.2% in the ABVD group (Hazard Ratio=0.77; 95% confidence interval [CI] 0.60, 0.98; p=0.04). PN is a known toxicity associated with anti-mitotic agents, including vinblastine and the MMAE component of brentuximab vedotin. In the ECHELON-1 study, the incidence of any-grade PN events was 67% (442 of 662 patients) and 43% (286 of 659 patients) in the A+AVD and ABVD arms, respectively; the incidence of grade ≥3 PN was 11% and 2%, respectively. At the time of the initial analysis, 67% of A+AVD-treated patients had either resolution (43%) or improvement (24%) of PN events. A total of the 92% of ongoing PN events were grade 1 (64%) or grade 2 (29%). Here, we report rates of PN resolution and improvement in patients participating in the ECHELON-1 study after long-term follow-up. Methods: Patients with Stage III or IV cHL were randomized 1:1 to receive up to six cycles of A+AVD (n=664) or ABVD (n=670). Pre-existing PN was an exclusion factor at study entry. Peripheral neuropathy was determined on the basis of a standardized MedDRA query; patients who developed PN were monitored throughout the study and those with ongoing PN at end of treatment were followed for resolution or improvement during the post-treatment follow-up period; follow-up visits were scheduled for every 12 weeks ±1 week until 36 months, then every 6 months until study closure. PN resolution was defined as completely resolved and improvement was defined as improved by ≥1 grade from worst grade as of the latest assessment. Results: At the time of the primary analysis, 51% (226/442) and 61% (174/286) of patients in the A+AVD and ABVD arms, respectively, had resolution or improvement of PN events at EOT. Upon continued follow-up (~10 additional months) for approximately 30 months (range 0-78.5) after end of treatment, 76% (335/442) of patients with PN in the A+AVD arm had either complete resolution (59%, 260/442) or improvement (17%, 75/442) of their PN events compared with 82% (234/286) with either resolution (72%) or improvement (10%) in the ABVD arm. In the A+AVD arm, 90% of ongoing PN cases (n=182) were grade 1/2; grade 1=58% (n=106), grade 2=32% (n=58). Residual grade 3 PN was reported in 9% (n=17) of patients (1 patient with grade 4 PN died before resolution). In the ABVD arm, residual PN (n=81) was grade 1 (65%; n=53), grade 2 (30%; n=24), and grade 3 (5%; n=4). For the subset of patients with PN that had not resolved by end of treatment, the median time to resolution of all PN events from AE start date was 28 weeks for A+AVD and 14 weeks for ABVD, the median time to improvement of PN was 39 weeks for A+AVD and 18.5 weeks for ABVD. Conclusions: After approximately 2.5 years of continued follow-up, PN continues to resolve and improve for patients who were treated with A+AVD or ABVD in the ECHELON-1 study. In both study arms, the majority of ongoing PN cases are grade 1 or grade 2. Further follow-up is ongoing. Disclosures Radford: Celgene: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Speakers Bureau; GlaxoSmithKline: Equity Ownership; Takeda: Consultancy, Research Funding, Speakers Bureau; Pfizer: Research Funding; BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; AstraZeneca: Equity Ownership. Connors:Takeda: Research Funding; Seattle Genetics: Honoraria, Research Funding; Roche Canada: Research Funding; Genentech: Research Funding; Cephalon: Research Funding; Bristol Myers-Squibb: Research Funding; Janssen: Research Funding; Bayer Healthcare: Research Funding; NanoString Technologies: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding; Merck: Research Funding; F Hoffmann-La Roche: Research Funding; Amgen: Research Funding; Lilly: Research Funding. Younes:Astra Zeneca: Research Funding; J&J: Research Funding; Curis: Research Funding; BMS: Honoraria, Research Funding; Bayer: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Merck: Honoraria; Seattle Genetics: Honoraria; Celgene: Honoraria; Incyte: Honoraria; Abbvie: Honoraria; Novartis: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding. Gallamini:Takeda: Consultancy, Speakers Bureau. Ansell:Affimed: Research Funding; Merck & Co: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Bristol-Myers Squibb: Research Funding; Celldex: Research Funding; Seattle Genetics: Research Funding. Gopal:Aptevo: Consultancy; Janssen: Consultancy, Research Funding; Merck: Research Funding; Gilead: Consultancy, Research Funding; Brim: Consultancy; Spectrum: Research Funding; Takeda: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Seattle Genetics: Consultancy, Research Funding; Incyte: Consultancy; Teva: Research Funding; Asana: Consultancy. Flinn:Trillium: Research Funding; Calithera: Research Funding; Forma: Research Funding; Portola: Research Funding; Verastem: Research Funding; Janssen: Research Funding; Infinity: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Constellation: Research Funding; Merck: Research Funding; Curis: Research Funding; Takeda: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Incyte: Research Funding; ArQule: Research Funding; Verastem: Consultancy, Research Funding; Celgene: Research Funding; Agios: Research Funding; Novartis: Research Funding; Gilead: Research Funding; Pfizer: Research Funding; TG Therapeutics: Research Funding; Kite: Research Funding; BeiGene: Research Funding. Pettengell:CTI: Honoraria; Pfizer: Honoraria; Roche: Honoraria; Servier: Honoraria; Takeda: Honoraria. Dlugosz-Danecka:Servier: Consultancy; Roche: Consultancy. Engley:Seattle Genetics: Employment. Fenton:Seattle Genetics, Inc.: Employment, Equity Ownership. Liu:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Purevjal:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Miao:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Gautam:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Kuruvilla:Janssen: Consultancy, Honoraria, Research Funding; Princess Margaret Cancer Foundation: Research Funding; BMS: Consultancy, Honoraria; Abbvie: Consultancy; Karyopharm: Honoraria; Celgene: Honoraria; Seattle Genetics: Consultancy, Honoraria; Lundbeck: Honoraria; Merck: Consultancy, Honoraria; Amgen: Honoraria; Roche: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria; Leukemia and Lymphoma Society Canada: Research Funding.

Abstract Introduction:The prognosis is poor for patients with follicular lymphoma (FL) who experience early relapse within 2 years of initial diagnosis and for those who are double refractory to both rituximab and chemotherapy (Casulo et al. J Clin Oncol 2015). Avadomide, a cereblon-modulating agent that promotes degradation of the hematopoietic transcription factors Aiolos and Ikaros, is being examined in this setting. Avadomide demonstrated promising clinical activity in combination with obinutuzumab or rituximab in relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and FL (Michot et al. Blood 2017; Ribrag et al. Blood 2017). Herein, we report FL subgroup analyses for the avadomide plus rituximab combination (Arm D) of the CC-122 DLBCL-001 study in both lenalidomide-naïve and treated patients. Methods: CC-122-DLBCL-001 (NCT02031419) is aphase Ib dose escalation/expansion study of avadomide, CC-223, and CC-292 given orally as doublets, and as triplets in combination with rituximab, as well as avadomide plus rituximab doublets, in patients with R/R DLBCL or FL after ≥1 prior line of therapy. In the dose expansion phase of the study, patients received avadomide once daily (QD) for 5 days/week (5/7 d), with a fixed dose of intravenous rituximab 375 mg/m2/cycle (28-day cycle). The study endpoints were safety, tolerability, pharmacokinetics, preliminary efficacy (overall response rate [ORR] and complete response [CR]), and blood pharmacodynamic markers of avadomide. Results: As of May 1, 2018, 37 patients with FL were enrolled in the Arm D expansion group, including 29 in cohort 1 (no prior lenalidomide) and 8 in cohort 2 (≥2 cycles of prior lenalidomide). Baseline patient characteristics were similar between the two cohorts. In the total FL population, the median age was 61 years (range, 41-81 years), 54% were male, and 46% had an Eastern Cooperative Oncology Group performance status of 1. The median number of prior systemic anticancer regimens was 3 (range, 1-8). At disease diagnosis, three patients (8%) had bulky disease (≥7 cm in single dimension) and 7 (19%) had high Follicular Lymphoma International Prognostic Index scores. Twenty-three patients (62%) were refractory to rituximab and 11 (30%) were double-refractory to rituximab and an alkylating agent. As of the data cutoff, 27 patients (71%) were ongoing and no evaluable patients had experienced a dose-limiting toxicity. The most common (≥10%) any-grade adverse events (AEs) were neutropenia (46%) and anemia (24%). Grade 3/4 AEs occurring in >1 patient were neutropenia (32%); fatigue, dizziness, and anemia (8% each); febrile neutropenia and diarrhea (5% each). Six patients (16%) experienced serious AEs related to study drugs. One patient died during the study (sepsis considered possibly related to study treatment). Avadomide dose reduction occurred in 7 (19%) patients. Among all FL patients, the ORR was 65% with 8 patients (22%) achieving a CR. Response rates appeared to be independent of prior lenalidomide treatment, with an ORR of 62% (CR=14%) in cohort 1 and an ORR of 75% (CR=50%) in cohort 2. The median follow up for progression-free survival (PFS) was 6.3 months and 49% of patients had <6 months of PFS follow up. In the total FL population, 6-month and 12-month PFS rates were 83 (95% CI, 64-93) and 66 (37-84), respectively. Conclusions: Avadomide combined with rituximab was well tolerated. AEs were generally consistent with the known safety profile of avadomide and toxicities associated with rituximab. Moreover, this combination showed promising efficacy in patients with R/R FL independent of prior treatment with lenalidomide. These findings support the role of avadomide plus an anti-CD20 antibody as a novel chemotherapy-free treatment for this difficult to treat patient population. Disclosures Nastoupil: TG Therappeutics: Research Funding; Karus: Research Funding; Novartis: Honoraria; Merck: Honoraria, Research Funding; Juno: Honoraria; Celgene: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Research Funding; Spectrum: Honoraria; Genentech: Honoraria, Research Funding. Ribrag:Amgen: Research Funding; Roche: Honoraria, Other: travel; epizyme: Consultancy, Honoraria; MSD: Honoraria; Infinity: Consultancy, Honoraria; NanoString Technologies: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Other: travel; Servier: Consultancy, Honoraria; pharmamar: Other: travel; Gilead: Consultancy, Honoraria; Incyte Corporation: Consultancy; argenX: Research Funding. Chavez:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Humanigen: Consultancy; Merck: Research Funding; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Speakers Bureau. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Andorsky:AstraZeneca: Consultancy; Genentech: Consultancy; Celgene: Research Funding; CTI BioPharma: Consultancy, Research Funding. Corradini:Janssen: Honoraria, Other: Lecturer; Amgen: Honoraria, Other: Advisory Board & Lecturer; Gilead: Honoraria, Other: Advisory Board & Lecturer; Celgene: Honoraria, Other: Advisory Board & Lecturer; Roche: Honoraria, Other: Advisory Board & Lecturer; Takeda: Honoraria, Other: Advisory Board & Lecturer; Sanofi: Honoraria, Other: Advisory Board & Lecturer; Novartis: Honoraria, Other: Advisory Board & Lecturer; Abbvie: Honoraria, Other: Advisory Board & Lecturer; Sandoz: Other: Advisory Board. Flinn:ArQule: Research Funding; Agios: Research Funding; TG Therapeutics: Research Funding; Calithera: Research Funding; BeiGene: Research Funding; Verastem: Consultancy, Research Funding; Janssen: Research Funding; Curis: Research Funding; Pharmacyclics: Research Funding; Incyte: Research Funding; Trillium: Research Funding; Forty Seven: Research Funding; Kite: Research Funding; Pfizer: Research Funding; Verastem: Research Funding; Novartis: Research Funding; Genentech: Research Funding; Merck: Research Funding; Portola: Research Funding; Takeda: Research Funding; Seattle Genetics: Research Funding; Constellation: Research Funding; Forma: Research Funding; Celgene: Research Funding; Gilead: Research Funding; Infinity: Research Funding. Sangha:Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Lilly: Honoraria, Membership on an entity's Board of Directors or advisory committees; Lundbeck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; BI: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Uttamsingh:Celgene Corporation: Employment, Equity Ownership. Hagner:Celgene Corporation: Employment, Equity Ownership. Gandhi:Celgene Corporation: Employment, Equity Ownership. Chen:Celgene Corporation: Employment, Equity Ownership. Hege:Mersana: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; SITC: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Employment, Equity Ownership, Patents & Royalties: multiple; Arcus Biosicences: Membership on an entity's Board of Directors or advisory committees. Pourdehnad:Celgene Corporation: Employment, Equity Ownership. Kuruvilla:Celgene: Honoraria; Roche: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria; Lundbeck: Honoraria; BMS: Consultancy, Honoraria; Abbvie: Consultancy; Merck: Consultancy, Honoraria; Amgen: Honoraria; Seattle Genetics: Consultancy, Honoraria; Karyopharm: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Princess Margaret Cancer Foundation: Research Funding; Leukemia and Lymphoma Society Canada: Research Funding.

Abstract Introduction: The phase 2 CheckMate 205 study (NCT02181738) of nivolumab (nivo) has demonstrated high objective response rates (ORRs), durable efficacy, prolonged overall survival (OS), and an acceptable safety profile in patients (pts) with relapsed/refractory classical Hodgkin lymphoma (R/R cHL) after failure of autologous hematopoietic cell transplantation (auto-HCT) irrespective of prior brentuximab vedotin (BV) treatment (Armand et al, J Clin Oncol 2018). Atypical response patterns have been observed with checkpoint inhibitors, and clinical benefits may be experienced by pts who are treated beyond progression (TBP) as defined by conventional criteria (Cheson et al, Blood 2016; Younes et al, Ann Oncol 2017). Stable reductions in tumor burden without symptoms of active disease were seen in pts TBP in CheckMate 205, suggesting that pts might continue to derive clinical benefits from nivo beyond disease progression. As TBP was an option for some pts in CheckMate 205, we report here updated outcomes of those pts. Methods: This single-arm, multicenter study enrolled pts (age ≥18 y) with R/R cHL after failure of auto-HCT into 3 cohorts (A: BV naïve; B: BV after auto-HCT; C: BV before and/or after auto-HCT). Nivo was administered at 3 mg/kg IV every 2 wk until disease progression or unacceptable toxicity (or after 1 year in complete response [CR] for cohort C). Response was assessed by 2007 International Working Group (IWG) criteria. A protocol amendment allowed pts with stable performance status and perceived clinical benefit to be TBP per investigator assessment. Tumor burden after initial progression was assessed; exploratory analyses included OS and time to next therapy (TTNT). Pts TBP were further categorized as PD-1 resistant (failure to achieve CR/partial response [PR] during initial treatment with nivo or CR/PR with subsequent progressive disease [PD] ≤90 d of response) and non-resistant pts (CR/PR followed by PD >90 d from response). Results: At data cutoff, 130 pts had PD, among whom 80 (62%) were TBP, and 50 (38%) were not (non-TBP). Demographics of pts TBP and non-TBP were similar to the overall study population, although more pts TBP had ECOG performance status of 0 at baseline (59% vs 36%) and stage IV disease at diagnosis (30% vs 22%), but fewer had B symptoms at baseline (23% vs 30%). In pts TBP vs non-TBP, the cause of initial progression was new lesions in 50 (63%) vs 23 (46%), increased total tumor burden in 17 (21%) vs 11 (22%), and non-target lesion progression in 19 (24%) vs 4 (8%) (pts could have multiple reasons for progression). ORR prior to progression was similar between TBP (54%) and non-TBP (64%) pts. At data cutoff, the median (range) doses of nivo given beyond progression was 11 (1-64) and median TBP duration was 5 (95% CI: 3, 7) mo. Nine (11%) pts TBP remained on treatment compared with 2 (4%) non-TBP. The most common reason for discontinuation was further disease progression in 55 (69%) and 28 (56%) pts TBP and non-TBP, respectively. The majority of pts TBP (37/67 evaluable pts) had stable or reduced target lesion tumor burden and most had sustained further reduction compared with the burden presented at the time of disease progression (Figure). There was no discernible difference in the response to TBP between PD-1 resistant vs non-resistant pts. Median OS for pts TBP was not reached; 1- and 2-yr OS (95% CI) was 94% (85, 97) and 87% (77, 93), respectively. Median TTNT was 20 (95% CI: 14, 24) mo for all pts TBP. Treatment-related adverse events (TRAEs) occurred in 50% of pts after progression vs 68% prior to progression. The most common TRAEs reported after progression were fatigue (8%) and increased lipase (6%). Treatment-related serious AEs after progression were reported in 2 (3%) pts: aspartate aminotransferase increase (n=1) and hypercalcemia (n=1). No deaths occurred in pts TBP. Conclusions: Among pts treated beyond investigator-assessed progression, most commonly due to development of new lesions, continued reductions in tumor burden were observed in a majority with further nivo treatment irrespective of prior PD-1 resistance status. Nivo continued to be well tolerated during TBP with no new safety signals. Pts who have stable performance status despite progression according to conventional criteria may derive continued clinical benefit from TBP. Future work will focus on identifying subsets of pts TBP who may benefit the most from continued nivo treatment. Study support: BMS. Disclosures Cohen: Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioInvent: Consultancy; Bristol-Myers Squibb: Research Funding; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kuruvilla:Leukemia and Lymphoma Society Canada: Research Funding; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Princess Margaret Cancer Foundation: Research Funding; Seattle Genetics: Consultancy, Honoraria; Lundbeck: Honoraria; Gilead: Consultancy, Honoraria; Celgene: Honoraria; Amgen: Honoraria; Karyopharm: Honoraria; Roche: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy; Merck: Consultancy, Honoraria. Ansell:Celldex: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; LAM Therapeutics: Research Funding; Merck & Co: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding. Younes:Abbvie: Honoraria; J&J: Research Funding; Roche: Honoraria, Research Funding; Merck: Honoraria; Curis: Research Funding; Janssen: Honoraria, Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Takeda: Honoraria; BMS: Honoraria, Research Funding; Seattle Genetics: Honoraria; Sanofi: Honoraria; Bayer: Honoraria; Celgene: Honoraria; Astra Zeneca: Research Funding; Incyte: Honoraria; Genentech: Research Funding. Trněný:Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; F. Hoffman-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board, Research Funding; Gilead: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Morphosys: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Sandoz: Honoraria; Abbvie: Honoraria, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board. Ramchandren:Bristol-Myers Squibb: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Collins:BMS: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria; Celgene Corporation: Research Funding; Amgen: Research Funding; Takeda: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Speakers Bureau; Celleron: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau. Zinzani:Astra Zeneca: Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees. De Boer:EISA: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding. Shipp:Merck: Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria; Bayer: Research Funding. Sacchi:Bristol-Myers Squibb: Employment, Equity Ownership. Sy:Bristol-Myers Squibb: Employment. Armand:Otsuka: Research Funding; Affimed: Consultancy, Research Funding; Infinity: Consultancy; Pfizer: Consultancy; Merck: Consultancy, Research Funding; Adaptive: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Roche: Research Funding; Tensha: Research Funding.

Abstract Classical Hodgkin lymphomas (cHLs) include infrequent malignant Hodgkin Reed-Sternberg (HRS) cells within an extensive but ineffective inflammatory/immune cell infiltrate. HRS cells exhibit frequent copy number alterations (CNAs) of 9p24.1/CD274 (PD-L1)/PDCD1LG2(PD-L2), ranging from low-level polysomy to relative copy gain and high-level amplification, all associated with increased expression of programmed death receptor-1 (PD-1) ligands on the tumor cell. PD-1 ligands engage the PD-1 receptor on T cells, inhibiting T cell activation and anti-tumor immune responses. cHL patients (pts) with the highest-level 9p24.1 alterations, PD-L1/PD-L2 amplification, have inferior progression-free survival (PFS) after standard primary chemotherapy (Roemer et al. J Clin Oncol 2016). Given the demonstrated responsiveness of cHL to PD-1 blockade, we examined the prevalence and type of 9p24.1 genetic alterations, PD-L1 expression, and association of these alterations with clinical outcome in pts receiving nivolumab (nivo; anti-PD-1) for relapsed/refractory (R/R) cHL. CheckMate205 is a multicenter, multicohort, phase 2 trial of nivo in R/R cHL. This analysis focused on 2 cohorts: pts with recurrent cHL following autologous stem cell transplantation (ASCT) and subsequent brentuximab vedotin (BV) (cohort B), and pts with R/R cHL following ASCT and BV given pre- or post-ASCT (cohort C). Pts received nivo 3 mg/kg every 2 weeks. Best overall response (BOR) and PFS were assessed by an independent radiological review committee (IRRC). In pts with available tumor biopsies, 9p24.1 genetic alterations were evaluated via fluorescence in situ hybridization (FISH) assay; probes encompassed CD274 (PD-L1, red) or PDCD1LG2 (PD-L2, green)and included a centromeric control (aqua).Dual immunohistochemical staining of PD-L1/PAX5 was performed to delineate PD-L1 expression in PAX5dim+ HRS cells and PAX5- cells in the tumor microenvironment. A modified PD-L1 H-score (range 0-300) was calculated by multiplying the percentage of PAX5+ (malignant) or PAX5- (non-malignant) cells with positive staining (0-100%) and the average intensity of positive staining (1-3+; ≥50 RS cells counted). All p-values are nominal. 96 pts had evaluable baseline tumor biopsy specimens; all 96 had detectable 9p24.1 alterations: polysomy in 10/96 (10%), copy gain in 56/96 (58%), amplification in 28/96 (29%), and presumptive rearrangement (split-apart FISH signal) in 2/96 (2%) (Figure). There was a significant association between PD-L1 protein expression (H-score) and the level of 9p24.1 alterations in HRS cells (p=0.002) (Figure). We next evaluated the association between BOR and defined 9p24.1 alterations and PD-L1 H-scores. The level of 9p24.1 CNAs was significantly associated with BOR (p=0.01); no pts with progressive disease (PD) had genomic amplification and no pts with complete response (CR) had polysomy. Similarly, there was significant association between PD-L1 H-score in HRS cells and BOR (p=0.02); all pts with PD had PD-L1 H-scores in quartiles (Q) 1/2, whereas most pts with CR had PD-L1 H-scores in Q4. We also assessed the association of PFS with 9p24.1 status and PD-L1 H-scores. The level of 9p24.1 alterations was associated with PFS; pts with 9p24.1 amplification had the most favorable PFS with nivo. HRS cell PD-L1 H-score (by quartiles) was also significantly associated with PFS (p=0.048), as pts with PD-L1 H-scores in Q1/Q2 had significantly shorter PFS than those with scores in Q3/Q4 (p=0.01). In contrast, there was no association between PD-L1 expression on non-malignant cells in the tumor microenvironment and PFS (p=0.43). In conclusion, all evaluable pts in this study had genetic alterations of 9p24.1/PD-L1/PD-L2 and copy number-dependent increased expression of PD-L1 in HRS cells. Although high-level alterations of 9p24.1 and increased PD-L1 expression were previously linked with inferior response to standard primary chemotherapy, we now associate these parameters with more favorable outcomes to targeted PD-1 blockade. These analyses also highlight the importance of quantifying and delineating PD-L1 expression in HRS cells and non-malignant cells in the tumor microenvironment in cHL biopsy evaluation. While further research is needed to guide possible use in clinical practice, these data advance understanding of 9p24.1 alterations and PD-L1 expression as prognostic biomarkers in cHL. Disclosures Engert: Takeda, BMS: Consultancy, Honoraria, Research Funding. Zinzani:Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celegene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Timmerman:Bristol-Myers Squibb, Kite Pharma, Valor Biopharmaceuticals, Janssen: Research Funding; Seattle Genetics, Genmab, Celgene: Consultancy, Honoraria. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Armand:Bristol-Myers Squibb: Consultancy, Research Funding; Pfizer: Research Funding; Sequenta Inc: Research Funding; Roche: Research Funding; Merck: Consultancy, Research Funding; Infinity Pharmaceuticals: Consultancy. Kuruvilla:BMS: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Amgen: Honoraria; Celgene: Consultancy, Honoraria; Merck: Honoraria; Roche Canada: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Lundbeck: Honoraria. Cohen:Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Collins:Takeda: Consultancy, Honoraria, Speakers Bureau. Trneny:Roche, Celgene, Takeda, Janssen, Gilead, Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche, Celgene: Research Funding. Farsaci:Bristol-Myers Squibb: Employment. Kato:Bristol-Myers Squibb: Employment. Sumbul:Bristol-Myers Squibb: Employment. Rodig:Bristol-Myers Squibb: Honoraria, Research Funding; Perkin Elmer: Membership on an entity's Board of Directors or advisory committees. Shipp:Bayer: Research Funding; Merck, Gilead, Takeda: Other: Scientific Advisory Board; Cell Signaling: Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding.

Abstract Background: Bruton’s tyrosine kinase (BTK) is an essential component of the B-cell receptor signaling pathway, a pathway critical to the survival and proliferation of malignant B cells. Ibrutinib, a small molecule inhibitor of BTK, has shown significant activity in several B-cell malignancies and is currently FDA approved for the treatment of patients (pts) with CLL or mantle cell lymphoma who have received at least one prior treatment.In a Phase 1 dose-escalation study, ibrutinib induced a response in 6 (38%) of 16 patients (pts) with relapsed/refractory FL and 6/11 (54%) of pts treated at doses ≥ 2.5 mg/kg (Advani JCO 2013, Fowler ASH abstr 156:2012). 560 mg daily was identified as a well-tolerated dose in lymphoma resulting in full-target occupancy. On the basis of these results, the Mayo Clinic and Princess Margaret P2Cs conducted a CTEP-sponsored Phase 2 trial of single-agent ibrutinib in relapsed/refractory FL (NCI 9271). Methods: Eligible pts had relapsed or refractory FL (Gr 1, 2, or 3a) that had progressed during or after 1 or more prior chemotherapy regimens. Therapy consisted of ibrutinib, 560 mg daily, until progression or unacceptable toxicity. Response was assessed by CT at 8 weeks and then every 12 weeks. All pts were required to have an on-study biopsy and a second biopsy at progression after response with fresh tissue collected for correlative studies. The primary endpoint was overall response rate (ORR) and secondary endpoints were safety and tolerability, overall survival, time to response, time to treatment failure, duration of response, and progression-free survival (PFS). Planned exploratory correlative studies included C1D8 and C3D1 FDG-PET response evaluation in a subset of 20 patients, and whole-transcriptome sequencing for correlation of mutations with response and resistance. Results: 40 patients (38 evaluable for response) were accrued from April 2013 to April 2014. Median age was 64 years (range 46-82), 70% were men, 55% had FLIPI ≥ 3, median number of prior regimens was 3 (range 1-11), 20% had a prior stem cell transplant, 45% were rituximab refractory, and 36% were refractory to their most recent treatment. At a median follow-up of 6.5 months (mo) (range 1.8-14.6+), the ORR for the 40 intention-to-treat pts is 30% (95% CI: 17-47%) with 1 CR and 11 PRs by CT criteria (4/12 responders had a negative restaging PET/CT). 26 (65%) patients have exhibited tumor size reduction. Only 2/18 (11%) pts with rituximab-refractory disease responded, compared to 8/19 (42%) pts with rituximab-sensitive disease (P=0.06) and 2/3 who were rituximab-naïve. There was no correlation between response and number of prior regimens. Median time to response was 2.4 mo (range 1.8-12.9 mo). Median PFS is 9.9 mo (95% CI: 6 mo, not reached). One of 12 responders has progressed after 9.9 mo on treatment. Median treatment duration was 5 mo (range 1-15+ mo). Dose delays (2 pts) and reductions were infrequent (4 pts). 17 pts have discontinued treatment due to PD (12), refusal (2), AEs (2), and death (1). Gr 3-4 AEs occurred in 30% of pts, including the following AEs in more than 1 pt: anemia (2), neutropenia (3), and infection (2). 3 pts have died (1 PD, 1 pneumonia, 1 gastric hemorrhage). Of the 20 pts with C1D8 PET scans, 19 also had C3D1 PET scans and were evaluable for response. Six of these 19 pts had objective responses by CT criteria at week 8 or beyond. Of the 6 responders, C1D8 PET/CT showed qualitative (visual) improvement in 3 pts, no visual change in 1 pt, and qualitative worsening in 2 pts. On the C3D1 PET/CT, 4 of 6 had qualitative improvement and 2 had no change. Evaluation of quantitative PET data including SUVs and total lesion glycolysis is ongoing and will be presented. Conclusions: Single agent ibrutinib is well tolerated with a modest ORR in relapsed/refractory FL at this early assessment. Continued follow-up is warranted to capture late responders and to establish response duration. Ibrutinib appears less active in FL than in MCL and CLL. Early PET scans (C1D8) do not reliably predict for response. Support by N01-CM-2011-00099 Disclosures Bartlett: Gilead: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Astra Zeneca: Research Funding; Janssen: Research Funding; ImaginAb: Research Funding; Genentech: Research Funding; Millennium: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Novartis: Research Funding; Medimmune: Research Funding; Celgene: Research Funding. Off Label Use: PF-05082566 for B-NHL. Kuruvilla:Janssen: Honoraria. Reeder:Millennium, Celgene, Novartis: Research Funding.

Abstract Purpose: To evaluate safety and efficacy outcomes for subjects on the ECHELON-1 study treated in North America (NA). Patients and Methods: ECHELON-1 is a global, open-label, randomized phase III study comparing doxorubicin, vinblastine, and dacarbazine in combination with brentuximab vedotin (A+AVD) versus ABVD (AVD + bleomycin) as first-line therapy in subjects with stage III or IV classical Hodgkin lymphoma (cHL; NCT01712490). Subjects were randomized 1:1 to receive A+AVD or ABVD intravenously on days 1 and 15 of each 28-day cycle for up to 6 cycles. Results: The NA subgroup consisted of 497 subjects in the A+AVD (n = 250) and ABVD (n = 247) arms. Similar to the primary analysis based on the intent-to-treat population, the primary endpoint [modified progression-free survival (PFS) per independent review] demonstrated an improvement among subjects who received A+AVD compared with ABVD (HR = 0.60; P = 0.012). For PFS, the risk of progression or death was also reduced (HR = 0.50; P = 0.002). Subsequent anticancer therapies were lower in the A+AVD arm. Grade 3 or 4 adverse events (AEs) were more common, but there were fewer study discontinuations due to AEs in the A+AVD arm as compared with ABVD. Noted differences between arms included higher rates of febrile neutropenia (20% vs. 9%) and peripheral neuropathy (80% vs. 56%), but lower rates of pulmonary toxicity (3% vs. 10%) in subjects treated with A+AVD versus ABVD. Conclusions: The efficacy benefit and manageable toxicity profile observed in the NA subgroup of ECHELON-1 support A+AVD as a frontline treatment option for patients with stage III or IV cHL.