Collins, Graham P.

Abstract Introduction: The phase 2 CheckMate 205 study (NCT02181738) of nivolumab (nivo) has demonstrated high objective response rates, durable efficacy, and acceptable safety profiles in patients (pts) with relapsed/refractory classical Hodgkin lymphoma (R/R cHL) after failure of autologous hematopoietic cell transplantation (auto-HCT) regardless of prior brentuximab vedotin (BV) treatment (Younes A et al. Lancet Oncol 2016; Fanale M et al. ICML 2017 [Oral 125]). Recently proposed new response criteria aim to account for atypical patterns of response with checkpoint inhibitors which may not be fully captured by conventional response criteria (Cheson BD et al. Blood 2016; Younes A et al, Ann Oncol 2017). Studies in solid tumors have shown that pts may continue to derive clinical benefits from nivo beyond disease progression as defined by conventional criteria (George S et al, JAMA Oncol 2016; Long GV et al, JAMA Oncol 2017). Here we report outcomes among pts with R/R cHL treated beyond progression (TBP) in CheckMate 205. Methods: This single-arm, multicenter study enrolled pts (age ≥18 y) with R/R cHL after failure of auto-HCT into 3 independent cohorts (A: BV naïve, B: BV after auto-HCT, C: BV before and/or after auto-HCT). Nivo 3 mg/kg IV every 2 wk was given until disease progression or unacceptable toxicity. Response was assessed by 2007 International Working Group criteria. Best overall response (BOR) was assessed per investigator. A protocol amendment in July 2014 allowed pts to be TBP (investigator-assessed) if they met prespecified criteria, including deriving clinical benefit, stable performance status, and non-rapid progression. Pts TBP were required to discontinue in the event of further progression (≥10% increase in tumor burden). Tumor burden after initial progression was assessed in a prespecified analysis. Exploratory analyses assessed overall survival (OS) and time to next therapy (TTNT) in pts TBP. Results: In total, 70/243 (29%) pts were TBP: 19 in Cohort A, 23 in B, and 28 in C. Demographics were similar to the overall study population: 57% had stage IV disease at study entry, median (range) age was 37 (18-72) y, and median number of prior therapies was 3 (2-5). BOR prior to progression was complete remission (CR) in 5 (7%) pts, partial remission (PR) in 31 (44%), stable disease (SD) in 20 (29%), and progressive disease in 13 (19%) (BOR was non-evaluable in 1 pt). Among pts TBP, the initial cause of progression was a ≥50% increase in total tumor burden in 13 (19%) pts, non-target lesion progression in 17 (24%), and new lesions in 47 (67%) (pts could have multiple findings as reasons for progression). The median time to initial progression in pts TBP was 6 mo; 11 mo in pts with initial BOR of CR and 7 mo in pts with initial PR or SD. At December 2016 database lock, median (range) doses of nivo beyond progression were 8 (1-43), and median duration of treatment beyond progression was 5 (0-19) mo. Overall, 21 (30%) pts TBP remained on treatment; the most common reason for discontinuation was further disease progression (80%). The majority of pts TBP demonstrated stable reductions in tumor burden with continued treatment. Median (95% CI) TTNT from first study dose of nivo was 17 (14, not estimable) mo (Figure). Median OS from date of initial progression was not reached in pts TBP and OS was 84% (95% CI 70, 92) at 1 y. Treatment-related adverse events (TRAEs) occurred in 46% of pts (13% grade [G] 3-4) after progression, vs 64% (9% G3-4) prior to progression. Serious TRAEs after progression were aspartate aminotransferase increase (n=1) and hypercalcemia (n=1), both G3-4. Ten deaths occurred in pts TBP; 7 were due to disease progression and none were considered related to study drug. Conclusions: In total, 29% of pts from CheckMate 205 Cohort A/B/C were TBP. New lesions were the most common reason for initial progression in pts TBP. Stable reductions in tumor burden were seen with continued treatment in pts TBP, and median TTNT and OS remained high. Proposed updates to response criteria may help to better assess the long-term efficacy of checkpoint inhibitors. These data suggest that pts considered to show stable performance status, non-rapid progression, and clinical benefits despite progression according to conventional response criteria may derive long-term benefits from continued nivo treatment. Study funding: BMS. Writing support: Simon Wigfield, Caudex, funded by BMS. Disclosures Cohen: Bioinvent: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takada: Research Funding; Bristol Myers Squibb: Research Funding; Abbvie: 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; Janssen: 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; LAM Therapeutics, Inc: Research Funding. Engert: Amgen: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Affimed: Consultancy, Honoraria, Research Funding. Ansell: Merck: Research Funding; Celldex: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding. Younes: Roche: Consultancy, Honoraria, Other: Third-party medical writing assistance, under the direction of Anas Younes, was provided by Scott Malkin of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd.; Bayer: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis: Research Funding; Janssen: Honoraria; Merck: Honoraria; Curis: Research Funding; Sanofi: Honoraria; Takeda Millenium: Honoraria; Johnson & Johnson: Research Funding; Seattle Genetics: Honoraria; Incyte: Honoraria; Celgene: Honoraria. Trneny: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Savage: Roche: Research Funding; Seattle Genetics: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria; Merck: Honoraria; Celgene: Consultancy. Ramchandren: Seattle Genetics: Consultancy; Janssen: Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding. Collins: ADC Therapeutics: Research Funding; Roche: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; Celgene: Research Funding; Celleron: Consultancy; MSD: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Research Funding; Amgen: Research Funding. Fanale: AMGEN: Membership on an entity's Board of Directors or advisory committees; CELGENE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TAKEDA: Honoraria, Research Funding; ONYX: Research Funding; SEATTLE GENETICS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MOLECULAR TEMPLATES: Research Funding; MERCK: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GENENTECH: Research Funding; ADC THERAPEUTICS: Research Funding. Armand: Bristol-Myers Squibb: Consultancy, Other: research funding (institutional); Merck: Consultancy, Other: research funding (institutional); Infinity: Consultancy; Pfizer: Consultancy, Other: research funding (institutional); Affimed: Other: research funding (institutional); Otsuka: Other: research funding (institutional); Sequenta: Other: research funding (institutional); Sigma Tau: Other: research funding (institutional); Roche: Other: research funding (institutional); Tensha: Other: research funding (institutional). Zinzani: Bayer: 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; Celgene: 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; Johnson & Johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: 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; Merck: 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. De Boer: Bristol-Myers Squibb: 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, Other: Non-restricted grant for research in head and neck cancer; Eisai: Membership on an entity's Board of Directors or advisory committees; Astellas: Other: member of Independent Data Monitoring Committee. Shipp: Cell Signaling: Honoraria; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Takeda: Other: Scientific Advisory Board; Merck: Other: Scientific Advisory Board; Gilead: Other: Scientific Advisory Board; AstraZeneca: Honoraria. Santoro: Merck: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Timmerman: Seattle Genetics: Consultancy; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Genmab: Consultancy, Equity Ownership; Kite Pharma: Research Funding; ImmuneGene: Research Funding. Sacchi: Bristol-Myers Squibb: Employment. Sy: Bristol-Myers Squibb: Employment. Kuruvilla: BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria; Janssen: Consultancy; Hoffman LaRoche: Consultancy; Seattle Genetics: Consultancy, Honoraria; Amgen: Honoraria; Roche: Honoraria; Janssen: Honoraria; Lundbeck: Honoraria; Merck: Honoraria; Karyopharm: Research Funding; Roche: Research Funding; Celgene: Honoraria, Research Funding.

Introduction: Novel approaches to treating patients (pts) with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) have improved outcomes but some pts do not respond or, despite initial response, develop progressive disease and have limited treatment options. Camidanlumab tesirine (ADCT-301; Cami) is an antibody-drug conjugate composed of a human IgG1 anti-CD25 monoclonal antibody stochastically conjugated to a potent pyrrolobenzodiazepine (PBD) dimer warhead, which triggers cell death via formation of highly cytotoxic interstrand cross-links. Data from a Phase (Ph) 1 dose-escalation, dose-expansion trial demonstrated an overall response rate (ORR) in pts with cHL of 86.5% (48.6% complete response [CR] rate) at the 45 μg/kg dose. Cami had a generally acceptable safety profile at Ph 1 but there were 5/77 cases (6.5%) of Guillain-Barré syndrome (GBS)/polyradiculopathy (Preferred Terms: 4 GBS and 1 radiculopathy) (Collins et al, ICML June 18-22, 2019, Lugano, Switzerland, Abstract 055). Here, we present preliminary efficacy and safety results of a Ph 2 trial of single-agent Cami in pts with R/R cHL (NCT04052997). Methods: A single-arm, multi-center, open-label, Ph 2 trial is currently enrolling pts ≥16 yrs (US) and ≥18 yrs (outside US) with R/R cHL following ≥3 prior treatment lines (or ≥2 lines in pts ineligible for hematopoietic stem cell transplantation). Eligible pts had prior treatment with brentuximab vedotin and PD-1 blockade, measurable disease per 2014 Lugano Classification, and Eastern Cooperative Oncology Group performance status 0-2. The primary objective is to evaluate efficacy of single-agent Cami by ORR as determined by central review. Secondary objectives include further characterization of additional efficacy endpoints and safety. Pts receive 30-min IV infusions of Cami on Day 1 of each 3-week cycle at a dose of 45 μg/kg for 2 cycles, followed by 30 μg/kg for subsequent cycles for up to 1 yr or until discontinuation due to disease progression, unacceptable toxicity, or other reasons. Pts deriving clinical benefit at 1 yr may be able to continue treatment on a case-by-case basis. Treatment-emergent adverse events (TEAEs) were defined as AEs occurring/worsening from time of first dose to either 30 days post last dose or to start of new anticancer therapy/procedure, whichever occurs first. This analysis was conducted after meeting a protocol-specified criterion for pausing enrollment (≥2 cases of GBS or other relevant severe neurologic toxicity). Results: As of June 15, 2020, 47 pts with R/R cHL were enrolled and are included in this analysis. Median age was 36 (range 23-74) yrs and pts had received a median of 7 (range 3-20) lines of prior therapy, including transplant (Table 1). Pts received a median of 5 (range 2-10; mean 4.9 [SD 1.86]) cycles of Cami. ORR was 80.9% (38/47 pts), with 18 (38.3%) and 20 (42.6%) pts attaining CR and partial response, respectively; 6 pts (12.8%) had stable disease (Figure 1). TEAEs were experienced by all 47 pts; the most common (≥20% of pts) were fatigue (22, 46.8%); nausea, pyrexia, and maculopapular rash (18, 38.3% each); anemia and headache (12, 25.5% each); pruritus (11, 23.4%); arthralgia, constipation, diarrhea, hypophosphatemia, and rash (10, 21.3% each). TEAEs thought to be PBD-associated included skin reactions and nail disorders (36, 76.6%), liver function test abnormalities (14, 29.8%), and edema or effusion (7, 14.9%). There were 3 (6.4%) pts with GBS/polyradiculopathy (Preferred Terms: grade 4 subacute inflammatory demyelinating polyneuropathy, grade 2 radiculopathy, and grade 2 peripheral motor and sensory neuropathy updated to GBS after data cut-off date). In total, 27 (57.4%) pts had grade ≥3 TEAEs; the most common (≥5% of pts) were hypophosphatemia (6, 12.8%) and gamma-glutamyltransferase increased (3, 6.4%). Overall, 3 (6.4%) pts had TEAEs leading to dose reduction/delay and 6 (12.8%) pts had TEAEs leading to treatment discontinuation. Conclusions: Current data show that therapy with Cami has encouraging anti-tumor activity in heavily pretreated pts with R/R cHL. Safety was consistent with that reported at Ph 1, with no new safety concerns identified and similar incidence of GBS/polyradiculopathy. Following a positive risk-benefit assessment, the enrollment pause was lifted, and pts continue to be enrolled. Updated efficacy and safety results will be presented at the meeting. Funding: Study funded by ADC Therapeutics SA. Disclosures Herrera: Pharmacyclics: Research Funding; Bristol Myers Squibb: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding; Merck: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Karyopharm: Consultancy; AstraZeneca: Research Funding; Immune Design: Research Funding. Carlo-Stella:Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen Oncology, AstraZeneca: Honoraria; ADC Therapeutics and Rhizen Pharmaceuticals: Research Funding; Boehringer Ingelheim and Sanofi: Consultancy; Servier, Novartis, Genenta Science srl, ADC Therapeutics, F. Hoffmann-La Roche, Karyopharm, Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Collins:Taekda: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding; Celleron: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Amgen: Research Funding; BeiGene: Consultancy; Roche: Consultancy, Honoraria, Other: travel, accommodations, expenses , Speakers Bureau. Maddocks:Morphosys: Consultancy, Honoraria; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; Seattle Genetics: Consultancy, Honoraria; ADC Therapeutics, AstraZeneca: Consultancy; Pharmacyclics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Bartlett:Autolus: Research Funding; BMS/Celgene: Research Funding; Forty Seven: Research Funding; Immune Design: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Roche/Genentech: Consultancy, Research Funding; ADC Therapeutics: Consultancy; BTG: Consultancy; Acerta: Consultancy; Affimed Therapeutics: Research Funding. Savage:BeiGene: Other: Steering Committee; Roche (institutional): Research Funding; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie: Honoraria; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie, Servier: Consultancy. Caimi:ADCT, Kite Therapeutics, Genentech, Amgen, Verastem, TG Therapeutics, Bayer: Consultancy; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genentech, ADC Therapeutics: Research Funding; Celgene: Speakers Bureau. Hess:ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS, AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zinzani:ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: 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, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cruz:ADC Therapeutics SA: Current Employment, Current equity holder in publicly-traded company. Wang:ADC Therapeutics America, inc: Current Employment, Current equity holder in publicly-traded company. Feingold:ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Wuerthner:ADC Therapeutics SA: Current Employment, Current equity holder in publicly-traded company. Ansell:Takeda: Research Funding; Bristol Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; ADC Therapeutics: Research Funding; Affimed: Research Funding; AI Therapeutics: Research Funding.

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.

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 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.