Nivolumab Treatment Beyond Investigator-Assessed Progression: Outcomes in Patients with Relapsed/Refractory Classical Hodgkin Lymphoma from the Phase 2 Checkmate 205 Study
Authors: Cohen Jonathon B , Engert Andreas , Ansell Stephen M , Younes Anas , Trneny Marek , Savage Kerry J , Ramchandren Radhakrishnan , Collins Graham , Fanale Michelle A. , Armand Philippe , Zinzani Pier Luigi , De Boer Jan Paul , Shipp Margaret A. , Santoro Armando , Timmerman John M , Sacchi Mariana , Sy Oumar , Kuruvilla John 
Published: April 2021

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.