Nivolumab for Newly Diagnosed Advanced-Stage Classical Hodgkin Lymphoma (cHL): Results from the Phase 2 Checkmate 205 Study
Authors: Ramchandren Radhakrishnan , Fanale Michelle A. , Rueda Antonio , Armand Philippe , Trněný Marek , Feldman Tatyana A , Ansell Stephen M , Provencio Mariano , Jaeger Ulrich , Cohen Jonathon B , Savage Kerry J , Willenbacher Wolfgang , Sacchi Mariana , Sumbul Anne , Domingo Domenech Eva 
Published: April 2021

Abstract
Introduction: Nivolumab (nivo), an immune checkpoint inhibitor targeting the programmed death-1 (PD-1) receptor, augments T-cell activation and restores antitumor T-cell function. In the phase 2 CheckMate 205 study (NCT02181738), nivo demonstrated frequent (65-73%) and durable objective responses across 3 cohorts of patients (pts) with relapsed/refractory (R/R) cHL after failure of autologous hematopoietic cell transplantation (Fanale M et al. ICML 2017 [oral 125]). While most pts with cHL are cured with first-line therapy, those with advanced-stage disease are more likely to relapse or progress. More aggressive regimens (eg, BEACOPPesc., Borchmann P et al. Lancet Oncol 2017) are associated with improved progression-free survival (PFS) but are hampered by excessive toxicities and have limited applicability in elderly pts.PD-1 ligand gene amplification has been linked to poorer outcomes in cHL pts treated with standard induction regimens (Roemer MG et al. J Clin Oncol 2016) but is associated with improved responses to nivo in R/R cHL (Younes A et al. Lancet Oncol 2016), suggesting that PD-1 blockade may benefit pts in the frontline setting. We therefore assessed the safety and efficacy of nivo as a single-agent lead-in treatment followed by nivo in combination with chemotherapy, excluding bleomycin due to potential overlapping pulmonary toxicity, for pts with previously untreated advanced-stage cHL.
Methods: Cohort D of CheckMate 205 enrolled untreated pts (aged ≥18 y) with advanced-stage newly diagnosed cHL (stage III, IV, or II with B symptoms and extranodal or bulky disease) and ECOG score 0-1. Pts received 4 biweekly doses of nivo monotherapy (240 mg IV flat dose) followed by nivo plus chemotherapy (nivo 240 mg IV, doxorubicin, vinblastine, dacarbazine [N-AVD]) for 6 cycles (12 doses). The primary endpoint was safety and tolerability: proportion of pts with ≥1 grade (G) 3-5 treatment-related adverse event (TRAE) ≤30 d after last dose. Additional endpoints included rates of discontinuation and of independent radiologic review committee-assessed complete remission (CR).
Results: At database lock (June 2017), 51 pts had been treated, with a median (range) follow-up of 8 (1-11) mo. Median (range) age was 37 (18-87) y; 29 (57%) pts had stage IV disease, and 41 (80%) had B symptoms. At baseline, 7 (14%) pts had bulky disease and 17 (33%) had extranodal involvement. International prognostic score was ≥3 in 25 (49%) pts. At analysis, 49 (96%) pts had completed nivo monotherapy treatment, receiving all 4 doses; 1 pt discontinued due to disease progression and 1 due to study drug toxicity (G1-2 hyperthyroidism), subsequently receiving AVD only. TRAEs for both treatment phases are shown in the Table. During nivo monotherapy, 2 pts had 1 dose delay each due to an AE; 2 (4%) pts had serious AEs (SAEs; 1 G1-2 hyperthyroidism; 1 G1-2 polyneuropathy); an immune-mediated AE (IMAE), G1-2 hyperthyroidism, was reported in 2 (4%) pts. Fifty pts started combination therapy; at database lock, 35 (70%) had completed therapy, with 34 (69%) receiving 12 N-AVD doses. With N-AVD, 10 (20%) pts had SAEs, 6 G3-4; the most common G3-4 SAE was febrile neutropenia in 2 (4%) pts; IMAEs occurring in &gt;1 pt were hypothyroidism in 8 (16%) pts and increased ALT in 2 (4%). AEs leading to discontinuation of N-AVD occurred in 2 pts: G1-2 hepatic abnormality, and G3-4 febrile neutropenia (FN) and Klebsiella bacteremia. The pt who developed FN and Klebsiella bacteremia died 38 d after the first dose of his fifth cycle of N-AVD due to study drug toxicity of acute respiratory insufficiency. Important primary, secondary, and exploratory endpoints (including CR and objective response rates at end of monotherapy, after 2 combocycles and end of therapy, and PFS) will be presented at the meeting.
Conclusions: Nivo monotherapy followed by N-AVD combination therapy was well-tolerated in pts with newly diagnosed, untreated, advanced-stage cHL. Nearly all pts completed nivo monotherapy treatment and started combination therapy with N-AVD. The safety profile was consistent with historical experience of nivo and AVD separately, with no new safety signals. Nivo followed by N-AVD may provide a tolerable alternative treatment option to standard-of-care multi-agent chemotherapy for pts with newly diagnosed advanced-stage cHL.
Study support: BMS. Writing support: Matthew Thomas, PhD, Caudex, funded by BMS.

Disclosures
Ramchandren: Janssen: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy. Fanale: CELGENE: Honoraria, 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; ADC THERAPEUTICS: Research Funding; GENENTECH: Research Funding; MERCK: Membership on an entity's Board of Directors or advisory committees, Research Funding; MOLECULAR TEMPLATES: Research Funding; AMGEN: Membership on an entity's Board of Directors or advisory committees; SEATTLE GENETICS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TAKEDA: Honoraria, Research Funding; ONYX: Research Funding. Rueda: Bristol-Myers Squibb: Consultancy. Armand: Roche: Research Funding; Genmab: Consultancy; Infinity: Consultancy; Sigma Tau: Research Funding; Tensha: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Otsuka: Research Funding; Pfizer: Consultancy, Research Funding; Merck & Co., Inc.: Consultancy, Research Funding; Sequenta/Adaptive: Research Funding. Trněný: Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Feldman: Pharmacyclics: Speakers Bureau; Celgene: Speakers Bureau; Bristol-Myers Squibb: Consultancy; Kite Pharma: Speakers Bureau; Seattle Genetics: Honoraria, Research Funding, Speakers Bureau; AbbVie: Speakers Bureau; Janssen: Speakers Bureau. Ansell: Merck: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Celldex: Research Funding; Affimed: Research Funding. Jaeger: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: 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, Other: Travel, Accommodations, Expenses. Cohen: Bioinvent: Consultancy, Membership on an entity's Board of Directors or advisory committees; LAM Therapeutics, Inc: Research Funding; Abbvie: 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; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takada: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Research Funding; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees. Savage: Bristol-Myers Squibb: Honoraria; Seattle Genetics: Consultancy, Honoraria; Roche: Research Funding; Celgene: Consultancy; Merck: Honoraria. Willenbacher: Bristol-Myers Squibb: Consultancy, Honoraria. Sacchi: Bristol-Myers Squibb: Employment. Sumbul: Bristol-Myers Squibb: Employment.