Five-Year Follow-up of Keynote-087: Pembrolizumab Monotherapy in Relapsed/Refractory Classical Hodgkin Lymphoma (R/R cHL)
Authors: Armand Philippe , Zinzani Pier Luigi Luigi , Lee Hun Ju , Johnson Nathalie , Brice Pauline , Radford John , Ribrag Vincent , Molin Daniel , Vassilakopoulos Theodoros P. , Tomita Akihiro , von Tresckow Bastian , Shipp Margaret A. , Herrera Alex F. , Lin Jianxin , Kim Eunhee , Chakraborty Samhita , Marinello Patricia , Moskowitz Craig H. 
Published: November 2021

Introduction: Prognosis remains poor for patients (pts) with R/R cHL who relapse after or are ineligible for autologous stem cell transplant (ASCT). Programmed death 1 (PD-1) inhibitors are an effective therapeutic option for such pts. Previous analyses from the phase 2 KEYNOTE-087 (NCT02453594) trial demonstrated that monotherapy with the PD-1 inhibitor pembrolizumab (pembro) had effective antitumor activity and acceptable safety in pts with R/R cHL, leading to FDA approval for adult and pediatric pts with R/R cHL who relapsed after ≥3 prior lines of therapy. However, durability of response after pembro, its relationship with response depth, and safety of treatment discontinuation for pts achieving complete response (CR) remain salient clinical questions. We present efficacy and safety from KEYNOTE-087 after ~5 y of follow-up.

Methods: Pts with R/R cHL that progressed after ASCT and subsequent brentuximab vedotin (BV, cohort 1), progressive disease (PD) after salvage chemotherapy and BV therapy without ASCT (cohort 2), or PD after ASCT without subsequent BV therapy (cohort 3) received pembro 200 mg every 3 wks for up to 2 y. Pts who discontinued treatment after initial CR and relapsed were eligible to receive up to 17 additional cycles (~1 y) of pembro (2nd course). Primary end points: ORR per blinded independent central review (BICR), and safety. Additional end points: ORR per Lugano classification, DOR, and PFS by BICR; OS and 2nd-course ORR per investigator. DOR, PFS, and OS were estimated by Kaplan-Meier (K/M) method. Data cutoff was March 15, 2021.

Results: At data cutoff, median time from first dose to date of death or data cutoff was 62.9 mo (range, 1.0-68.7). In the total population (N=210), 46 pts completed 2 y of treatment and 164 pts discontinued (primarily due to progressive disease [n=86]). ORR was 71.0% (95% CI, 64.8-77.4; CR, 27.6%; partial response [PR, 43.8%]); results were similar per Lugano classification (ORR, 73.3% [95% CI, 66.8-79.2]; CR, 32.9%; PR, 40.5%). ORR was 84.1% (CR, 36.2%; PR, 47.8%) in cohort 1 (n=69), 67.9% (CR, 28.4%; PR, 39.5%) in cohort 2 (n=81), and 68.3% (CR, 35.0%; PR, 33.3%) in cohort 3 (n=60). In the total population, median DOR was 16.6 mo (95% CI, 11.8-27.1). Four pts (24.8% per K/M method; cohort 1, n=1; cohort 2, n=0; cohort 3, n=3) had response ≥60 mo. In the total population, median PFS was 13.7 mo (95% CI, 11.1-19.4) and the 5-y PFS rate was 14.2%: 16.4 mo (95% CI, 11.3-27.6) in cohort 1, 11.1 mo (95% CI, 7.5-13.7) in cohort 2, and 19.7 mo (95% CI, 10.8-27.3) in cohort 3. In the total population, median OS was not reached (NR) and the 5-y OS rate was 70.7%: 71.3% in cohort 1, 69.2% in cohort 2, and 71.5% in cohort 3. Of 58 pts in the total population who achieved CR (Table), median DOR was NR (95% CI, 16.1-NR) and 4 pts (51.6% per K/M method; cohort 1, n=1; cohort 2, n=0; cohort 3, n=3) had a response ≥60 mo. Median PFS was 56.5 mo (95% CI, 21.7-NR) and 5-y PFS rate was 44.3%; median OS was NR and 5-y OS rate was 82.8%. Ten pts with CR received allogeneic stem cell transplant (allo-SCT) and 48 pts with CR did not undergo allo-SCT. Of 20 pts who received 2nd-course treatment (cohort 1, n=10; cohort 2, n=7; cohort 3, n=3), 10 pts (cohort 1, n=2; cohort 2, n=6; cohort 3, n=2) completed 17 additional cycles of treatment; 1 pt each from cohort 1 and cohort 3 were mid-treatment. ORR based on 19 evaluable pts from cohorts 1-3 was 73.7% (95% CI, 48.8-90.9). Median DOR for 2nd course was 15.2 mo (95% CI, 3.9-32.9), and 1 pt (13.7%) had a second response ≥36 mo. Treatment-related adverse events (AEs) of any grade occurred in 72.9% of pts; most common (&gt;10%) were hypothyroidism (14.3%), pyrexia (11.4%), and fatigue (11.0%). Grade 3-4 treatment-related AEs occurred in 12.9% of pts; neutropenia (n=5), diarrhea and pericarditis (n=2, each) occurred in ≥2 pts. All-cause grade 5 AEs (n=3) were due to acute graft-versus-host disease, infection, and septic shock; these AEs were not considered treatment related.

Conclusions: With median of follow-up &gt;5 y, pembro monotherapy demonstrated sustained antitumor activity in pts with R/R cHL. ORRs were high and responses durable in the overall population and in those with varied treatment histories. Pts with CR had especially durable responses, and in those relapsing from CR, 2nd-course pembro frequently re-induced sustained response. Safety was manageable with no new signals.

Figure 1 Figure 1.

Disclosures

Armand: Merck & Co., Inc.: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; Affimed: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Infinity: Consultancy; ADC Therapeutics: Consultancy; Celgene: Consultancy; Morphosys: Consultancy; Daiichi Sankyo: Consultancy; Miltenyi: Consultancy; Tessa: Consultancy; GenMab: Consultancy; C4: Consultancy; Enterome: Consultancy; Regeneron: Consultancy; Epizyme: Consultancy; AstraZeneca: Consultancy; Genentech: Consultancy, Research Funding; Roche: Research Funding; Tensha: Research Funding; Otsuka: Research Funding; Sigma Tau: Research Funding; IGM: Research Funding; Kite: Research Funding. Zinzani: Celgene: Consultancy, 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; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics Inc: 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; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, 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; Celltrion: 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; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ImmuneDesign: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck Sharp & Dohme: Consultancy, Honoraria, 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; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lee: Oncternal: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Seagen: Research Funding; Century Therapeutics: Consultancy; Guidepoint: Honoraria; Aptitude Health: Honoraria; BMS: Honoraria, Research Funding; Janssen: Honoraria; Pharmacyclics: Research Funding. Johnson: AbbVie: Consultancy, Research Funding; Merck: Consultancy; Roche: Consultancy, Honoraria; BMS: Consultancy; Seattle Genetics: Consultancy; Gilead: Consultancy. Brice: MSD: Research Funding; Amgen: Other: Travel/accommodations/expenses; Takeda: Research Funding; Roche: Other: Travel/accommodations/expenses. Radford: Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Current holder of individual stocks in a privately-held company; ADC Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Honoraria, Speakers Bureau; BMS: Honoraria. Ribrag: Roche: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Argen-X: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; PharmaMar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Epizyme: Honoraria, Research Funding; MSD Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Molin: Roche: Honoraria; MSD: Honoraria; BMS: Honoraria; Takeda: Honoraria. Vassilakopoulos: AbbVie: Consultancy, Honoraria; GlaxoSmithKline: Honoraria, Other: Travel; Amgen: Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Merck: Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria, Other: Travel; Roche: Consultancy, Honoraria, Other: Travel; Takeda: Consultancy, Honoraria, Other: Travel, Research Funding; Integris: Honoraria; AstraZeneca: Honoraria; Pfizer: Research Funding; Dr. Reddy's: Research Funding; Karyopharm: Research Funding. Tomita: Kyowa Kirin: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Nippon Shinyaku: Consultancy, Honoraria, Research Funding; Janssen Pharmaceutical: Honoraria; Zenyaku Kogyo: Honoraria; AbbVie GK: Honoraria; Bristol Myers Squibb: Honoraria; SymBio Pharmaceutical: Consultancy, Honoraria; Otsuka Pharmaceutical: Research Funding; Ono Pharmaceutical: Research Funding; Shionogi: Research Funding; Suitomo Dainippon Pharma: Research Funding; Taiho Pharmaceutical: Research Funding; Teijin: Research Funding; Pfizer Japan: Research Funding; Mochida Pharmaceutical: Research Funding; Yakult Honsya: Research Funding; Perseus Proteomics: Research Funding. von Tresckow: Pentixafarm: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; AstraZeneca: Honoraria, Other: congress and travel support; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other, Research Funding; BMS-Celgene: Consultancy, Honoraria, Other: congress and travel support; Novartis: Consultancy, Honoraria, Other: congress and travel support, Research Funding; Kite-Gilead: Consultancy, Honoraria; MSD: Consultancy, Honoraria, Other: congress and travel support, Research Funding; AbbVie: Other: congress and travel support. Shipp: Bristol Myers Squibb: Research Funding; Merck: Research Funding; AstraZeneca: Consultancy, Research Funding; Immunitas Therapeutics: Consultancy; Abbvie: Other: Institution: Research Grant/Funding; Bayer: Other: Institution: Research Grant/Funding. Herrera: Genentech: Consultancy, Research Funding; Karyopharm: Consultancy; Seagen: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Takeda: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Kite, a Gilead Company: Research Funding; Gilead Sciences: Research Funding; Merck: Consultancy, Research Funding; Tubulis: Consultancy. Lin: Merck (MSD): Current Employment. Kim: Merck: Current Employment, Other: Current Stockholder. Chakraborty: Merck & Co., Inc.: Current Employment, Other: Current Stockholder. Marinello: Merck & Co., Inc.: Current Employment, Other: Current Stockholder. Moskowitz: Merck & Co., Inc.: Research Funding.