Three-Year Follow-up of Keynote-087: Pembrolizumab Monotherapy in Relapsed/Refractory Classic Hodgkin Lymphoma
Authors: Zinzani Pier Luigi , Lee Hun Ju , Armand Philippe , 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 , Farooqui Mohammed , Marinello Patricia , Moskowitz Craig H. 
Published: February 2020

Introduction: Standard of care for patients (pts) with relapsed or refractory classic Hodgkin lymphoma (R/R cHL) remains salvage chemotherapy with subsequent autologous stem cell transplantation (ASCT), which leads to long-term remission in about half of pts. Prognosis is poor for pts who relapse or progress after ASCT, particularly among pts who relapse after prior treatment with brentuximab vedotin (BV). Programmed death 1 (PD-1) inhibitors are an effective therapeutic option. Previous analyses of the multicohort phase 2 KEYNOTE-087 (NCT02453594) study showed that PD-1 pathway inhibition with pembrolizumab (pembro) led to effective antitumor activity and acceptable safety in pts with R/R cHL. KEYNOTE-087 results led to FDA approval of pembro for adult and pediatric pts with R/R cHL who relapsed after ≥3 prior lines of therapy. Long-term durability of response is a key clinical question for pts receiving immunotherapy. We present efficacy and safety of patients in KEYNOTE-087 who received 3 y of follow-up and evaluate antitumor activity in pts who were re-treated after disease progression.
Methods: Pts with R/R cHL who progressed after ASCT and subsequent BV therapy (cohort 1), underwent salvage chemotherapy and BV and were ineligible for ASCT (cohort 2), or progressed after ASCT but were not treated with BV after ASCT (cohort 3) were enrolled and received pembro 200 mg IV Q3W. Pts who discontinued pembro after initial confirmed CR after ≥6 mo of treatment and then experienced disease progression were eligible to receive an additional ≤17 cycles (~1 y) of pembro (second course). Response was assessed Q12W per 2007 Revised Response Criteria for Malignant Lymphomas. Primary end points were safety and overall response rate (ORR) per blinded independent central review in all pts in each cohort. Secondary end points included complete remission (CR) rate, duration of response (DOR), progression-free survival (PFS), and overall survival (OS).
Results : At data cutoff, median follow-up was 39.5 mo (range, 1.0-44.8). In the total population (N=210), 46 pts completed 2 y of treatment, 164 pts discontinued (primary reason, progressive disease [n=86]). ORR was 71.0% (95% CI, 64.3-77.0) with 58 CRs (27.6%) and 91 PRs (43.3%). ORR was 78.3% (CR, n=18; PR, n=36) in cohort 1 (n=69), 64.2% (CR, n=21; PR, n=31) in cohort 2 (n=81), and 71.7% (CR, n=19; PR, n=24) in cohort 3 (n=60). Overall median DOR was 16.6 mo (95% CI, 0.0+ to 39.1+). 45.1% of pts had a response duration ≥24 mo; 26.9% had a response duration ≥36 mo. 19/149 (12.8%) pts had an ongoing response. Median DOR was 25.0 mo in cohort 1, 11.1 mo in cohort 2, and 16.8 mo in cohort 3. In the total population, median PFS was 13.6 mo (95% CI, 11.1-16.7) and the 36-mo PFS rate was 18.8%. Median PFS was 16.4 mo (95% CI, 11.3-27.6) in cohort 1, 11.1 mo (95% CI, 7.3-13.5) in cohort 2, and 19.4 mo (95% CI, 8.4-22.1) in cohort 3. Median OS was not reached in the total population or in the cohorts; 36-mo OS rate was 86.4% in the total population, 86.3% in cohort 1, 85.7% in cohort 2, and 87.6% in cohort 3. 17 pts entered the second-course phase, of whom 16 were evaluable for response (8 in cohort 1, 6 in cohort 2, 2 in cohort 3). 4 pts completed 17 cycles of treatment; 7 pts have ongoing treatment. Second-course ORR was 68.8% with 5 CRs (31.3%) and 6 PRs (37.5%); 4 pts (25.0%) had stable disease. ORR for cohorts 1, 2, and 3 was 75.0% (CR, n=1; PR, n=5), 83.3% (CR, n=4; PR, n=1), and 0.0%, respectively. Both pts in cohort 3 had stable disease; 1 completed 17 cycles of pembro and the other is still receiving treatment. Treatment-related adverse events (AEs) of any grade occurred in 72.9% of pts; the most commonly reported were hypothyroidism (14.3%), pyrexia (11.4%), fatigue (11.0%), and rash (11.0%). Grade 3-4 treatment-related AEs occurred in 11.9% of pts; only neutropenia (n=5) and diarrhea (n=2) occurred in ≥2 pts. No grade 5 treatment-related AEs occurred.
Conclusions: With a median of 39.5 mo of follow-up, pembro continued to demonstrate clinically important antitumor activity in pts with R/R cHL. In the total population and in pts with different treatment histories, ORRs were high and responses were durable. Second-course pembro was able to re-induce remission in most patients who previously reached CR. Safety was manageable, and no unexpected AEs occurred.

Disclosures
Zinzani: VERASTEM: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELLTRION: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GILEAD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; JANSSEN-CILAG: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SERVIER: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SANDOZ: Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; IMMUNE DESIGN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELGENE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PORTOLA: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ROCHE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSAPHARMA: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; KYOWA KIRIN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SANOFI: Consultancy. Armand:Sigma-Tau: Research Funding; Otsuka: Research Funding; Pfizer Inc: Research Funding; Merck & Co.: Employment, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others, Research Funding; Affimed: Research Funding; Serventa: Research Funding; Bristol Myers Squibb Pharmaceuticals: Employment, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others, Research Funding; Infinity Pharmaceuticals: Employment, Membership on an entity's Board of Directors or advisory committees; Dana-Farber Cancer Institute: Employment; Roche: Research Funding. Johnson:Lundbeck: Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others, Research Funding; BD Biosciences: Other: Provided a significant proportion of the antibodies used in this project free of cost.; Seattle Genetics: Honoraria; BMS: Consultancy, Honoraria; Roche: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others, Research Funding; Abbvie: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria. Brice:Millennium Takeda: Research Funding; BMS: Honoraria; Takeda France: Consultancy, Honoraria. Radford:Novartis: Consultancy, Honoraria; GSK: Equity Ownership; BMS: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; AstraZeneca: Equity Ownership, Research Funding. Ribrag:Incyte: Membership on an entity's Board of Directors or advisory committees; AZ: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses ; Infinity: Membership on an entity's Board of Directors or advisory committees; Nanostring: Membership on an entity's Board of Directors or advisory committees; ArgenX: Research Funding; Epizyme: Consultancy, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel, accommodations, and expenses . Molin:Merck & Co., Inc.: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceuticals: Honoraria; Roche Holding AG: Honoraria. Vassilakopoulos:Takeda Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others; Genesis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others; Novartis: 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. Tomita:Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Kyowa Kirin: Research Funding; Taiho Pharma: Research Funding. Von Tresckow:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others, Research Funding; Takeda Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others, Research Funding; Amgen: Honoraria; Celgene: Honoraria; Merck Sharp & Dohme Corp: Research Funding. Shipp:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Merck & Co.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees. Herrera:Merck: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; Pharmacyclics: Research Funding; Immune Design: Research Funding; Kite Pharma: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; AstraZeneca: Research Funding; Gilead Sciences: Consultancy, Research Funding. Lin:Merck & Co., Inc.: Employment. Kim:Merck & Co., Inc.: Employment, Other: Stock or other ownership. Farooqui:Merck & Co., Inc.: Employment, Other: Stock or Other Ownership. Marinello:Merck & Co., Inc.: Employment, Other: Travel fees, gifts, and others; stock or other ownership. Moskowitz:Genentech: Consultancy, Research Funding; Celgene: Consultancy; Pharmacyclics: Research Funding; ADC Therapeutics: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Merck: Consultancy, Research Funding.