Chen and colleagues report excellent durability of response at 2 years for patients responding to pembrolizumab for relapsed Hodgkin lymphoma.

No abstract

The KEYNOTE-013 study was conducted to evaluate pembrolizumab monotherapy in hematologic malignancies; classical Hodgkin lymphoma (cHL) was an independent expansion cohort. We present long-term results based on >4 years of median follow-up for the cHL cohort. The trial enrolled cHL patients who experienced relapse after, were ineligible for, or declined autologous stem cell transplantation and experienced progression with or did not respond to brentuximab vedotin. Patients received IV pembrolizumab 10 mg/kg every 2 weeks for up to 2 years or until confirmed progression or unacceptable toxicity. Primary end points were safety and complete response (CR) rate by central review. Enrolled patients (N = 31) had received a median of 5 therapies (range, 2 to 15). After a median follow-up of 52.8 months (range, 7.0 to 57.6 months), CR rate was 19%, and median duration of response (DOR) was not reached; 24-month and 36-month DOR rates were both 50% by the Kaplan-Meier method. Median overall survival was not reached; 36-month overall survival was 81%. Six patients (19%) experienced grade 3 treatment-related adverse events (AEs); there were no grade 4 or 5 treatment-related AEs. With long-term follow-up among a heavily pretreated cohort, pembrolizumab had a favorable safety profile; some patients maintained long-term response with pembrolizumab years after end of treatment. This trial was registered at www.clinicaltrials.gov as #NCT01953692.

8005 Background: PD-1 blockade via pembro monotherapy showed antitumor activity in R/R cHL. KEYNOTE-204 (NCT02684292) was a randomized, international, open-label, phase III study of pembro vs BV in R/R cHL. Methods: Patients (pts) were aged ≥18 y, were post−autologous stem cell transplant (auto-SCT) or ineligible for auto-SCT, and had measurable disease and ECOG PS 0 or 1. BV-naive and BV-exposed pts were eligible. Pts were randomized 1:1 to pembro 200 mg IV Q3W or BV 1.8 mg/kg IV Q3W and stratified by prior auto-SCT (yes vs no) and status after 1L therapy (primary refractory vs relapsed <12 mo vs relapsed ≥12 mo after end of 1L therapy). Primary end points: PFS by blinded independent central review (BICR) per International Working Group (IWG) criteria including clinical and imaging data after auto-SCT or allogeneic SCT (allo-SCT) and OS. Key secondary end points: PFS excluding clinical and imaging data after auto-SCT or allo-SCT (PFS-secondary), and ORR by BICR per IWG, PFS by investigator review per IWG, and safety. Exploratory end point: DOR by BICR per IWG. Results: 304 pts were randomized and 300 were treated (148, pembro; 152, BV); 256 discontinued. Median (range) follow-up: 24.7 (0.6-42.3) mo. 15 pts were BV exposed. Median (range) time on treatment was 305.0 (1-814) and 146.5 (1-794) days with pembro and BV, respectively. Statistically significant improvement was observed with pembro vs BV for primary PFS analysis (HR 0.65 [95% CI 0.48-0.88; P =0.00271]; median 13.2 vs 8.3 mo); 12-mo PFS rates were 53.9% vs 35.6%, respectively. Benefit was observed in all subgroups tested, including pts with no auto-SCT (HR=0.61), primary refractory disease (HR=0.52), prior BV (HR=0.34) and BV naive (HR=0.67). Significant improvement in PFS-secondary was observed with pembro vs BV (HR 0.62 [95% CI 0.46-0.85]; median 12.6 vs 8.2 mo). Per investigator assessment, PFS was longer with pembro vs BV (HR 0.49 [95% CI 0.36-0.67]; median 19.2 vs 8.2 mo). ORR was 65.6% for pembro and 54.2% for BV; CR rates were 24.5% and 24.2%, respectively. Median (range) DOR was 20.7 mo (0.0+ to 33.2+) for pembro and 13.8 mo (0.0+ to 33.9+) for BV. Grade 3-5 TRAEs: 19.6% of pts with pembro and 25.0% with BV. One death due to TRAE occurred with pembro (pneumonia). Conclusions: In pts with R/R cHL, pembro was superior to BV and demonstrated statistically significant and clinically meaningful improvement in PFS across all subgroups, with safety consistent with previous reports. Pembro monotherapy should be standard of care for this pt population with R/R/cHL. Clinical trial information: NCT02684292 .

Introduction: The near-universal genetic amplification events at 9p24.1 in classic Hodgkin lymphoma (cHL) results in overexpression of the programmed death 1 (PD-1) ligands and betrays an unusual dependence on the PD-1 pathway. Inhibition of this pathway by use of pembrolizumab has shown effective antitumor activity and acceptable safety in patients with relapsed or refractory cHL (R/RcHL) in the multicohort KEYNOTE-087 study. This led to FDA approval of pembrolizumab for the treatment of adult and pediatric patients who have refractory cHL or who have relapsed after ≥3 prior lines of therapy. A critical remaining question is the durability of responses, specifically whether a subgroup of patients can have durable remission with PD-1 blockade. Therefore, we present the results for the total population and by cohort, with an additional ~12 months of follow-up from last presentation. Methods: The multicenter, single-arm, phase 2 KEYNOTE-087 (NCT02453594) study was conducted to evaluate pembrolizumab in patients with R/R cHL that progressed after autologous stem cell transplantation (ASCT) and subsequent brentuximab vedotin (BV) therapy (cohort 1); salvage chemotherapy and BV (cohort 2); or ASCT but not treated with BV after ASCT (cohort 3). Patients received pembrolizumab 200 mg intravenously every 3 weeks. Response was assessed every 12 weeks 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 patients and in each cohort; secondary end points were complete remission rate (CRR), progression-free survival (PFS), duration of response (DOR), and overall survival (OS). All patients who received at least 1 dose of pembrolizumab were included in the analyses. Results : At data cutoff (Mar 21, 2018), median follow-up was 27.6 mo (range, 1.0-32.9), and 5 of 210 enrolled patients were still in treatment. Baseline characteristics were previously presented (Chen et al. J Clin Oncol. 2017; 35(19):2125-2132). In the total population, ORR was 71.9% (95% CI, 65.3-77.9); CRR, 27.6% (95% CI, 21.7-34.2); partial response (PR), 44.3% (95% CI, 37.5-51.3). Response rates by cohort were as follows: cohort 1 (n=69): ORR: 76.8%; CRR: 26.1%; cohort 2 (n=81): ORR: 66.7%; CRR: 25.9%; cohort 3 (n=60): ORR: 73.3%; CRR: 31.7%. Median DOR was 16.5 mo overall (range 0.0+ to 27.0+; [+, no progressive disease at last assessment]). Of 151 responders, 87 (75.6%) had response ≥6 mo; 61 (58.5%) had response ≥12 mo; 16 (42.5%) had response ≥24 mo; 37 (24.5%) pts had ongoing response. Median DOR by cohort was 22.1 mo in cohort 1, 11.1 mo in cohort 2, and 24.4 mo in cohort 3 (Table). In patients with CR (n=58), median DOR was not reached (NR) in the total population and was 25.0 mo in cohort 1, 19.2 mo in cohort 2, and NR in cohort 3. In patients with PR (n=93), median DOR was 10.9 mo overall, 19.5 mo in cohort 1, 7.9 mo in cohort 2, and 13.9 mo in cohort 3. Median PFS for all patients was 13.7 mo (95% CI, 11.1-17.0) (Table); 24-mo PFS rate was 31.3%. In patients with CR, median PFS was NR in the total population, 27.6 mo in cohort 1, 21.9 mo in cohort 2, and NR in cohort 3 (Table). In patients with PR, median PFS was 13.8 mo in the total population, 22.2 mo in cohort 1, 13.4 mo in cohort 2, and 19.4 mo in cohort 3. Median OS was not reached in the total population or in any cohort; 24-mo OS rate was 90.9% in the overall population, 92.5% in cohort 1; 90.6% in cohort 2, and 89.4% in cohort 3 (Table). Any-grade treatment-related adverse events (AEs) occurred in 153 (72.9%) patients; those occurring in ≥10% patients were hypothyroidism (14.3%), pyrexia (11.4%), fatigue (11.0%), and rash (11.0%). Grade 3/4 treatment-related AEs occurred in 25 (11.9%) pts, most commonly, neutropenia (5 [2.4%]) and diarrhea (3 [1.4%]); none resulted in death. Treatment-related AEs led to discontinuation in 14 (6.7%) patients. Conclusions: With more than 2 years of median follow-up, pembrolizumab continued to demonstrate effective antitumor activity with high ORR, durable response, and manageable safety in patients with R/R cHL in 3 cohorts of patients in whom treatment history was different. ORR, DOR, and PFS seemed higher in patients in cohorts 1 and 3 than in cohort 2, in which patients likely had more chemoresistant disease; nonetheless, pembrolizumab is still an effective treatment in this hard-to-treat patient population. Table. Table. Disclosures Zinzani: Astra Zeneca: Speakers Bureau; Celltrion: 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; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Merck: 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; 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; Roche: 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; Janssen: Honoraria, Speakers Bureau; MSD: Honoraria, Speakers Bureau; Celgene: 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; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Chen:Affimed: Research Funding; Genentech Inc.: Consultancy; Millennium Pharmaceuticals: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck & Co., Inc.: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding. Johnson:Bristol-Myers Squibb: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria, Other: travel, Research Funding; Roche: Consultancy, Honoraria, Other: travel, Research Funding; Seattle Genetics: Honoraria; AbbVie Inc.: Consultancy, Honoraria, Research Funding. Radford:Pfizer: Research Funding; AstraZeneca: Equity Ownership; Takeda: Consultancy, Research Funding, Speakers Bureau; Celgene: Research Funding; ADC Therapeutics: Consultancy, Research Funding; GlaxoSmithKline: Equity Ownership; Novartis: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Ribrag:Gilead: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Other: travel; epizyme: Consultancy, Honoraria; argenX: Research Funding; NanoString Technologies: Consultancy, Honoraria; Incyte Corporation: Consultancy; Amgen: Research Funding; MSD: Honoraria; Infinity: Consultancy, Honoraria; pharmamar: Other: travel; Servier: Consultancy, Honoraria; Roche: Honoraria, Other: travel. Molin:Merck & Co., Inc: Honoraria; Takeda Pharmaceuticals: Research Funding; Bristol-Myers Squibb: Honoraria; Roche Holding AG: Honoraria. Vassilakopoulos:Genesis Pharmaceuticals: Consultancy, Other: travel; Takeda Pharmaceuticals: Consultancy, Honoraria, Other: travel; Roche: Consultancy, Honoraria, Other: travel; Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Von Tresckow:Amgen: Honoraria; Novartis: Consultancy, Honoraria, Other: travel, Research Funding; Merck Sharp & Dohme: Research Funding; Celgene: Honoraria; Takeda Pharmaceuticals: Consultancy, Honoraria, Other: travel, Research Funding. Shipp:AstraZeneca: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Merck: Research Funding. Nahar:Merck & Co., Inc.: Employment, Equity Ownership. Balakumaran:Amgen: Equity Ownership; Merck & Co., Inc.: Employment, Equity Ownership. Moskowitz:Celgene: Consultancy; Genentech: Consultancy, Research Funding; Merck & Co: Consultancy, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding.