Pembrolizumab in Relapsed/Refractory Classical Hodgkin Lymphoma: Primary End Point Analysis of the Phase 2 Keynote-087 Study

• Published in: Blood Vol. 128; no. 22; p. 1107
• Main Authors: Moskowitz, Craig H., Zinzani, Pier Luigi, Fanale, Michelle A., Armand, Philippe, Johnson, Nathalie A., Radford, John A., Ribrag, Vincent, Molin, Daniel, Vassilakopoulos, Theodoros P., Tomita, Akihiro, von Tresckow, Bastian, Shipp, Margaret A., Gustafson, Eric, Zhang, Yinghua, Ricart, Alejandro Daniel, Balakumaran, Arun, Chen, Robert W
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 02.12.2016
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V128.22.1107.1107

▪ Background: Classical Hodgkin lymphoma (cHL) is characterized by chromosome 9p24.1 alterations (including amplification), leading to overexpression of the PD-L1 and PD-L2 immune checkpoint ligands. This genetically determined dependence on the PD-1 pathway makes cHL an attractive target for PD-1 blockade with the anti-PD-1 monoclonal antibody, pembrolizumab. In the phase 1b KEYNOTE-013 study, pembrolizumab demonstrated high antitumor activity (objective response rate [ORR] of 65%) in heavily pretreated patients with cHL. KEYNOTE-087 is a phase 2 study designed to further evaluate the efficacy and safety of pembrolizumab in different subgroups of patients with relapsed/refractory (R/R) cHL. Methods: KEYNOTE-087 (ClinicalTrials.gov, NCT02453594) is a multicenter, single-arm, multicohort phase 2 study of pembrolizumab in 3 cohorts of patients with R/R cHL: R/R cHL after autologous stem cell transplantation (ASCT) and subsequent brentuximab vedotin (BV) therapy (cohort 1); ineligibility for ASCT due to chemoresistance (no response to salvage chemotherapy) and BV therapy failure (cohort 2); and R/R cHL after ASCT but not treated with BV after ASCT (cohort 3). Patients received pembrolizumab at a fixed dose of 200 mg intravenously every 3 weeks. Response was assessed every 12 weeks according to the 2007 Revised Response Criteria for Malignant Lymphomas. The primary end point was ORR per blinded independent central review (BICR); secondary end points included ORR per investigator review (IR), complete remission rate (CRR), progression-free survival, and overall survival. All patients who received at least 1 dose of pembrolizumab were included in the analyses. Informed consent was obtained for all patients. Biomarkers included PD-L1/PD-L2 expression in formalin-fixed, paraffin-embedded tissue; flow cytometry-based evaluation of absolute and relative numbers of circulating NK cells and T-cell subsets (naive and memory T cells, activated T cells, and regulatory T cells); and gene expression using the NanoString and Illumina RNAseq platforms. The data cutoff date for these analyses was June 27, 2016. Results: Among 210 treated patients in cohorts 1 (n = 69), 2 (n = 81), and 3 (n = 60), all patients had refractory disease or relapsed HL. Of these, 98.6%, 96.3%, and 60.0% had received ≥3 prior lines of therapy, and by design 100% of patients in cohorts 1 and 2 had progressive disease after BV. 41.7% of patients received BV before ASCT in cohort 3. Per IR, ORR (95% CI) was 66.7% (54.3%-77.6%) in cohort 1 (46/69 patients), 65.4% (54.0%-75.7%) in cohort 2 (53/81 patients), and 68.3% (55.0%-79.7%) in cohort 3 (41/60 patients). The CRR was 29.0% in cohort 1, 24.7% in cohort 2, and 21.7% in cohort 3. Per BICR, the ORRs (95% CI) for each cohort were 72.5% (60.4%-82.5%), 65.4% (54.0%-75.7%), and 66.7% (53.3%-78.3%), respectively, and the CRRs were 21.7%, 22.2%, and 21.7%, respectively. A pooled analysis with hierarchical mutually exclusive categories of refractory disease (RD, n = 170) or relapse after ≥3 prior lines of therapy (Re ≥3, n = 40) was conducted across cohorts. Per BICR, ORR was 70.0% (62.5%-76.8%) in RD and 60.0% (43.3%-75.1%) in Re ≥3. Among patients with postbaseline assessment across all cohorts, 93.7% (192/205) experienced a decrease from baseline in tumor size (Figure). With a median of 9 treatment cycles, the most common treatment-related AEs (TRAEs) were pyrexia (11.0%), hypothyroidism (10.5%), diarrhea (6.7%), fatigue (6.7%), headache (6.2%), rash (6.2%), and nausea (5.7%). The most common grade 3/4 TRAEs were neutropenia (1.4%), thrombocytopenia (1.0%), and diarrhea (1.0%). Two patients died; neither death was considered to be treatment-related. At the time of analysis, 115 patients (80% of responders) had an ongoing response. Two hundred patients had evaluable pretreatment tumor tissue (archival or obtained for study) for biomarker analyses. Conclusions: PD-1 blockade with pembrolizumab had substantial clinical activity in subsets of heavily pretreated patients with cHL. Of note, pembrolizumab induced a high ORR in chemoresistant cHL. Additional results, including duration of response per BICR and biomarker analysis, will be presented at the meeting. [Display omitted] Moskowitz:Celgene: Consultancy; Genentech: Consultancy; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Research Funding. Zinzani:Janssen: 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; TG Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees; Abbvie: Membership on an entity’s Board of Directors or advisory committees; Infinity: Membership on an entity’s Board of Directors or advisory committees; Takeda: Membership on an entity’s Board of Directors or advisory committees; 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; Karyopharm: Membership on an entity’s Board of Directors or advisory committees; Sandoz: Membership on an entity’s Board of Directors or advisory committees; Millennium: Membership on an entity’s Board of Directors or advisory committees. Fanale:molecular templates: Research Funding. Armand:Merck & Co., Inc.: Consultancy, Research Funding; Roche: Research Funding; Infinity: Consultancy; BMS: Consultancy, Research Funding; Otsuka: Research Funding; Tensha: Research Funding; Sequenta: Research Funding; Sigma Tau: Research Funding. Radford:Takeda: Honoraria, Research Funding; Seattle Genetics: Honoraria; Novartis: Honoraria; GlaxoSmithKline: Equity Ownership; Astra Zeneca: Equity Ownership. Ribrag:Pharmamar: 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; ArgenX: Research Funding; Gilead: Membership on an entity’s Board of Directors or advisory committees; Infinity: Membership on an entity’s Board of Directors or advisory committees; Esai: Membership on an entity’s Board of Directors or advisory committees; Incyte: Membership on an entity’s Board of Directors or advisory committees; Nanostring: Membership on an entity’s Board of Directors or advisory committees. Vassilakopoulos:Takeda: 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; Roche: Membership on an entity’s Board of Directors or advisory committees; Genesis Pharma: Membership on an entity’s Board of Directors or advisory committees. von Tresckow:Novartis: Consultancy, Other: travel grants, Research Funding; Takeda: Consultancy, Other: travel grants; Millenium: Consultancy. Shipp:Cell Signaling: Honoraria; Bayer: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Merck, Gilead, Takeda: Other: Scientific Advisory Board. Gustafson:Merck & Co., Inc.: Employment, Other: stock, stock options. Zhang:Merck: Employment, Other: stock, stock options. Ricart:Merck & Co.: Employment; Pfizer: Equity Ownership. Balakumaran:Merck & Co.: Employment, Other: stock, stock options. Chen:Merck: Consultancy, Research Funding; Genentech: Consultancy, Speakers Bureau; Millenium: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau.