Pembrolizumab in Patients with Relapsed or Refractory Primary Mediastinal Large B-Cell Lymphoma (PMBCL): Data from the Keynote-013 and Keynote-170 Studies
Authors: Armand Philippe , Rodig Scott J , Melnichenko Vladimir , Thieblemont Catherine , Bouabdallah Krimo , Tumyan Gayane , Özcan Muhit , Portino Sergio , Fogliatto Laura , Caballero Dolores , Walewski Jan , Gulbas Zafer , Ribrag Vincent , Christian Beth A. , Perini Guilherme Fleury , Salles Gilles Andre , Svoboda Jakub , Zain Jasmine M. , Patel Sanjay S , Chen Pei-Hsuan , Ligon Azra H. , Ouyang Jing , Neuberg Donna S , Redd Robert A. , Chatterjee Arkendu , Orlowski Robert J , Balakumaran Arun , Shipp Margaret A. , Zinzani Pier Luigi 
Published: October 2019

Abstract

Introduction: Patients (pts) with relapsed/refractory PMBCL (rrPMBCL) are typically treated like those with diffuse large B cell lymphoma (DLBCL), often with limited effective treatment options and poor outcomes. Unlike DLBCL and similar to classical Hodgkin lymphoma, PMBCL has frequent genetic abnormalities leading to over-expression of the programmed death (PD)-1 ligands, PD-L1 and PD-L2. This suggests that rrPMBCL should be sensitive to PD-1 blockade. In the phase 1b KEYNOTE (KN)-013 study (NCT01953692), pembrolizumab was associated with frequent and durable responses (Zinzani, Blood 2017) in pts with rrPMBCL. The international phase 2 KN170 (NCT02576990) study was conducted to extend these findings and evaluate correlative biomarkers of response. Here, we present updated results of all pts in KN013 (n=21) and the first full analysis of pts in KN170 (n=53).
Methods: KN013 enrolled pts with rrPMBCL who had failed, were ineligible for, or refused autologous stem cell transplant (ASCT). KN170 enrolled pts with rrPMBCL who had relapsed after or were ineligible for ASCT with ≥2 lines of prior therapy. In KN013, the initial 10 pts received pembrolizumab 10 mg/kg Q2W; the remaining 11 patients and all patients on KN170 received pembrolizumab 200 mg Q3W for up to 2 years. Archival or fresh tumor tissue obtained before pembrolizumab initiation was used for correlative studies. Tumor response was assessed with PET/CT scans by IWG 2007 criteria. The primary endpoint of KN170 was objective response rate (ORR) by blinded independent central review (BICR). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety/tolerability. Exploratory endpoints included response by Lugano 2014 criteria and biomarker analyses. Data cutoff dates for this analysis were Apr 4, 2018 for KN013 and April 13, 2018 for KN170.
Results: KN013 enrolled 21 pts with a median of 3 prior lines of therapy, of whom 13 (62%) were ASCT-ineligible. KN170 enrolled 53 pts also with a median of 3 prior lines, of whom 39 (74%) were ASCT-ineligible due to chemorefractoriness. In KN013, ORR was 48% (10/21; 95% CI, 26-70), with a CR rate of 33% (7/21). In KN170, ORR was 45% (24/53; 95%CI, 32-60), with a CR rate of 13% (7/53; 11/53 [21% by Lugano criteria]). In KN013, after a median follow-up duration of 29.1 mo (range, 0.6-49.6), median DOR was not reached (range, 1.9+ to 39.8+ mo) (Panel A). 2 patients in KN013 in CR at 2 years remained in CR after a further 12 and 18 mo of follow-up off therapy. After a median follow-up of 12.5 mo for KN170 (range, 0.1-25.6), median DOR was not reached (range, 1.1+ to 22.0+ mo) (Panel A). At data cutoff, no patient who achieved a CR on KN170 had relapsed. In KN013, median PFS was 10.4 mo (95%CI, 3.4 to not reached) with 12-mo PFS rate of 47%; median OS was 31.4 mo with 12-mo OS rate of 65% (Panel B). In KN170, median PFS was 5.5 mo (95%CI, 2.8-12.1) with 12-mo PFS rate of 38%; median OS was not reached (95% CI, 7.3 to not reached) with 12-mo OS rate of 58% (Panel B). In KN013, no new safety signals were observed compared with prior analyses. In KN170, 30 (57%) pts had a treatment-related AE (TRAE). Common (≥5%) TRAEs included neutropenia (19%), hypothyroidism and asthenia (8% each), and pyrexia (6%). 12 (23%) pts had a grade 3-4 TRAE, including 5 (9%) with grade 3 and 2 (4%) with grade 4 neutropenia. Six (11%) pts had an immune-mediated AE including 1 (2%) with grade 4 pneumonitis. There were no treatment-related deaths.
Conclusion: Together with the longer follow-up results of KN013, KN170, the largest prospective clinical trial in rrPMBCL, establishes the robust antitumor activity of pembrolizumab in this disease, with exceptionally durable responses and survival in responding patients. These results provided the basis for the FDA accelerated approval of pembrolizumab in patients with rrPMBCL.

Disclosures
Armand: Otsuka: Research Funding; Adaptive: Research Funding; Merck: Consultancy, Research Funding; Affimed: Consultancy, Research Funding; Pfizer: Consultancy; Infinity: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Roche: Research Funding; Tensha: Research Funding. Rodig:Merck & Co., Inc.: Research Funding; Affimed Inc.: Research Funding; KITE Pharma: Research Funding; Bristol-Meyers-Squibb: Research Funding. Özcan:Jazz: Other: Travel support; Bayer: Research Funding; BMS: Honoraria; MSD: Other: travel support, Research Funding; Janssen: Other: Travel Support, Research Funding; Jazz: Other; Celgene: Other: Travel support, Research Funding; Roche: Honoraria, Research Funding; Archigen: Research Funding; Novartis: Research Funding; MSD: Research Funding; Abbvie: Other: Travel payment; Takeda: Honoraria, Other: Travel payment, Research Funding. Fogliatto:Novartis: Consultancy; Roche: Consultancy, Speakers Bureau; Janssen: Honoraria, Research Funding. Walewski:Roche, Celegene, Takeda, Janssen-Cilag, and Servier: Membership on an entity's Board of Directors or advisory committees; Roche, Celgene, Takeda, Janssen-Cilag, and Servier: Honoraria; Roche, GSK/Novartis, Takeda, and Janssen-Cilag: Research Funding. Gulbas:Pfizer: Other: Travel expenses; Roche and Janssen: Honoraria; Gilead: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees. Ribrag:Incyte Corporation: Consultancy; MSD: Honoraria; NanoString Technologies: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Other: travel; Gilead: Consultancy, Honoraria; Roche: Honoraria, Other: travel; Infinity: Consultancy, Honoraria; epizyme: Consultancy, Honoraria; Amgen: Research Funding; pharmamar: Other: travel; Servier: Consultancy, Honoraria; argenX: Research Funding. Christian:Immunomedics: Research Funding; Bristol-Myers Squibb: Research Funding; Merck: Research Funding; Acerta: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding. Perini:Janssen and Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen and Takeda: Speakers Bureau; Janssen and Takeda: Other: Travel expenses. Salles:Merck: Honoraria; Novartis: Consultancy, Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; AbbVie: Honoraria; Acerta: Honoraria; Takeda: Honoraria; Pfizer: Honoraria; Morphosys: Honoraria; Servier: Honoraria; Amgen: Honoraria; Epizyme: Honoraria; Gilead: Honoraria; Janssen: Honoraria. Svoboda:Pharmacyclics: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Kyowa: Consultancy; Regeneron: Research Funding; TG Therapeutics: Research Funding; KITE: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Research Funding. Chatterjee:Merck & Co., Inc.: Employment. Orlowski:Merck & Co., Inc.: Employment. Balakumaran:Amgen: Equity Ownership; Merck & Co., Inc.: Employment, Equity Ownership. Shipp:Bayer: Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria; Merck: Research Funding. Zinzani:PFIZER: 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; Janssen: Honoraria, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, 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; Celltrion: 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; 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; 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; MSD: Honoraria, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: 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; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.