ALBERT

Description: 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.

Description: Background: Programmed death - ligand 1 (PD-L1) expression is a dominant immune escape mechanism across human cancers. Ubiquitous copy gains of chromosome 9p24.1 - a region containing the PD-L1 and PD-L2 loci - lead to PD-L1 expression on Hodgkin-Reed-Sternberg cells in classical Hodgkin lymphoma. PD-L1 gene alterations also occur in diffuse large B cell lymphoma (DLBCL), albeit less commonly. Hypothesizing that PD-L1 gene alterations identify DLBCLs in which potent anti-lymphoma immune responses have been activated, we aimed to characterize the immune landscape of PD-L1 gene-altered DLBCLs, describe the key clinical features of these patients, and determine the degree to which PD-L1 gene alterations predict for response to PD-1 blockade therapy in DLBCL. Methods: FISH was performed on 105 formalin-fixed, paraffin-embedded (FFPE) DLBCL specimens with DNA probes to PD-L1, a region centromeric to PD-L2, and centromere 9. Lymphoma-infiltrating T cell numbers (68 cases), HLA class I/II expression (74 cases), and PD-L1 protein expression (93 cases) were assessed by IHC. RNA sequencing (seq) was performed on FFPE samples utilizing the Illumina HiSeq 2000 platform. Differentially-expressed genes were identified between PD-L1-altered and not altered DLBCLs using a false discovery rate (FDR) of 0.05 and log2 fold change of 〉1.5. Whole exome seq (WES) was performed on DNA from DLBCL specimens and 22 matched blood samples using the Illumina HiSeq exome kit in collaboration with Theragen Etex Bio Institute. Results: PD-L1 gene alterations were identified by FISH in 28/105 samples (27% - 16% relative PD-L1 copy gains, 7% PD-L1 amplifications, 2% PD-L1 translocations, 2% chromosome 9 polysomy), were enriched in non-germinal center (GC) DLBCLs (75% non-GC vs 25% GC; p=0.001), and were associated with robust PD-L1 protein expression (Fig 1A-B). PD-L1 gene-altered DLBCLs were more heavily infiltrated by CD8+ T cells compared to PD-L1 not altered DLBCLs (22.6 vs 13.8 CD8+ T cells/hpf; p

Description: Introduction: No standard of care exists for patients (pts) with relapsed or refractory primary mediastinal B-cell lymphoma (rrPMBCL). As such, pts typically receive therapies recommended for diffuse large B-cell lymphoma, with poor prognosis. Similar to classical Hodgkin lymphoma, rrPMBCL tumors often overexpress the programmed death 1 (PD-1) ligands, PD-L1 and PD-L2. Data from the first full analysis of the phase 2 KEYNOTE (KN)-170 (NCT02576990) study showed that pembrolizumab provided effective and durable antitumor activity with a manageable safety profile in patients with rrPMBCL. These data led to the FDA approval of pembrolizumab for pts with rrPMBCL after ≥2 prior therapies. In this aggressive malignancy with few salvage options, duration of remission with PD-1 blockade remains a critical question. Here we present data from KN170 with an additional 24 months of follow-up in patients with rrPMBCL. Methods: Pts with rrPMBCL who had relapsed after or were ineligible for autologous stem cell transplant with ≥2 lines of prior therapy were enrolled in KN170 to receive 200 mg pembrolizumab IV Q3W until disease progression or toxicity, for up to 2 years. Tumor response was assessed Q12W with PET/CT scans by IWG 2007 criteria. The primary endpoint 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. Exploratory endpoints included response by Lugano 2014 criteria. The data cutoff date for this analysis was May 7, 2020. Results: At the data cutoff date, among all treated pts (N=53), 13 had completed 2 years of treatment and 40 had discontinued largely due to progression (n=30). The ORR was 45% (24/53; 95% CI 32-60) with a CR rate of 19% (10/53; 13/53 [25%] by Lugano criteria). No patient who achieved CR by BICR had received consolidation therapy or had progressed at data cutoff. After a median study follow-up of 43.1 months (range, 35.6-50.7) the median DOR was not reached (range, 1.1+ to 46.9+ mo); 76% of pts had a response duration ≥36 mo. Median PFS was 5.5 mo (95% CI, 2.7-15.1), with 36-mo PFS rate of 34%. The median OS was 22.3 mo (95% CI, 7.3 to not reached) with 36-mo OS rate of 45%. At data cutoff, 50 (94%) pts had at least one adverse event (AE), with 30 (57%) having a treatment-related AE. The most common treatment-related AEs were neutropenia (19%), asthenia (9%), hypothyroidism (8%), fatigue (6%), and pyrexia (6%). Grade ≥3 treatment-related AEs occurred in 12 (23%) pts. Six (11%) pts had an immune-mediated AE. There were no treatment-related grade 5 events. Conclusion: Results from the longer-term follow-up of KN170, the largest prospective clinical trial in rrPMBCL, shows that pembrolizumab provides robust and durable antitumor activity with a manageable safety profile in patients with rrPMBCL. Disclosures Zinzani: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Kirin Kyowa: 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; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Celgene: Consultancy, 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; 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; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: 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; ADC Therapeutics: Honoraria, 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. Bouabdallah:Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria. Walewski:Roche: Consultancy, Honoraria, Other: travel expenses, Research Funding; GSK/Novartis: Research Funding; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy. Caballero:Gilead: Other: travel; Roche: Other: travel; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: travel; Kite: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: travel; BMS: Other: travel. Christian:Acerta: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Merck: Research Funding; Millenium: Research Funding; MorphoSys: Research Funding; F Hoffman-La Roche: Research Funding; Triphase: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; AstraZenica: Membership on an entity's Board of Directors or advisory committees. Özcan:Takeda: Honoraria, Other: travel, Research Funding; Roche: Other: travel, Research Funding; Bayer: Research Funding; Abbvie: Other: travel, Research Funding; Archigen: Research Funding; Celgene: Research Funding; MSD: Research Funding; Novartis: Research Funding; Amgen: Honoraria, Other: travel; BMS: Other; Jazz: Other; Sanofi: Other; Abdi Ibrahim: Other; Janssen: Other: travel, Research Funding. Salles:Bristol Myers Squibb: Consultancy, Other; Takeda: Consultancy, Honoraria, Other; Gilead: Consultancy, Honoraria, Other: Participation in educational events; Debiopharm: Consultancy; Kite: Consultancy, Honoraria, Other; MorphoSys: Consultancy, Honoraria, Other; Janssen: Consultancy, Honoraria, Other: Participation in educational events; Novartis: Consultancy, Honoraria, Other; F. Hoffman-La Roche Ltd: Consultancy, Honoraria, Other; Celgene: Consultancy, Honoraria, Other: Participation in educational events; Epizyme: Consultancy; Karyopharm: Consultancy; Autolus: Consultancy; Amgen: Honoraria, Other: Participation in educational events; Abbvie: Consultancy, Honoraria, Other: Participation in educational events; Genmab: Consultancy. Shipp:Celgene: Honoraria; Ono Pharmaceutical: Honoraria; Bayer: Honoraria; Bristol Myers Squibb: Consultancy, Research Funding; Merck: Research Funding. Thompson:Merck Sharp & Dohme Corp.: Current Employment. Orlowski:Merck Sharp & Dohme Corp.: Current Employment. Marinello:Merck & Co., Inc., Kenilworth, NJ, USA: Other: Stock ownership; Merck & Co., Inc.: Other: Travel, accommodations, expenses; Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA: Current Employment. Armand:Pfizer: Consultancy; Merck & Co., Inc.: Consultancy, Honoraria, Research Funding; Adaptive: Consultancy, Research Funding; Affimed: Consultancy, Research Funding; Sigma Tau: Research Funding; Celgene: Consultancy; IGM: Research Funding; Otsuka: Research Funding; Tensha: Research Funding; Genentech: Research Funding; Infinity: Consultancy; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Roche: Research Funding.