Abstract
Background: Programmed death 1 (PD-1) inhibitors are a standard of care for relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) but optimized treatment strategies are yet to be defined for patients (pts) whose disease progresses after anti-PD-1 therapy. Lymphocyte-activation gene 3 (LAG-3) is involved in T-cell regulation and is commonly coexpressed with PD-1 on anergic T cells. Dual blockade of PD-1 and LAG-3 has demonstrated antitumor activity leading to US Food and Drug Administration approval for the treatment of pts with unresectable or metastatic melanoma. Favezelimab (MK-4280), a humanized immunoglobulin G (IgG) 4 LAG-3 inhibitor, plus pembrolizumab (anti-PD-1) is being investigated in the multicohort phase 1/2 MK-4280-003 efficacy and safety study (NCT03598608) in pts with R/R hematologic malignancies. Initial results from the MK-4280-003 study showed effective antitumor activity and tolerable safety in heavily pretreated pts with R/R cHL whose disease progressed after anti-PD-1 therapy (cohort 2) (Timmerman J, et al. J Clin Oncol. 2022;40(16_suppl):7545). Updated results from cohort 2 after additional follow-up are presented.
Methods: This study included a safety lead-in phase (part 1) to determine recommended phase 2 dose (RP2D) followed by a dose-expansion phase (part 2). Eligible pts in cohort 2 had R/R cHL after autologous stem cell transplantation (ASCT) or were ineligible for ASCT, and progressed after ≥2 doses of anti-PD-1 therapy. In part 1, pts from all cohorts received favezelimab IV 200 mg or 800 mg Q3W plus pembrolizumab IV 200 mg Q3W. Dose-finding based on occurrence of dose-limiting toxicities (DLT) was determined using a modified toxicity probability interval design. In part 2, pts received pembrolizumab plus favezelimab at the established RP2D (800 mg Q3W) for ≤35 cycles (~2 years). CT scans were performed Q12W and PET scans at Weeks 12 and 24 were performed to assess response by investigator review per the IWG 2007 criteria. Adverse event (AE) severity was graded per the NCI CTCAE v4.0. The primary end points were safety and RP2D. The secondary end point was ORR. Duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were exploratory.
Results: Cohort 2 enrolled 34 total pts. The median age was 37.5 years, 62% had Eastern Cooperative Oncology Group performance status 0, and 94% had ≥4 prior lines of therapy; 70% of responders had an anti-PD-1-based regimen as their most recent line of therapy at study entry. At database cutoff (May 03, 2022), 3 (9%) pts had completed 2 years of study treatment and 24 (71%) had discontinued (12 progressive disease; 7 AEs; 3 with clinical progression; 2 patient withdrawal/physician decision); 6 (18%) pts discontinued due to treatment-related AEs (TRAE). No treatment-related deaths occurred. Among the 28 (82%) pts who had TRAEs; the most common (≥10%) were hypothyroidism and nausea (18%, each), diarrhea and fatigue (15%, each), and arthralgia and headache (12%, each). Grade 3 or 4 TRAEs occurred in 6 (18%) pts; 2 (6%) events of hyponatremia, and 1 (3%) event each of autoimmune encephalitis, autoimmune hepatitis, increased alanine aminotransferase, neutropenia, diabetic ketoacidosis, and migraine with aura. One patient who received allogeneic hematopoietic stem cell transplantation after completion of study treatment had a grade 3 or 4 AE unrelated to study treatment (acute graft versus host disease) that resolved. A total of 25 of 28 (89%) pts with a post-dose scan had a baseline reduction in target lesions and 12 (43%) pts had ≥50% reduction from baseline (Figure). After a median follow-up of 19.0 months, 10 pts had objective response (ORR, 29% [95% CI, 15-48]; complete response [CR], 3 [9%]; partial response [PR], 7 [21%]). Of the 10 responders, 7 had ≥5 prior lines of therapy (CR, 3; PR, 4); 3 responders (all PR) had ≤4 prior lines of therapy. Median DOR was 19.4 months (range, 0.0+ to 19.4); 65% of pts had response ≥12 months. Median PFS was 10.7 months (95% CI, 5.1-14.7); 12-month PFS rate was 39%. Median OS was 25.7 months (95% CI, 25.7-NR); 12-month OS rate was 91%.
Conclusions: After additional follow-up, favezelimab plus pembrolizumab combination therapy continued to demonstrate sustained antitumor activity and acceptable safety in pts with R/R cHL whose disease progressed following anti-PD-1 therapy. A phase 3 study is planned to further investigate the promising results found in this patient population.
Disclosures
Timmerman:Merck: Research Funding; Bristol Myers Squibb: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Oncovalent: Consultancy; A2: Consultancy. Johnson:Merck, AbbVie, Roche, Gilead: Consultancy. Avigdor:Takeda, Gilead, Novartis, Roche, BMS: Consultancy; AbbVie: Honoraria. Borchmann:Miltenyi Biotec: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novarts: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Andreadis:Merck & Co., Inc.: Research Funding; Novartis: Research Funding; BMS: Honoraria; Kite: Honoraria. Gregory:BeiGene, Merck, AbbVie, Janssen: Research Funding; Janssen: Other: Expert testimony; Roche: Speakers Bureau; Roche, Novartis, BMS, Janssen: Consultancy; Roche, Novartis: Other: Travel/ Accommodations/ Expenses; Roche, BMS: Honoraria. Keane:Roche, Beigene, MSD: Consultancy. Vucinic:Novartis, Gilead Kite, Takeda, MSD, BMS Celgene, Abbvie, Amgen: Honoraria; MSD, BMS Celgene, Novartis, Gilead Kite, Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sobi, BMS Celgene: Other: travel, accommodations, expenses. Zinzani:Secura Bio: Membership on an entity's Board of Directors or advisory committees; Servier: 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; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: 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; Beigene: 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; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, 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; Eusapharma: Consultancy, 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; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: 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; University of Bologna: Current Employment. West:Merck & Co., Inc.: Current Employment. Pillai:Merck & Co., Inc.: Current Employment, Current holder of stock options in a privately-held company. Nahar:Merck & Co., Inc.: Current Employment. Herrera:Tubulis: Consultancy; Regeneron: Consultancy; Genmab: Consultancy; Pfizer: Consultancy; Caribou: Consultancy; Adicet Bio: Consultancy; KiTE Pharma: Research Funding; Gilead: Research Funding; Karyopharm: Consultancy; Takeda: Consultancy; ADC Therapeutics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding.
