Introduction: Programmed cell death protein 1 (PD-1) inhibitors such as pembrolizumab play an important role in the treatment of patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL), but treatment failure remains a significant challenge. Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint receptor that downregulates T-cell activity and plays a role in regulating T-cell function. Dual blockade of PD-1 and LAG-3 demonstrated antitumor activity in patients with advanced melanoma in the RELATIVITY-047 trial, which led to FDA approval in this setting. Favezelimab is a humanized IgG4 monoclonal antibody directed against LAG-3 that is being investigated in combination with pembrolizumab in patients with R/R hematologic malignancies in a multicohort phase 1/2 study (NCT03598608). Prior analyses of this study demonstrated that pembrolizumab 200 mg plus favezelimab 800 mg every 3 weeks (Q3W) exhibited sustained antitumor activity and acceptable safety in the cohort of patients with anti-PD-1-naive R/R cHL (cohort 1). We present updated results from this cohort.

Methods: A safety lead-in phase to determine the recommended phase 2 dose (RP2D) was followed by a dose-expansion phase. Eligible patients were ≥18 years of age; had R/R cHL after autologous stem cell transplantation (ASCT), were ineligible for ASCT, or did not respond to salvage chemotherapy; had not received prior anti-PD-1 therapy; and had an ECOG performance status of 0 or 1. In the safety lead-in, patients received pembrolizumab 200 mg IV Q3W and favezelimab at a starting dose of 200 mg that was escalated to 800 mg IV Q3W using a modified toxicity probability interval method. In the dose-expansion phase, patients received pembrolizumab 200 mg Q3W plus favezelimab at the established RP2D of 800 mg Q3W for up to 35 cycles (~2 years). CT was performed every 12 weeks and PET at weeks 12 and 24. The primary end point was safety. Objective response rate (ORR) per IWG 2007 criteria by investigator review was a secondary end point. Duration of response (DOR) and progression-free survival (PFS) per IWG 2007 criteria by investigator review and overall survival (OS) were exploratory.

Results: Thirty patients with anti-PD-1-naive cHL were enrolled in cohort 1. The median age was 40.5 years (range, 19-82), 17 patients (57%) were male, 16 (53%) had an ECOG performance status of 0, and 24 (80%) had received 3 or fewer prior lines of therapy. At data cutoff (March 2, 2023), 13 patients (43%) had completed 35 cycles of study treatment, 16 (53%) had discontinued treatment (10 [33%] progressive disease, 5 [17%] adverse event [AE], 1 [3%] noncompliance with study drug), and 1 (3%) was ongoing on treatment. The median time from first dose to data cutoff was 31.5 months (range, 24.0-43.2). Treatment-related AEs occurred in 27 patients (90%), of which the most common (≥20%) were hypothyroidism (27%), infusion-related reaction (23%), and fatigue (20%). Grade 3/4 treatment related AEs occurred in 9 patients (30%). Five patients (17%) discontinued treatment because of treatment-related AEs. No deaths due to treatment-related AEs were reported. AEs of clinical interest occurred in 20 patients (67%); 3 patients (10%) had grade 3 events (colitis, pneumonitis, severe skin reaction) and 1 patient (3%) had a grade 4 event (hepatitis). Of 5 patients who received allogeneic stem cell transplantation after discontinuation or completion of study treatment, 1 had a grade 3/4 AE (increased blood bilirubin) that was unrelated to study treatment and resolved. The ORR was 80% (n = 24; 95% CI, 61-92); 10 patients (33%) had a complete response and 14 (47%) had a partial response. Twenty-nine patients (97%) had any reduction in target lesions size from baseline, and 25 (83%) had a reduction of ≥50%. Median DOR was 17.0 months (range, 2.6-30.2), and an estimated 47% of responders remained in response ≥24 months. Median PFS was 19.4 months (95% CI, 9.0-28.5), and the 24-month PFS rate was 46%. Median OS was not reached (NR; 95% CI, NR-NR), and the 24-month OS rate was 93%.

Conclusion: With additional follow-up, the combination of favezelimab and pembrolizumab continued to demonstrate sustained antitumor activity and manageable safety in patients with anti-PD-1-naive R/R cHL. Analyses are underway to identify biomarkers predictive of response to the combination of favezelimab and pembrolizumab. Further studies to investigate this combination are warranted.

Johnson:Abbvie: Consultancy; Roche: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Gilead: Consultancy. Lavie:MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel/Accommodation expenses, lecture; Roche: Honoraria, Other: Advisory Board; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Lecture; Medisson: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board and Travel/Accommodation expenses; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Lecture. Borchmann:Takeda Oncology: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Merck Sharp & Dohme: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; MPI: Research Funding. Gregory:Prelude Therapeutics: Honoraria; Sandoz: Honoraria; Gilead: Honoraria; Clinigen: Honoraria; MSD: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Janssen: Consultancy, Other: Expert Testimony, Research Funding; BeiGene: Research Funding; Merck: Research Funding; Roche: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses; BMS: Consultancy, Honoraria; Merck: Research Funding. Herrera:Takeda: Consultancy; Tubulis GmbH: Consultancy; Pfizer: Consultancy; Merck: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; AbbVie: Consultancy; Kite, a Gilead Company: Research Funding; Caribou Biosciences: Consultancy; Karyopharm Therapeutics: Consultancy; Genmab: Consultancy; Regeneron: Consultancy; ADC Therapeutics: Consultancy, Research Funding; AstraZeneca/MedImmune: Consultancy; Allogene Therapeutics: Consultancy; Gilead Sciences: Research Funding; Seattle Genetics: Consultancy, Research Funding; BMS: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding; Adicet Bio: Consultancy; AstraZeneca: Research Funding. Vucinic:Takeda: Consultancy, Honoraria; Sobi: Honoraria, Other: Travel/Accommodations/Expenses; Amgen: Honoraria; MSD: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses; Gilead/Kite: Consultancy, Honoraria; Janssen: Honoraria; AstraZeneca: Honoraria; Abbvie: Honoraria. Armand:Kite - a Gilead company: Research Funding; ADC Therapeutics: Consultancy; GenMab: Consultancy; Enterome: Consultancy; Genentech/Roche: Consultancy, Research Funding; ATB Therapeutics: Consultancy; IGM: Research Funding; Adaptive Biotechnologies: Research Funding; Xencor: Consultancy; Affimed Therapeutics: Research Funding; Foresight Diagnostics: Consultancy; Regeneron: Consultancy; AstraZeneca: Consultancy, Research Funding; MSD: Consultancy, Research Funding; Tessa Therapeutics: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Avigdor:Gilead: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Travel/Accommodations/Expenses; Takeda: Membership on an entity's Board of Directors or advisory committees; MSD: Research Funding. Gasiorowski:Abbvie: Honoraria; Janssen: Honoraria; Astellas: Honoraria; Novartis: Honoraria; Otsuka: Honoraria; MSD: Honoraria; Antengene: Honoraria. Herishanu:Medison: Honoraria; Roche: Honoraria; Janssen: Honoraria, Research Funding; AbbVie: Honoraria; Lilly: Honoraria. Keane:AstraZeneca: Speakers Bureau; Beigene: Consultancy; Janssen: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy; Bristol Myers Squibb: Research Funding. Kuruvilla:Abbvie, BMS, Gilead, Merck, Roche, Seattle Genetics: Consultancy; Karyopharm: Other: DSMB; Abbvie, Amgen, Astra Zeneca, BMS, Genmab, Gilead, Incyte, Janssen, Merck, Novartis, Pfizer, Roche, Seattle Genetics: Honoraria; Roche, Astra Zeneca, Merck: Research Funding. Marceau West:Merck & Co., Inc.: Current Employment. Pillai:Merck & Co., Inc.: Current Employment, Current equity holder in publicly-traded company. Marinello:Merck & Co., Inc.: Current Employment, Current equity holder in publicly-traded company. Timmerman:DAVA Oncology: Consultancy; Merck & Co., Inc.: Research Funding; BMS: Other: Travel/Accommodations/Expenses, Research Funding; Oncovalent Therapeutics: Consultancy; Kite/Gilead: Consultancy, Honoraria, Research Funding.

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2023
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