Background: PD-1 inhibitors are a standard of care in pts with R/R cHL but new approaches are still needed to deepen and lengthen responses. Dual blockade of PD-1 and LAG-3 has demonstrated antitumor activity in preclinical models. The multicohort phase 1/2 MK-4280-003 study (NCT03598608) evaluated the safety and efficacy of favezelimab (MK-4280), a humanized IgG4 LAG-3 inhibitor, plus pembrolizumab (pembro; a PD-1 inhibitor) in pts with R/R hematologic malignancies. This analysis focused on anti–PD-1–naïve pts with R/R cHL (cohort 1). Methods: This study included a safety lead-in phase (part 1) to determine the recommended phase 2 dose (RP2D) followed by a dose-expansion phase (part 2). Eligible pts in cohort 1 must have R/R cHL after autologous stem cell transplantation (ASCT) or be ineligible for ASCT and have had no prior anti–PD-1 therapy. In part 1, patients from all cohorts received pembro IV 200 mg Q3W and favezelimab IV 200 mg or 800 mg Q3W. Dose escalation followed the mTPI design. In part 2, pts received pembro + favezelimab at the established RP2D for up to 35 cycles. Primary end point was safety. Secondary end point was ORR. DOR, PFS, and OS were exploratory end points. Results: Only 1 dose-limiting toxicity (DLT; autoimmune hepatitis [grade 4]) was identified among the first 6 pts from all cohorts in part 1 at the favezelimab 200 mg dose; thus, the dose was escalated to 800 mg. No DLTs were observed in the 15 additional pts treated at the 800 mg dose. The RP2D for the combination was defined as 800 mg Q3W + pembro 200 mg Q3W. In cohort 1, 30 pts were enrolled; median age was 40 years, 53% had ECOG PS 0, and 80% had ≤3 prior lines of therapy. After a median follow-up of 13.5 mo, ORR for cohort 1 was 73% (95% CI, 54-88; CR, 7 pts [23%]; PR, 15 pts [50%]). 28 of 30 pts (93%) had reduction from baseline in target lesions. Median DOR was not reached (NR; 95% CI, 0+ to 23+ mo); 6 pts (51%) had response ≥12 mo. Median PFS was 19 mo (95% CI, 8-NR); 12-mo PFS rate was 57%. Median OS was NR (95% CI, NR-NR); 12-mo OS rate was 94%. As of the database cutoff (Nov 1, 2021), 9 of 30 pts had discontinued (3 AEs; 6 PD). Treatment-related AEs (TRAE) occurred in 26 pts (87%); most common (≥10%) were hypothyroidism (27%), fatigue (20%), infusion-related reactions (20%), headache (17%), and arthralgia, hyperthyroidism, myalgia, and nausea (10% each); grade 3 or 4 TRAEs occurred in 6 pts (20%). 10% of pts discontinued due to TRAEs. No treatment-related deaths occurred. Conclusions: Favezelimab 800 mg + pembrolizumab 200 mg Q3W demonstrated a tolerable safety profile and effective antitumor activity in pts with anti–PD-1–naïve R/R cHL. Further studies will be useful to compare its activity to that of pembrolizumab alone. Clinical trial information: NCT03598608.