Background: PD-1 inhibitors are a standard of care for R/R cHL but optimal therapy after anti–PD-1 therapy failure is yet to be defined. LAG-3/PD-1 coblockade has demonstrated antitumor activity in preclinical models. This multicohort phase 1/2 study (NCT03598608) evaluated the safety and efficacy of favezelimab (MK-4280), a humanized IgG4 LAG-3 inhibitor, plus the PD-1 inhibitor pembrolizumab (pembro) in pts with R/R hematologic malignancies. Cohort 2 focused on pts with R/R cHL refractory to anti–PD-1 therapy. 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, relapsed after or were ineligible for autologous stem cell transplantation (ASCT), and progressed after ≥2 doses of anti–PD-1 therapy (within 12 weeks of last dose). In part 1, pts from all cohorts received pembro IV 200 mg Q3W and favezelimab IV 200 mg or 800 mg Q3W. Dose-finding based on occurrence of dose-limiting toxicities (DLT) was determined using an 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. Results: Only 1 DLT (autoimmune hepatitis [grade 4]) was observed 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 15 additional pts at the 800 mg dose. Favezelimab RP2D was defined as 800 mg Q3W + pembro 200 mg Q3W. In cohort 2, 33 pts were enrolled; median age was 37 yrs, 64% had ECOG PS 0, and 94% had ≥4 prior lines of therapy. After a median follow-up of 16.5 mo, ORR for pts receiving favezelimab 800 mg (n = 29) was 31% (95% CI, 15-51; CR, 2 [7%]; PR, 7 [24%]); 66% of responders had an anti–PD-1–based regimen as most recent line of therapy at study entry. 23 of 29 pts (79%) had reduction from baseline in target lesions. Median DOR for pts who received favezelimab 800 mg was not reached (NR; 95% CI, 0+ to 14+ mo). For all pts in cohort 2, median PFS was 9 mo (95% CI, 5-15); 12-mo PFS rate was 39%. Median OS was 26 mo (95% CI, 26-NR); 12-mo OS rate was 91%. At database cutoff (Nov 1, 2021), 20 pts discontinued treatment (7 AEs, 11 PD/clinical progression, 2, withdrawal/physician decision). TRAEs occurred in 28 pts (85%); most common ( > 10%) were hypothyroidism (18%), nausea and fatigue (15% each), and arthralgia and diarrhea (12% each); grade 3 or 4 TRAEs occurred in 6 pts (18%); 18% discontinued treatment due to TRAEs. No treatment-related deaths occurred. Conclusions: Favezelimab 800 mg + pembro 200 mg Q3W showed a tolerable safety profile and effective antitumor activity in heavily pretreated pts with R/R cHL whose disease had progressed after anti–PD-1 therapy, suggesting that the combination may reinduce a response in these pts. Clinical trial information: NCT03598608.