Background: Optimizing therapies for pts with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) after anti–PD-1 therapy failure remains of clinical interest. The multicohort phase 1/2 MK-4280-003 study (NCT03598608) evaluated the safety and efficacy of a LAG-3 inhibitor, favezelimab (MK-4280), + pembrolizumab (pembro) in pts with R/R hematologic malignancies. Cohort 2 focused on pts with R/R cHL after anti–PD-1 therapy.
Methods: Part 1 was the safety lead-in phase to determine the recommended phase 2 dose (RP2D), followed by a dose-expansion phase (part 2). Eligible pts in cohort 2 had cHL and relapsed after or were ineligible for autologous stem cell transplantation and PD after ≥2 doses of anti–PD-1 therapy. Pts in part 1 received escalating doses (per mTPI design) of pembro IV 200 mg Q3W and favezelimab IV 200 mg or 800 mg Q3W. In part 2, pts received pembro + favezelimab at RP2D for ≤35 cycles. Primary end point was safety. ORR was a secondary end point. DOR, PFS, and OS were exploratory end points. Database cutoff was March 21, 2022.
Results: Part 1 identified 1 dose-limiting toxicity (DLT; autoimmune hepatitis [grade 4]) among the first 6 pts from all cohorts at the favezelimab 200 mg dose. No DLTs were found after an additional 15 pts at the 800 mg dose; RP2D was defined as 800 mg Q3W + pembro 200 mg Q3W. 34 pts were enrolled in cohort 2; median age was 37.5 y, 62% had ECOG PS 0, and 94% had ≥4 prior lines of therapy. At database cutoff, 22/34 pts had discontinued (11 PD; 7 AEs; 2 clinical progression; 2 pt withdrawal/physician decision); 18% discontinued due to treatment-related AEs (TRAE). No deaths were treatment related. 28 pts (82%) had TRAEs; most common (≥15%) were hypothyroidism (18%) and fatigue and nausea (15%, each); 6 pts (18%) had grade 3 or 4 TRAEs. After median follow-up of 18.4 mo, ORR was 30% (95% CI,16-49; CR, 3 [9%]; PR, 7 [21%]). 25/27 (93%) pts with a postdose scan had a baseline reduction in target lesions. 70% of responders had an anti–PD-1–based regimen as most recent line of therapy at study entry. Median DOR was 19.4 mo (range, 0+ to 19.4); 4 pts (65%) had response ≥12 mo. Median PFS was 9.4 mo (range, 5.1-14.7). and median OS was 25.7 mo (range, 21.2-NR).
Conclusion: Favezelimab 800 mg + pembrolizumab 200 mg Q3W demonstrated acceptable safety and effective antitumor activity in pts with R/R cHL and PD following anti–PD-1 therapy. This combination shows potential to reinduce a response in this pt population.