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.
John Timmerman, David Lavie, Nathalie A. Johnson, Abraham Avigdor, Peter Borchmann, Charalambos Andreadis, Ali Bazargan, Gareth Gregory, Colm Keane, Inna Tzoran, Vladan Vucinic, Pier Luigi Zinzani, Hong Zhang, Pallavi Pillai, Akash Nahar, Alex F. Herrera