P1067: estimating the relative efficacy of favezelimab when used in combination with pembrolizumab in patients with pd-1–refractory classical hodgkin lymphoma

Topic: 17. Hodgkin lymphoma - Clinical Background: Treatment options are limited for patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) whose disease has progressed after a PD-1 inhibitor. LAG-3 is an inhibitory receptor involved in T-cell regulation that is coexpressed with PD-1 on tumor-infiltrating T cells. Favezelimab is a LAG-3 inhibitor that showed promising antitumor activity when used in combination with the PD-1 inhibitor pembrolizumab in patients with PD-1–refractory R/R cHL in the phase 1/2 MK-4280-003 study (Timmerman J et al. J Clin Oncol. 2022;40(16 suppl):7545). Although the objective response rate (ORR) in this study was promising, the contribution of favezelimab to this response was unclear. Aims: This post hoc analysis aimed to evaluate the relative efficacy of favezelimab + pembrolizumab compared with pembrolizumab alone in patients with PD-1–refractory R/R cHL. Because no studies have investigated pembrolizumab monotherapy in this setting, historical data from patients with R/R cHL who received pembrolizumab beyond progression in the phase 2 KEYNOTE-087 study were used as a historical control. Methods: Patients from KEYNOTE-087 were included in the historical control arm if they had received more than 2 doses of pembrolizumab beyond progression, had confirmed disease progression within 12 weeks of the last dose of pembrolizumab (confirmatory scan ≥4 weeks from initial progression), and had undergone postprogression scans. All patients from MK-4280-003 with a baseline and postbaseline assessment available were included. Patients in KEYNOTE-087 received pembrolizumab 200 mg IV every 3 weeks (Q3W). Patients in MK-4280-003 received pembrolizumab 200 mg IV Q3W plus favezelimab 200 mg or 800 mg IV Q3W. For patients in the historical control arm, baseline tumor size was reset to the time of the first progression, and best change in target lesion size was calculated for the postprogression period. ORR was assessed using Cheson 2007 criteria. A bootstrapping method with 1000 samples was used to compare best change in target lesion size between the studies. Results: 27 of 33 patients enrolled in MK-4280-003 qualified for radiographic analysis and were included. In KEYNOTE-087, 123 patients developed progressive disease during treatment with pembrolizumab monotherapy, of whom 81 received postprogression pembrolizumab and were included in the historical control arm. The ORR was 31% (range, 15-51) for patients treated with favezelimab + pembrolizumab compared with 2.5% (range, 0-5.9) among patients who received pembrolizumab monotherapy beyond progression. The average response was also deeper with favezelimab + pembrolizumab compared with the historical pembrolizumab control (mean of waterfall plots, −46.6% vs −0.37%). A larger proportion of patients treated with favezelimab + pembrolizumab had a ≥50% reduction in target lesion size compared with the historical pembrolizumab control (44% vs 5%). Using the bootstrapping method, 26,826 of 27,000 (99.4%) samples showed a better response for favezelimab + pembrolizumab relative to pembrolizumab monotherapy.Summary/Conclusion: In this post hoc analysis, the combination of favezelimab + pembrolizumab was associated with a higher ORR and deeper responses than pembrolizumab monotherapy in patients with PD-1–refractory R/R cHL. Although limited by its retrospective nature, the results support the hypothesis that favezelimab contributed substantially to the efficacy observed in the MK-4280-003 study. Keywords: Clinical trial, Hodgkin’s lymphoma, Immunotherapy