Phase I Study of Fianlimab, a Human Lymphocyte Activation Gene-3 (LAG-3) Monoclonal Antibody, in Combination With Cemiplimab in Advanced Melanoma

Abstract

Purpose: Coblockade of lymphocyte activation gene-3 (LAG-3) and PD-1 receptors could provide significant clinical benefit for patients with advanced melanoma. Fianlimab and cemiplimab are high-affinity, human, hinge-stabilized IgG4 monoclonal antibodies, targeting LAG-3 and PD-1, respectively. We report results from a first-in-human phase-I study of fianlimab and cemiplimab safety and efficacy in various malignancies including advanced melanoma.

Methods: Patients with advanced melanoma were eligible for enrollment into four cohorts: three for patients without and one for patients with previous anti-PD-1 therapy in the advanced disease setting. Patients were treated with fianlimab 1,600 mg and cemiplimab 350 mg intravenously once every 3 weeks for up to 51 weeks, with an optional additional 51 weeks if clinically indicated. The primary end point was objective response rate (ORR) per RECIST 1.1 criteria.

Results: ORRs were 63% for patients with anti-PD-1-naïve melanoma (cohort-6; n = 40; median follow-up 20.8 months), 63% for patients with systemic treatment-naïve melanoma (cohort-15; n = 40; 11.5 months), and 56% for patients with previous neo/adjuvant treatment melanoma (cohort-16; n = 18, 9.7 months). At a median follow-up of 12.6 months for the combined cohorts (6 + 15 + 16), the ORR was 61.2% and the median progression-free survival (mPFS) 13.3 months (95% CI, 7.5 to not estimated [NE]). In patients (n = 13) with previous anti-PD-1 adjuvant therapy, ORR was 61.5% and mPFS 12 months (95% CI, 1.4 to NE). ORR in patients with previous anti-PD-1 therapy for advanced disease (n = 15) was 13.3% and mPFS 1.5 months (95% CI, 1.3 to 7.7). Treatment-emergent and treatment-related adverse events ≥grade 3 (G3) were observed in 44% and 22% of patients, respectively. Except for increased incidence of adrenal insufficiency (12%-G1-4, 4%-G3-4), no new safety signals were recorded.

Conclusion: The current results show a promising benefit-risk profile of fianlimab/cemiplimab combination for patients with advanced melanoma, including those with previous anti-PD-1 therapy in the adjuvant, but not advanced, setting.

Trial registration: ClinicalTrials.gov NCT03005782.

FIG 1.

Efficacy of fianlimab/cemiplimab combination in patients with no previous systemic anti–PD-1 treatment for advanced disease (cohorts 5, 15, and 16). (A) Waterfall plot showing that any tumor response was seen in 72% of patients. (B) Spider plot showing tumor responses were fast, deep, and durable in a high proportion of patients. ^aFive patients who had nonevaluable response and one more patient who only had nontarget lesion response were not included in the waterfall plot. CR, complete response; NE, not estimated; PD, progressive disease; PR, partial response; SD, stable disease; SOD, sum of diameters.

FIG 2.

Progression-free survival in all patients with no previous systemic anti–PD-1 treatment for advanced disease (cohorts 5, 15, and 16 combined). The median Kaplan-Meier estimated progression-free survival in these patients was 13 months (95% CI, 8 to non evaluated). The estimated event-free probability at 12 months was 52% (95% CI, 41 to 62). PFS, progression-free survival.