Fianlimab Plus Cemiplimab Falls Short of PFS Goal in First-Line Melanoma

Fianlimab (REGN3767), a LAG-3 inhibitor, in combination with the PD-1 inhibitor cemiplimab (Libtayo) did not achieve statistical significance for its primary end point of progression-free survival (PFS) improvement vs pembrolizumab (Keytruda) monotherapy in patients with previously untreated unresectable locally advanced or metastatic melanoma, according to a news release from Regeneron.¹

In the randomized phase 3 trial (NCT05352672), there was a numeric improvement of 5.1 months median PFS, but this was insufficient to establish the benefit of the combination vs single-agent anti–PD-1 therapy.

Trial Design

The randomized, double-blind trial enrolled 1546 patients aged 12 years and older with no prior systemic treatment for advanced disease. Participants were assigned to 1 of 4 arms: high-dose fianlimab (1600 mg) plus cemiplimab (350 mg) every 3 weeks; low-dose fianlimab (400 mg) plus cemiplimab every 3 weeks; pembrolizumab (200 mg) plus placebo every 3 weeks; or cemiplimab plus placebo every 3 weeks. The cemiplimab monotherapy arm was included to define the contribution of individual components but was not incorporated into formal statistical comparisons. Secondary end points included disease control rate, duration of response, pharmacokinetics, and immunogenicity.

Results

The high-dose combination demonstrated a median PFS of 11.5 months (95% CI, 6.3-16.8) vs 6.4 months (95% CI, 4.4-11.1) for pembrolizumab monotherapy, representing a numerical improvement of 5.1 months. However, this difference did not reach statistical significance (HR, 0.845; 95% CI, 0.709-1.008; P =.0627).

The low-dose combination yielded a median PFS of 9.6 months (95% CI, 6.2-13.9) compared with 6.4 months among a subset of concurrently randomized pembrolizumab-treated patients (n = 421), also falling short of significance (HR, 0.931; 95% CI, 0.773-1.122; P =.4661). The cemiplimab monotherapy arm reported a median PFS of 6.3 months (95% CI, 4.0-17.2), broadly consistent with the pembrolizumab control. No new safety signals were identified.

Context and Implications

The high-dose fianlimab/cemiplimab combination demonstrated promising early efficacy in a previous phase 1 trial (NCT03005782) with a 63% overall response rate in PD-1–naive metastatic melanoma cohorts with a favorable safety profile that was consistent with cemiplimab monotherapy, with an approximately 20% rate of grade 3 or higher treatment-related adverse events.²

The approval of nivolumab plus relatlimab-rmbw (Opdualag) in 2022 validated the combination of PD-1 and LAG-3 inhibition in treatment-naive advanced melanoma, demonstrating superior PFS over nivolumab (Opdivo) monotherapy in a phase 2/3 trial.³ However, the observed 5.1-month numerical improvement in median PFS with the high-dose combination over pembrolizumab, while clinically suggestive, was insufficient to cross the prespecified statistical threshold in this large, adequately powered trial.¹

A separate ongoing phase 3 head-to-head trial (NCT06246916) is directly comparing the high-dose fianlimab-plus-cemiplimab combination against nivolumab/relatlimab in first-line unresectable or metastatic melanoma. That trial, which positions fianlimab against an active LAG-3–containing comparator rather than PD-1 monotherapy, may offer a more granular assessment of whether the drug’s distinct mechanism and higher LAG-3 target engagement confer a meaningful advantage within the dual-checkpoint inhibitor class.

Detailed results from this trial are forthcoming at an upcoming medical meeting, where subgroup analyses and secondary endpoint data may provide further context for interpreting the numerical PFS benefit observed with the high-dose combination.

REFERENCES

1. Regeneron provides update on phase 3 trial of fianlimab (LAG-3 Inhibitor) combination in first-line unresectable or metastatic melanoma. News release. Regeneron. May 17, 2026. Accessed May 18. 2026. https://tinyurl.com/4vyy7u4a

2. Hamid O, Lewis KD, Weise A, et al. Phase I study of fianlimab, a human lymphocyte activation gene-3 (LAG-3) monoclonal antibody, in combination with cemiplimab in advanced melanoma. J Clin Oncol. 2024;42(24):2928-2938. doi:10.1200/JCO.23.02172

3. Long GV, Stephen Hodi F, Lipson EJ, et al. Overall survival and response with nivolumab and relatlimab in advanced melanoma. NEJM Evid. 2023;2(4):EVIDoa2200239. doi:10.1056/EVIDoa2200239