Fianlimab/Cemiplimab Yields Activity in Pretreated Metastatic Melanoma


The safety of fianlimab plus cemiplimab appears consistent with the safety profile previously observed with each individual agent among patients with previously treated metastatic melanoma in a phase 1 study.

Fianlimab/Cemiplimab Yields Activity in Pretreated Metastatic Melanoma | Image Credit: © David A Litman -

A phase 3 trial (NCT05352672) of fianlimab plus cemiplimab in treatment-naive advanced melanoma is currently underway with a targeted enrollment approximately of 1590 patients.

The addition of fianlimab to cemiplimab (Libtayo) demonstrated tolerability and efficacy in patients with previously treated advanced melanoma, according to findings from a phase 1 study (NCT03005782) presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting.1

The phase 1 study (NCT03005782) enrolled 98 patients, 13.3% of whom had received PD-1/PD-L1 inhibitors as adjuvant or neoadjuvant therapy. The objective response rate (ORR) for fianlimab/cemiplimab was 61.2% in all patients, 60.9% in patients with any adjuvant treatment, and 61.5% in those who had received adjuvant PD-1 therapy.

“In the combination of fianlimab and cemiplimab, we showed a consistent and reproducible high clinical activity in 3 independent cohorts of patients who were naive to anti–PD-1 in the advanced melanoma setting,” Omid Hamid, MD, chief of translational research and immunotherapy and director of melanoma therapeutics at The Angeles Clinic and Research Institute in Los Angeles, California, stated in his presentation. “Similar clinical activity was observed in patients treated with prior adjuvant therapies including anti–PD-1.”

Patients with unresectable or metastatic melanoma who had not received prior anti–PD-1/PD-L1 therapy for advanced disease were enrolled in 3 expansion cohorts of the study. Two of these cohorts had previously been reported on at an earlier data cut-off of July 1, 2022; in those results, the combination of the LAG-3 inhibitor fianlimab with the PD-1 inhibitor cemiplimab had an ORR of 62.5% in patients in an initial first or second-line cohort and a confirmatory first-line cohort which had both received no prior anti–PD-1/PD-L1 therapy.2

Hamid presented updated results from these cohorts with a total of 40 patients in each cohort, plus 18 in an additional cohort of first-line patients with metastatic disease who had received prior adjuvant/neoadjuvant therapy. They received 1600 mg fianlimab plus 350 mg cemiplimab every 3 weeks for 12 months, with an additional 12 months if clinically indicated.1 Tumors were measured every 6 weeks for 24 weeks, then every 9 weeks thereafter.

The median age of patients was 68.0 years. Two percent of patients had received prior treatment for metastatic disease, 23.5% had received adjuvant or neoadjuvant systemic treatment with a disease-free interval of at least 6 months. The 13 patients who received adjuvant/neoadjuvant PD-1/PD-L1 therapy had been treated with nivolumab (Opdivo) or pembrolizumab (Keytruda). Thirty patients across the 3 cohorts had a BRAF mutation and 21 had liver metastases.

At the data cut-off of November 1, 2022, the median follow-up was 12.6 months and the median duration of treatment was 32.9 weeks. Three patients (8%) in the initial cohort, 14 (35%) in the confirmatory cohort, and 5 (28%) in the prior adjuvant cohort were ongoing treatment; others had completed or discontinued therapy.

The RECIST 1.1-based investigator-assessed ORR of 61.2% included 12 complete responses (CR) and 48 partial responses (PR). The disease control rate was 78%. The median duration of response (DOR) was not reached (95% CI: 23-not estimated [NE]). The Kaplan-Meier estimated median progression-free survival (PFS) was 15.3 months (95% CI, 9.4-NE).

“Tumor responses in these cohorts together compared favorably with historical controls in relation to follow-up, overall response, disease control rate, and estimated median [PFS],” Hamid said.

When looking at the patients who had prior adjuvant therapy of any type, including 5 in the initial cohort, 14 out of 23 responded to the fianlimab/cemiplimab combination, with a median DOR that was not reached and a median PFS of 13.3 months. Adjuvant/neoadjuvant therapies included PD-1 agents, interferon, and BRAK/MEK-targeted treatments. For those who had received prior adjuvant nivolumab or pembrolizumab, 8 out of 13 responded to the combination, including 1 complete response. They had a median DOR that was not reached and a median PFS of 11.8 months.

A subgroup analysis was conducted for patients with poor prognosis melanoma including 21 with liver metastases, 32 with high baseline lactate dehydrogenase (LDH), and 17 M1c stage plus LDH greater than the upper limit of normal. These subgroups had an ORR of 43%, 53%, and 35%, respectively, and this analysis was also presented in detail by Inderjit Mehmi, MD, in a poster at the conference.

Fifty-five patients had LAG-3 expression of at least 1% and 26 had PD-L1 expression of at least 1%. According to Hamid, “In this cohort, efficacy was observed regardless of LAG-3 or PD-L1 tumor expression.”

In terms of safety, 43.9% had grade 3 or higher treatment-emergent adverse events (TEAEs) and 32.7% had serious TEAEs. Immune-related adverse events (irAEs) occurred in 65.3%, with 12% being grade 3 or higher. Patients required treatment discontinuation in 16.3% due to TEAEs. Rates of irAEs were similar to PD-1 monotherapy in general.

“Overall, the safety overview of this combination was generally consistent with the safety profile that we are familiar with of single-agent cemiplimab and other anti–PD-1 agents,” Hamid said. “Only adrenal insufficiency, at a rate of 11%, appeared to be higher in this cohort, most grade 1 or 2, and all cases successfully managed with steroid replacement.” One case of adrenal insufficiency was associated with treatment discontinuation.

A phase 3 trial (NCT05352672) of fianlimab plus cemiplimab in treatment-naive advanced melanoma is currently underway with a targeted enrollment approximately of 1590 patients. It includes 4 arms including 1 using the dose level of the phase 1 trial, 1 with a lower dose of fianlimab, and 2 comparator arms of pembrolizumab plus placebo and cemiplimab plus placebo. Another phase 3 trial (NCT05608291) is taking place in the adjuvant setting in comparison to pembrolizumab plus placebo.

These data support the efficacy and safety of the anti–PD-1/LAG-3 combination even in patients who have received prior adjuvant immunotherapy, as well as those with poor prognostic features.


1. Hamid O, Lewis KD, Weise AM, et al. Significant durable response with fianlimab (anti–LAG-3) and cemiplimab (anti–PD-1) in advanced melanoma: Post adjuvant PD-1 analysis. J Clin Oncol. 2023;41(suppl_16):9501. doi:10.1200/JCO.2023.41.16_suppl.9501

2. Hamid O, Weise AM, Kim TM, et al. Phase I study of fianlimab, a human lymphocyte activation gene-3 (LAG-3) monoclonal antibody, in combination with cemiplimab in advanced melanoma (mel). Ann Oncol. 2022;33(suppl_7):S356-S409. doi:10.1016/annonc/annonc1059

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