Fianlimab Combined With Cemiplimab Elicits Durable Responses in Advanced Melanoma

Omid Hamid, MD

Cemiplimab (Libtayo) plus fianlimab (formerly REGN 3767) has demonstrated favorable clinical activity in in patients with advanced melanoma in comparison with FDA-approved immune checkpoint inhibitor (ICI) combinations.¹

The results come from an analysis of 3 separate expansion cohorts that included adult patients with unresectable or metastatic melanoma, excluding those with uveal melanoma. The population of 98 patients were all naïve to treatment with an anti-PD-L1 agent. Patients had a median age of 68.0 years and were predominantly male (60.2%). Patients identifying as White made up the majority of the population (89.9%). In terms of prior treatment, 2.0% of patients received treatment in the metastatic setting, and 23.5% received systemic therapy in the adjuvant or neoadjuvant settings. Of those who received adjuvant/neoadjuvant therapy, 13.3% had either nivolumab (Opdivo) or pembrolizumab (Keytruda).

Patients in each cohort received fianlimab 1600 mg plus cemiplimab 350 mg administered by intravenous (IV) infusion every 3 weeks, for up to 51 weeks. The study evaluated the primary end point of objective response rate (ORR), and the secondary end points of progression-free survival (PFS), duration of response (DOR), disease control rate (DCR), safety, and pharmacokinetics.

The ORR per RECIST v1.1 criteria observed in the 3 cohorts overall was 61.2% (95% CI, 51%-71%). The favorable ORR was seen regardless of LAG-3 or PD-L1 expression. The median DOR was not reached, (95% CI, 22.6% to not evaluable [NE]). The overall PFS was 15.3 months (95% CI, 9.4 months to not evaluable). PFS was also consistent regardless of LAG-3 or PD-L1 expression.

For safety, results showed that grade 3-5 treatment-emergent adverse events (TEAEs) occurred in 44% of patients, any-grade TEAEs were considered serious for 33% of patients, and any grade of treatment-emergent immune-related AEs were observed in 65% of patients. These treatment-emergent immune-related AEs were grade 3-5 in 12%, and the most common were rash (20%), pruritis (16%), diarrhea (15%), and arthralgia (13%).

The occurrence of TEAEs lead to treatment discontinuation in 16% of the analysis population.

Overall, investigators led by Omid Hamid, MD reported that the clinical activity of fianlimab combined with cemiplimab was high, including in high-risk subgroups. Moreover, the safety profile of the combination was acceptable.

“Although this is a small number of patients, this experience is one of, if not the best, experiences we must answer the question of which is the appropriate therapy in patients who have failed adjuvant anti PD-1 therapy. This is a valid and important question for us to begin to answer, as most patients with melanoma will have the opportunity to see an anti-PD-1 in the adjuvant setting if they're a high-risk stage II patient or any stage III patient,” said Hamid, medical oncologist at The Angeles Clinic and Research Institute in Los Angeles, California, chief of translational research and immune-oncology and the co-director of the cutaneous malignancy program, in an interview with Targeted Oncology™.

In the interview, Hamid discussed the efficacy of finanlimab, an anti-LaG-3 antibody, in combination with centrilimab, an anti PD-1 antibody, for patients with advanced melanoma who had not received a PD-1 inhibitor. The results of the study show new possibilities for treating patients who have failed adjuvant anti PD-1 therapy.

Targeted Oncology: Can you provide an overview of your recent presentation at the 2023 ASCO Annual Meeting?

Hamid: Fianlimab is a checkpoint inhibitor or targets LaG-3, so it's an anti-LaG-3 antibody. The data I presented at ASCO are expansion cohorts of a clinical protocol, which was a phase 1/2 of fianlimab, an anti-LAG antibody, and cemiplimab, which is an anti PD-1 antibody, that are given in combination at fixed doses of 1600 mg for fianlimab and 350 mg for cemiplimab IV every 3 weeks for 51 weeks in advanced melanoma that has not seen a PD-1 inhibitor.

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Can you explain the design of this analysis?

These are expansion cohorts in a phase 2 pattern. Patients were included on 3 separate cohorts. The first cohort were patients who could have seen prior therapy if it was not an anti PD-1 or a LaG-3 inhibitor. The second cohort were [patients with] advanced melanoma that were treatment naive. The third cohort was for patients who had seen prior neoadjuvant or adjuvant therapy, and then had a 6-month or more disease-free interval and recurred in the advanced setting.

What is your take on the efficacy findings from this analysis?

What we saw here is that responses were rapid, deep, and durable, the response rate was significant at 61%. Across all 98 patients, what we saw was a duration of response that was not reached at this point, and a median progression-free survival of 15 months with this combination of an anti LaG-3 that's given at a higher dosage than historical and more frequent than historical combinations. This is a fantastic response that is in line with what we've seen in other combinations, including RELATIVITY-047 [NCT03470922] and CheckMate 067 [NCT01844505]. It's very tolerable with no real new signals, with an increased incidence of adrenal sufficiency that was manageable.

The most interesting data comes from the third cohort of patients that were accrued. These were patients who had adjuvant or neoadjuvant therapy with a recurrence in the advanced setting of at least 6 months. In these patients, we had 13 patients who had seen prior PD-1 antibody in 1 form or another in that adjuvant neoadjuvant setting. In those patients, there was a significant response rate of 61%. Although this is a small number of patients, this experience is one of if not the best experience, we have to answer the question of what an appropriate therapy in patients who have failed adjuvant anti PD-1 therapy. This is a valid and important question for us to begin to answer, as most patients with melanoma will have the opportunity to see an anti PD-1 in the adjuvant setting, if they're a high-risk stage II patient or any stage III patient. The therapeutic paradigm has shifted where now we were seeing the majority of our patients who are recurring after seeing checkpoint inhibitor.

What are the next steps for the space?

The next steps for this space are further long-term data and some of that's going to be presented at ASCO, but the belief of combination of 2 checkpoint inhibitors is valid because it moves our therapeutic paradigm for everyone globall. But for those of us who are doing phase 1 clinical trials, the next step is looking at triplets, quadruplets, or others. Not only checkpoint with checkpoint, but checkpoints with T-cell manipulative therapies, checkpoints with tumor microenvironment therapies or bispecifics, and those trials are coming. [This] brings me to my final and most important point which is that if you're looking for the next option, clinical trials are where we should be going. The future is bright. We are doing those trials now and should report them shortly.

_REFERENCE:

_{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}