Dr McKean on the Rationale For Evaluating LAG-3 Inhibitors in Advanced Melanoma

Meredith McKean, MD, MPH, director, Melanoma and Skin Cancer Research Program, Sarah Cannon Research Institute, discusses the rationale for investigating the LAG-3 inhibitor fianlimab (REGN3767) in combination with cemiplimab-rwlc (Libtayo) in patients with advanced melanoma, highlighting the combination's efficacy in both PD-1 inhibitor-exposed and –naïve populations, as well as the combinations itspotential clinical significance within the advanced melanoma space.

A phase 1, first-in-human study (NCT03005782) was conducted to evaluate the use of LAG-3 inhibition in combination with anti–PD-1 therapy to enhance treatment outcomes in patients with advanced melanoma. This approach was derived from the successes observed with other combination checkpoint inhibitors, such as ipilimumab (Yervoy) and anti-PD–1 agents, McKean explains. Although these combinations typically resulted in igh response rates, this often came at the cost of significant toxicity. In turn, this raised the question of whether response rates could be maintained with the addition of a LAG-3 inhibitor to a PD-1 inhibitor while minimizing treatment-related toxicity, McKean says.

The study included patients who received anti–PD-1 treatment in the neoadjuvant or adjuvant setting, as well as those who had not been previously exposed to a PD-1 inhibitor. Results were presented at the 2023 ASCO Annual Meeting.

In PD-1 treatment-naïve patients with metastatic or locally advanced disease, the LAG-3 inhibitor fianlimab plus the PD-1 inhibitor cemiplimab generated an overall response rate of 63.8% and a median progression-free survival (PFS) of 24.0 months, McKean reports. Notably, observed toxicity levels were not substantially higher than what would typically be expected with single-agent anti–PD-1 therapy, she states.

Additionally, response rates in patients who had previously been exposed to anti–PD-1therapy and subsequently experienced disease recurrence ranged from 50% to 60%, a result that exceeded expectations, McKean details. Many of these patients had completed their prior anti–PD-1 treatment or were not currently receiving it, potentially contributing to the favorable outcomes, McKean notes.

Further investigation is needed to confirm these findings in randomized studies, McKean continues. If validated, the combination of fianlimab plus cemiplimab may provide patients with a highly effective, yet less toxic alternative to ipilimumab (Yervoy) and nivolumab (Opdivo) in the front line, McKean states. Moreover, this approach holds promise for patients who developed refractory disease and for whom previous LAG-3 inhibitors have had limited efficacy, McKean adds. Additionally, combining LAG-3 and anti–PD-1 therapies in the adjuvant setting may improve outcomes for patients who previously had few treatment options, McKean says. The study's findings mark a significant step forward in advancing treatment options in melanoma while prioritizing patient safety and efficacy, she concludes.