FDA Approves Relatlimab Plus Nivolumab for Unresectable or Metastatic Melanoma

The FDA has granted approval to the fixed-dose combination of relatlimab plus nivolumab (Opdualag) for the treatment of adult and pediatric patients who are 12 years of age or older and who have unresectable or metastatic melanoma, according to an announcement by Bristol Myers Squibb.¹

The FDA’s decision to approve the combination is based on findings from the phase 2/3 RELATIVITY-047 trial (NCT03470922), in which relatlimab plus nivolumab demonstrated a 20% reduction in risk death and numerically improved overall survival rates compared to nivolumab alone, according to results presented during the recent ASCO Plenary Series: March 2022 Session.^1,2

“Since the approval of the first immune checkpoint inhibitor more than 10 years ago, we’ve seen immunotherapy, alone and in combination, revolutionize the treatment of patients with advanced melanoma,” said F. Stephen Hodi, MD, director of the Melanoma Center and the Center for Immuno-Oncology at Dana-Farber Cancer Institute, in a press release.¹ “Today’s approval is particularly significant, as it introduces an entirely new combination of two immunotherapies that may act together to help improve anti-tumor response by targeting two different immune checkpoints — LAG-3 and PD-1.”

Results appeared consistent with those of the primary analysis as the study previously met its primary end point of progression-free survival (PFS). Relatlimab and nivolumab also continues to demonstrate benefit compared to nivolumab alone in patients with previously untreated metastatic or unresectable melanoma, according to findings from the RELATIVITY-047 study (NCT03470922).²

In the global, randomized, double-blind, phase 2/3 study, RELATIVITY-047, 714, patients with melanoma were randomized 1:1 and received relatlimab at 160 mg plus nivolumab at 480 mg fixed dose combination or nivolumab at 480 mg alone, given intravenously every 4 weeks.

To enroll patients must have had previously untreated, unrespectable or metastatic melanoma and an ECOG status of either 1 or 0. Some stratification factors included LAG-3, PD-L1, and BRAF.

The primary end point of the study was PFS according to RECIST v1.1 which was assessed by blinded independent central review (BICR). Secondary end points included OS and overall response rate (ORR) by BICR, tested hierarchically.

At a median follow-up was 19.3 months, median PFS was 10.2 months (95% CI, 6.5-14.8) with the combination compared to 4.6 months (95% CI, 3.5-6.4) with nivolumab (HR 0.78; 95% CI, 0.644-0.94).

The median OS was not reached (NR; 95% CI, 34.2NR) with the relatlimab and nivolumab combination while it was 34.1 months (95% CI. 25.2-NR) with nivolumab (HR 0.80; 95% CI, 0.6-1.0; p = .0593). ORR was higher with relatlimab plus nivolumab and the safety profile of the combination remained manageable with no new or unexpected safety signals.

Further, OS rates at 12 months were 77.0% (95% CI, 72.2-81.1) for the combination compared to 71.6% (95% CI, 66.6-76.0) for nivolumab alone, and 24 months, OS rates were 63.7% (95% CI, 58.1-68.7) versus 58.3% (95% CI, 52.7-63.4) respectively.

Rate and types of subsequent systemic therapy were shown to be similar between treatment groups. Confirmed ORR per BICR was 43.1% (95% CI, 37.9-48.4) with relatlimab and nivolumab versus 32.6% (95% CI, 27.8-37.7) with nivolumab. Complete responses were observed in 16.3% of patients on relatlimab and nivolumab and 14.2% on just nivolumab.

At the secondary analysis of OS, relatlimab plus nivolumab demonstrated a clinically meaningful improvement in OS but was not statistically significant. Additionally, there was a 20% reduction in risk of death (HR, 0.80; 95% Cl, 0.64-0.94) and OS rates were numerically higher with the combo compared with nivolumab monotherapy at 12, 24, and 36 months. Also, OS favored this combination versus nivolumab alone across stratification factors which include LAG-3 (1%), and PD-L1 (1%) expression.

Relatlimab in combination with nivolumab had a manageable safety profile with no new or unexpected safety signals. In 75 (21.1%) patients on relatlimab and nivolumab versus 40 (11.1%) patients on nivolumab, grade 3/4 treatment-related adverse events (TRAEs) were observed.

Four treatment-related deaths in the relatlimab and nivolumab group, which included 1 more than observed in previous analysis, and 2 total in the nivolumab group. Any-grade TRAEs leading to treatment discontinuation were observed in 14.6% patients on relatlimab and nivolumab versus 6.7% nivolumab alone.

“While we have made great progress in the treatment of advanced melanoma over the past decade, we are committed to expanding dual immunotherapy treatment options for these patients,” said Samit Hirawat, chief medical officer, global drug development, Bristol Myers Squibb, in the press release “Inhibiting LAG-3 with relatlimab, in a fixed-dose combination with nivolumab, represents a new treatment approach that builds on our legacy of bringing innovative immunotherapy options to patients. The approval of a new medicine that includes our third distinct checkpoint inhibitor marks an important step forward in giving patients more options beyond monotherapy treatment.”

_REFERENCES:

_{1. U.S. Food and Drug Administration approves first LAG-3-blocking antibody combination, Opdualag™ (nivolumab and relatlimab-rmbw), as treatment for patients with unresectable or metastatic melanoma. News release. Bristol Myers Squibb. March 18, 2022. Accessed March 18, 2022.}

_{2. Long GV, Hodi FS, Lipson EJ, et al. Relatlimab and nivolumab versus nivolumab in previously untreated metastatic or unresectable melanoma: Overall survival and response rates from RELATIVITY-047 (CA224-047). Presented at: ASCO Plenary Series: March 2022 Session; March 15, 2022; virtual. Abstract 360385. Accessed March 15, 2022. https://bit.ly/3KNB9KM}