Relatlimab/Nivolumab Shows Clinical Activity in Patients With Heavily Pretreated Advanced Melanoma

Paolo Antonio Ascierto, MD

Among patients with advanced melanoma with disease progression following treatment with anti–PD-1/L1 therapy, relatlimab plus nivolumab (Opdualag) demonstrated early signs of clinical benefit, according to findings from cohort D of the phase 1/2 RELATIVITY-020 trial (NCT01968109) published in the Journal of Clinical Oncology.¹

A total of 518 patients with advanced melanoma received nivolumab plus relatlimab were included in this trial. The objective response rate (ORR) was 12.0% (95% CI, 8.8%-15.8%) among patients who had been treated with 1 anti–PD-L1/L1 containing regimen (D1; n = 351). In the cohort of patients who had received at least 1 anti–PD-1/L1 containing regimen (D2; n = 163), the ORR was 9.2% (95% CI, 5.2%-14.7%). Investigators noted that responses appeared most pronounced among patients whose tumors expressed PD-L1 or LAG-3; however, responses were observed regardless of expression.

In D1, the median duration of response (DOR) was not reached (NR; 95% CI, 12.9-NR) and in D2, the median DOR was 12.8 months (95% CI, 6.9-12.9). Moreover, the median progression-free survival (PFS) was 2.1 months (95% CI, 1.9-3.5) in D1 and 3.2 months (95% CI, 1.9-3.6) in D2. The 6-month PFS rates, between D1 and D2, respectively, were 29.1% (95 CI, 24.2%-34.1%) and 27.7% (95% CI, 20.5%-35.4%). The 12-month PFS rates were 21.4% (95% CI, 17.0%-26.1%) vs 16.0% (10.0%-23.0%), respectively.

The rate of grade 3 or 4 adverse events (AEs) with these treatments were 15.0% and 12.8% in the D1 and D2 cohorts, respectively. One case of grade 3 myocarditis was reported; however, no treatment-related deaths occurred in either cohort.

“These results demonstrate the safety and clinical activity of nivolumab and relatlimab in patients with advanced melanoma that had progressed on anti–PD-1/L1-containing regimens, including patients who were heavily pretreated, received prior CTLA-4 inhibitors, and had multiple poor prognostic factors,” Paolo Antonio Ascierto, MD, director of the Unit of Melanoma, Cancer Immunotherapy and Innovative therapy at the National Tumor Institute G. Pascale in Naples, Italy, and co-investigators, wrote in the study.

Findings from RELATIVITY-047 (NCT03470922) showed that the combination of relatlimab, a LAG-3 inhibitor, and nivolumab, a PD-1 inhibitor, induced a clinically significant PFS benefit for patients with untreated metastatic melanoma. The regimen also induced a clinically meaningful, although not statistically significant, improvement in overall survival (OS). Based on these findings, the FDA approved the combination for patients with untreated disease.²

In RELATIVITY-020, a dose-escalation and cohort-expansion trial, investigators sought to assess the safety, efficacy, and tolerability, of relatlimab alone, and in combination with nivolumab in patients with solid tumors. In cohort D, the combination was assessed in patient with melanoma who had documented disease progression following at least 1 anti–PD-1/L1 therapy.¹

To be eligible for enrollment, patients needed to have a histologically or cytologically confirmed metastatic or unresectable solid malignancy. Patients who were assigned to D1 were those who had received only 1 prior anti–PD-1/L1 containing regimen. These patients needed to have documented disease progression within 3 months of their last dose of said treatment. Patients were also allowed to have received prior CTLA-4 containing regimens. However, prior LAG-3 inhibitors, or PD-1 inhibitors were not allowed, nor were adjuvant or neoadjuvant PD-1 inhibitors. Prior BRAF inhibition was permitted but patients needed to have progressed on at least 1 line of this therapy in the advanced or metastatic setting. These patients had ECOG performance statuses of 0 to 1.¹

Patients who were assigned to the D2 cohort were allowed to have received multiple prior lines of anti–PD-1 containing regimens, or anti–PD-L1 containing regimens. These patients could have received prior adjuvant or neoadjuvant anti–PD-1/L1 therapy so long as progression had occurred within 6 months of their last dose of adjuvant therapy or if subsequent progression had occurred on additional anti–PD-1/L1 therapy in the metastatic setting. They were also allowed to have prior BRAF inhibitor therapy, and they did not need documented evidence of progression on BRAF inhibitor therapy. These patients had ECOG performance statuses of 0 to 2.

The dosing schedules differed between D1 and D2. Those in D1 received nivolumab and relatlimab 240 mg/80 mg once every 2 weeks via a single-agent vial (SAV); or they were randomly assigned 1:1 to received nivolumab and relatlimab 480 mg/160 mg once every 4 weeks via SAV vs nivolumab and relatlimab 480 mg/160 mg once every 4 weeks via fixed-dose combination (FDC). In D2, patients received nivolumab and relatlimab 480 mg/160 mg once every 4 weeks.

The primary objectives were to establish safety a safety profile and to demonstrate preliminary clinical evidence of efficacy, as measured by ORR. Another coprimary objective was to assess infusion-related reactions of SAV (coadministration in a single intravenous bag) and FDC (a single vial with the combination at a protein mass ratio of 3:1). The safety of the various dosing schedules were also key objectives.

For D1, at a minimum of 19.4 months follow-up, 189 patients received the combination at 240 mg/80 mg once every 2 weeks SAV, 83 patients received 480 mg/160 mg once every 4 weeks SAV, and 82 patients received 480 mg/160 mg once every 4 weeks FDC. In D2, 264 patients received 480 mg/160 mg once every 4 weeks SAV. The median duration of treatment was 16 weeks (range, 2-160) with SAV administrations vs 19.8 weeks with FDC administration (range, 4-128).

The pooled disease control rate (DCR) was 40.5% in D1 and 39.9% in D2. In a pooled analysis of patients with LAG-3 expression greater than 1% and less than 1%, the ORR by blinded independent control review was 14.1% (95% CI, 9.6%-19.88%) and 5.4% (95% CI, 1.8%-12.2%), respectively. In D2, the ORR rates, by LAG-3 expression, were 11.4% (95% CI, 5.6%-19.9%) and 4.2% (95% CI, 0.5%-14.3%), for expression of greater than 1% and less than 1%, respectively.

The pooled incidence of any-grade AEs was 67.5% in D1 and 68.9% in D2. The rate of AE-related treatment discontinuation was 5.1% and 4.3%, respectively.

Among patients who experienced an immune-mediated AEs, the most common to occur were rash (7.3%), hypothyroidism/thyroiditis (5.9%), and diarrhea/colitis (5.4%) in D1 pooled grouping and rash (8.5%), hypothyroidism/thyroiditis (4.3%), and hepatitis (4.3%) in D2. Further, the rate of hypersensitivity/infusion-related reactions was 8.5% among the patients receiving 240 mg/80 mg every 2 weeks SAV; 3.6% among patients receiving 480 mg/160 mg once every 4 weeks SAV; and 7.3% in the 480 mg/160 mg once every 4 weeks FDC. There were no grade 3 or 4 hypersensitivity or infusion-related reactions.

Although the study authors acknowledged that a single-arm design of the trail is a limitation, they assert that patients enrolled in part D are a population that generally presents treatment challenge sin routine practice. They state that these findings are a valuable data set for understanding the safety of this immunotherapy combination in heavily pretreated population.

“Taken together with the results from RELATIVITY-047, these findings demonstrate the activity of dual immunotherapy with nivolumab and relatlimab in advanced melanoma across lines of therapy,” the authors concluded.

Editor’s Note: This study was supported by Bristol Myers Squibb.

References

1. Ascierto PA, Lipson EJ, Dummer R, et al. Nivolumab and relatlimab in patients with advanced melanoma that had progressed on anti-programmed death-1/programmed death ligand 1 therapy: results from the phase I/IIa RELATIVITY-020 trial. J Clin Oncol. 2023;41(15):2724-2735. doi:10.1200/JCO.22.02072
2. US 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 May 25, 2023. https://bit.ly/3wk6PDx