Nivolumab Combo Yields Sustained Benefit in Advanced Melanoma

“The phase 3 trial RELATIVITY-047 had shown an improvement in PFS that was statistically significant and hit the primary end point even at a median follow-up of only 13.2 months. This has resulted in the FDA approval of this combination in the first line for patients with metastatic melanoma,” said Hussein A. Tawbi, MD, PhD, director of personalized cancer therapy and deputy chair in the Department of Melanoma Medical Oncology at The University of Texas MD Anderson Cancer Center.

Investigators observed a sustained benefit with nivolumab (Opdivo) plus relatlimab (Opdualag) compared with nivolumab alone in the treatment of patients with previously treated, unresectable, or metastatic melanoma, according to findings from the phase 3 RELATIVITY-047 trial (NCT03470922) presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting.

The updated progression-free survival (PFS) analysis data presented by Hussein A. Tawbi, MD, PhD favored the combination as patients receiving nivolumab plus relatlimab (n = 355) achieved a median PFS of 10.2 months (95% CI, 6.5-14.8) vs 4.6 months (95% CI, 3.5-6.5) for those given nivolumab monotherapy (n = 359; HR, 0.81; 95% CI, 0.67-0.97). Median overall survival (OS) was not reached in the doublet arm (95% CI, 31.5-NA) and was 33.2 months (95% CI, 25.2-45.8) in the monotherapy arm (HR, 0.82; 95% CI, 0.67-1.02).

“The phase 3 trial RELATIVITY-047 had shown an improvement in PFS that was statistically significant and hit the primary end point even at a median follow-up of only 13.2 months. This has resulted in the FDA approval of this combination in the first line for patients with metastatic melanoma,” said Tawbi, who is the director of personalized cancer therapy and deputy chair in the Department of Melanoma Medical Oncology at The University of Texas MD Anderson Cancer Center.

Efficacy

For patients receiving nivolumab plus relatlimab, the 12-, 24-, and 36-month PFS rates were 48% (95% CI, 43%-53%), 38% (95% CI, 33%-44%), and 31% (95% CI, 25%-36%), respectively. OS rates were 77% (95% CI, 72%-81%), 62% (95% CI, 56%-67%), and 54% (95% CI, 49%-59%), at these time points, respectively, with a 48-month OS rate of 52% (95% CI, 46%-57%).

For those given nivolumab alone, the 12-, 24-, and 36-month PFS rates were 37% (95% CI, 32%-42%), 31% (95% CI, 26%-36%), and 27% (95% CI, 22%-32%), respectively. OS rates were 72% (95% CI, 67%-76%), 58% (95% CI, 53%-63%), and 48% (95% CI, 43%-54%) respectively, with a 48-month OS rate of 42% (95% CI, 36%-49%).

In an exploratory analysis, PFS2, which was defined from the time of randomization until progression on the second immediate line of therapy, were presented with a median follow-up of 25.3 months. The median PFS2 in the combination arm was 28.4 months (95% CI, 22.3-37.1) compared with 20.1 months (95% CI, 16.1-24.7) in the monotherapy arm (HR, 0.79; 95% CI, 0.65-0.96).

For patients receiving nivolumab plus relatlimab, the 12-, 24-, 36-, and 48-month PFS2 rates were 71% (95% CI, 66%-75%), 54% (95% CI, 48%-59%), 46% (95% CI, 40%-51%), and 42% (95% CI, 37%-48%), respectively. For patients receiving single-agent nivolumab, the 12-, 24-, 36-, and 48-month PFS2 rates were 62% (95% CI, 57%-67%), 46% (95% CI, 40%-51%), 36% (95% CI, 31%-42%), and 35% (95% CI, 29%-40%), respectively.

The overall response rate (ORR) difference between the 2 arms was 9.8% (95% CI, 2.8%-16.8%) with those in the doublet arm experiencing an ORR of 44% (95% CI, 38%-49%) compared with 34% (95% CI, 29%-39%) in the monotherapy arm. Progressive disease occurred in 31% of patients vs 42%, respectively. The complete response rates were both 18%, stable disease rates were both 16%, and median duration of response was not reached in either arm.

Melanoma-Specific Survival

“This reflects the same pattern of the OS arm, and we see a consistent separation of the arms early on and we see a start of a flattening of the curve toward the end,” Tawbi explained. “The difference is a 23% decrease in the risk of death from melanoma, an HR of 0.77, [and] the confidence intervals here do not cross 1.”

Melanoma-specific survival reflected the time of randomization to death of melanoma and all other causes of death were censored. Further, causes of death included a study drug toxicity for 4 patients in the combination arm and 2 patients in the single agent arm as well as unknown causes of 7 and 10 patients, respectively. Other causes led to 25 and 19 deaths, respectively, with the most common being septic shock, myocardial infarction, stroke, pneumonia, and respiratory insufficiency.

Subsequent Therapy Subgroup

“Importantly, we started looking at subsequent therapy and we see that on both arms of the study there were approximately 46% of patients that received any subsequent therapy. That could have included any modality, so we have radiotherapy and surgery…and subsequent systemic therapy,” Tawbi said.

Of patients in the nivolumab/relatlimab arm (n = 131) and nivolumab arm (n = 136), 40% vs 49% received PD-1/CTLA-4 inhibitors and 37% vs 42% received BRAF or MEK inhibitors, respectively. Tawbi noted that although investigators did not report responses from a substantial number of patients, median PFS between both arms is similar and what would be expected from the combinations.

The subsequent median PFS for patients receiving the doublet who were previously treated with nivolumab plus ipilimumab (Yervoy; n = 16) was 8.4 months (95% CI, 3.0-NA), was 3.4 months (95% CI, 1.7-22.3) for those given ipilimumab alone (n = 9), and was 15.4 months (95% CI, 6.9-NA) for those given BRAF/MEK inhibitors (n = 43).

In the monotherapy arm, the subsequent median PFS for patients who previously received nivolumab plus ipilimumab (n = 16) was 2.9 months (95% CI, 1.9-11.6), was 2.9 months (95% CI, 1.9-3.7) for those given ipilimumab (n = 14), and was 10.6 months (95% CI, 6.0-14.9) for those given BRAF/MEK inhibitors (n = 45).

Subgroup Analysis

Tawbi explained that the PFS, OS, and ORR data by stratification factors has not changed with the subgroups continuing to show benefit with the combination treatment over single-agent nivolumab.

LAG-3 Expression

For patients with LAG-3 expression of 1% or higher given the doublet (n = 268) and the monotherapy (n = 269) the unstratified HR was 0.85 (95% CI, 0.69-1.05) for PFS, 0.82 (95% CI, 0.64-1.05) for OS, and the unweighted ORR difference was 10.6% (95% CI, 2.2%-18.7%).

For those with LAG-3 expression less than 1% given the doublet (n = 87) and the monotherapy (n = 90), the unstratified HR was 0.71 (95% CI, 0.50-1.00) for PFS, 0.86 (95% CI, 0.58-1.28) for OS, and the unweighted ORR difference was 7.7% (95% CI, –5.5%-20.7%).

PD-L1 Expression

For patients with PD-L1 expression of 1% or greater treated with the doublet (n = 146) and the monotherapy (n= 147) the unstratified HR was 1.04 (95% CI, 0.77-1.41) for PFS, 0.82 (95% CI, 0.58-1.16) for OS, and the unweighted ORR difference was 6.5% (-4.9%-17.6%).

Those with PD-L1 expression of less than 1% who received the combination (n = 209) and the monotherapy (n= 212) experienced an unstratified HR of 0.68 (95% CI, 0.54-0.86) for PFS, 0.83 (0.63-1.08) for OS, and the unweighted ORR difference was 12.3% (95% CI, 3.5%-20.9%).

BRAF Mutation Status

Patients with BRAF-mutant disease who received the doublet (n = 136) and monotherapy (n = 139) expereinced an unstratified HR of 0.78 (95% CI, 0.58-1.04) for PFS, 0.77 (95% CI, 0.54-1.11) for OS, and the unweighted ORR difference was 12.4% (95% CI, 1.0%-23.4%).

Patients with BRAF wild-type disease who received the doublet (n = 219) and monotherapy (n = 220) expereinced an unstratified hazard ratio of 0.82 (95% CI, 0.65-1.04) for PFS, 0.86 (95% CI, 0.66-1.11) for OS, and the unweighted ORR difference was 8.4% (95% CI, –0.8%-17.3%).

AJCC Staging

For patients with M0/M1any serum lactate dehydrogenase (LDH) not elevated who received the doublet (n = 233) and monotherapy (n = 237) the unstratified HR was 0.80 (95% CI, 0.64-1.01) for PFS, 0.83 (95% CI, 0.62-1.11) for OS, and the unweighted ORR difference was 13.5% (95% CI, 4.5%-22.2%).

For patients with M1any elevated LDH who received the doublet (n = 122) and monotherapy (n = 122) the unstratified HR was 0.78 (95% CI, 0.58-1.06) for PFS, 0.80 (95% CI, 0.59-1.09) for OS, and the unweighted ORR difference was 3.3% (95% CI, –8.1%-14.6%).

Safety

The updated data were consistent with previous reports and there were no new safety signals. Among patients in the combination arm, 22% experienced grade 3 to 4 treatment-related adverse events vs 12% in the monotherapy arm, leading to discontinuation rates of 10% and 4%, respectively. There were 4 treatment-related deaths in the nivolumab plus relatlimab group and 2 in the single-agent nivolumab group.

Patient Characteristics

Baseline characteristics were generally well balanced between the 2 arms. The median age of all patients was 63.0 years (range, 20-94) and 42% were women. The LDH levels were greater than the upper limit of normal in 39% of patients and greater than 2 times the upper limit of normal in 9% of patients. Further, 39% of patients had BRAF-mutant disease and 61% had wild-type disease.

Patients had M1a (26%), M1b (24%), M1c (39%), and M1d (2%) status as well as ECOG performance scores of 0 (67%) and 1 (33%). Additionally, they had cutaneous nonacral (70%), cutaneous acral (11%), or mucosal (7%) melanoma and 8% received prior neoadjuvant or adjuvant therapy. Median tumor burden was 59.0 mm (range, 10-317) and 54.5 mm (range, 10-548) for those in the combination and monotherapy arms, respectively.

LAG-3 expression was 1% or greater for 75% of patients and PD-L1 expression was 1% of greater was present among 41% of patients. The AJCC M stage was M0/M1any (LDH not elevated) for 66% of patients and was M1any (elevated LDH) for 34%.

Further, patients received the fixed-dose combination of 480 mg nivolumab plus 160 mg relatlimab or nivolumab at 480 mg every 4 weeks. The primary end point was PFS, and secondary end points included OS and ORR assessed by blinded independent central review.

Disclosures: This study was supported by Bristol-Myers Squibb. D. Tawbi has consulting or advisory roles with Boxer Capital, Bristol-Myers Squibb, Eisai, Genentech/Roche, Iovance Biotherapeutics, Jazz Pharmaceuticals, Karyopharm Therapeutics, Medicenna, Merck, Novartis, and Pfizer. He has received research funding from Bristol-Myers Squibb, Celgene, Dragonfly Therapeutics, Genentech/Roche, GlaxoSmithKline, Merck, Novartis, and RAPT Therapeutics.

Reference

Tawbi HA, Hodi FS, Lipson EJ, et al. Nivolumab (NIVO) plus relatlimab (RELA) vs NIVO in previously untreated metastatic or unresectable melanoma: 2-year results from RELATIVITY-047. J Clin Oncol. 2023;41(suppl 16):9502. doi:10.1200/JCO.2023.41.16_suppl.9502