Nivolumab Plus Relatlimab Demonstrates Sustained PFS Benefit in Advanced Melanoma

Georgina V. Long, MD, PhD, FRACP

Fixed-dose nivolumab plus relatlimab-rmbw (Opdualag) elicited continued progression-free survival (PFS) benefit vs nivolumab (Opdivo) alone in patients with treatment-naïve, unresectable or metastatic melanoma, according to updated results from the phase 2/3 RELATIVITY-047 trial (NCT03470922) that were presented at the 2022 ASCO Annual Meeting.

Updated PFS data by blinded independent central review (BICR) showed, at a median follow-up of 19.3 months, sustained improvement in PFS with the combination. The median PFS was 10.22 months with nivolumab plus relatlimab (95% CI, 6.51-14.75) vs 4.63 months with nivolumab alone (95% CI, 3.48-6.44; HR, 0.78; 95% CI, 0.64-0.94). The PFS rates were also higher among patients who received the combination than in those who received nivolumab alone. At 12 months, the PFS rate for nivolumab plus relatlimab was 48.0% (95% CI, 42.5%-53.4%) vs 36.9% (95% CI, 31.7%-42.1%) for nivolumab alone. At 24 months, the PFS rate for those who received the combination was 38.5% (95% CI, 32.7%-44.2%) vs 29.0% (95% CI, 23.8%-34.4%) in those who received the monotherapy.

“Nivolumab plus relatlimab continued to demonstrate a sustained and consistent PFS benefit vs nivolumab [alone] with longer follow-up,” said Georgina V. Long, MD, PhD, FRACP, co-medical director, chair of Melanoma Medical Oncology and Translational Research, Melanoma Institute of Australia and Royal North Shore Hospital, The University of Sydney.

Immune checkpoint inhibitors have expanded the treatment options available for patients with advanced melanoma. However, new combinations are necessary to improve the relative benefits and risks associated with these treatments.

PD-1 and LAG-3 are markers of exhausted T cells. Relatlimab, a human LAG-3 blocking antibody, in combination with PD-1 inhibitors, restores the effector function of exhausted T cells, activating them to induce tumor cell death.

The RELATIVITY-047 trial is a global, randomized, gated, double-blind study evaluating first-line therapy with fixed-dose nivolumab plus relatlimab in patients with advanced melanoma.

In addition to having previously untreated, unresectable or metastatic melanoma, patients needed to have an ECOG performance status of 0 or 1 to be eligible for enrollment.

Key stratification factors included PD-L1 expression, BRAF mutational status, AJCC v8 M stage, and baseline LAG-3 immunohistochemistry.

A total of 714 patients were randomized 1:1 to receive either fixed-dose intravenous (IV) nivolumab at a dose of 480 mg plus 160 mg of relatlimab every 4 weeks (Q4W; n = 355), or IV nivolumab at a flat dose of 480 mg Q4W (n = 359).

The 2 arms had similar baseline characteristics. A total of 36.1% of patients (n = 258) had elevated baseline lactate dehydrogenase levels, including 36.6% (n = 130) of the combination arm and 35.7% (n = 128) of the nivolumab arm.

The trial’s primary end point was PFS by BICR. Key secondary end points included overall survival (OS) and overall response rate (ORR) by BICR. The end points were tested hierarchically, beginning with PFS, then OS, then ORR.

Primary results performed at a median follow-up of 13.2 months showed superior PFS in the combination arm compared with the nivolumab arm (HR, 0.75; P = .006), with a manageable safety profile. Data presented at ASCO 2022 included the updated PFS by BICR, as well as OS and ORR by BICR with an additional 6.1 months of follow-up.

In terms of OS, at the median follow-up of 19.3 months, the combination arm displayed a clinically meaningful, though not statistically significant, improvement compared with the nivolumab arm. The median OS had not yet been reached (NR) in the combination arm (95% CI, 34.20-NR) vs 34.10 months in the nivolumab arm (95% CI, 25.23-NR; HR, 0.80; 95% CI, 0.64-1.01; P = .0593).

Notably, the 12-, 24-, and 36-month OS rates were higher in the combination arm than in the nivolumab arm. At 12 months, the OS rate was 77.0% in the combination arm (95% CI, 72.2%-81.1%) vs 71.6% in the nivolumab arm (95% CI, 66.6%-76.0%). At 24 months, the OS rate was 63.7% in the combination arm (95% CI, 58.1%-68.7%) vs 58.3% in the nivolumab arm (95% CI, 52.7%-63.4%). At 36 months, the OS rate was 55.8% in the combination arm (95% CI, 49.8%-61.4%) vs 48.8% in the nivolumab arm (95% CI, 42.7%-54.7%).

Subsequent therapies were similar between the 2 arms, with 11.8% of the combination arm and 15.9% of the nivolumab arm receiving PD-L1/CTLA-4 inhibitors and 12.4% of the combination arm and 14.8% of the nivolumab arm receiving BRAF/MEK inhibitors.

The PFS and OS benefits for nivolumab plus relatlimab were seen across all stratification factors.

The confirmed ORR by BICR was 43.1% (n = 153) in the combination arm (95% CI, 37.9%-48.4%) vs 32.6% (n = 117) in the nivolumab arm (95% CI, 27.8%-37.7%). There was a 10.3% difference between the ORRs in the 2 arms (95% CI, 3.4-17.3), with an odds ratio of 1.6 (95% CI, 1.2-2.2). Notably, the combination arm had a higher rate of complete response (CR), with 16.3% of the combination arm achieving CR (n = 58) compared with 14.2% (n = 51) of the nivolumab arm. Additionally, the progressive disease (PD) rate was lower in the combination arm than in the nivolumab arm, with 29.6% (n = 105) of the combination arm experiencing PD compared with 41.5% (n = 149) of the nivolumab arm.

A total of 26.8% of the combination arm achieved partial response (n = 95) vs 18.4% (n = 66) of the nivolumab arm. Additionally, 17.2% of the combination arm achieved stable disease (n = 61) vs 16.4% (n = 59) of the nivolumab arm.

No new safety signals were reported at this second analysis. Any-grade adverse effects (AEs) were experienced by 99.2% (n = 352) of the combination arm and 95.8% (n = 344) of the nivolumab arm. Grade 3 or 4 AEs were experienced by 43.4% (n = 154) of the combination arm and 35.1% (n = 126) of the nivolumab arm.

Notably, any-grade myocarditis occurred in 6 patients (1.7%) and 2 patients (0.6%) in the combination and nivolumab arms, respectively. The first 2 months of treatment included troponin monitoring, per protocol.

Common treatment-related AEs (TRAEs) included pruritis, fatigue, rash, hypothyroidism, arthralgia, diarrhea, and vitiligo. Any-grade TRAEs were experienced in 83.7% (n = 297) of the combination arm and 72.4% (n = 260) of the nivolumab arm, leading to treatment discontinuation in 15.2% (n = 54) and 7.2% (n = 26) of the combination and nivolumab arms, respectively. Grade 3 or 4 TRAEs were experienced in 21.1% (n = 75) of the combination arm and 11.1% (n = 40) of the nivolumab arm, leading to discontinuation in 9.0% (n = 32) and 3.6% (n = 13) of the combination and nivolumab arms, respectively.

A total of 4 (1.1%) and 2 (0.6%) treatment-related deaths occurred in the combination and nivolumab arms, respectively.

Going forward, more research, including studies across clinical subgroups, is needed to discern the best placement for fixed-dose nivolumab plus relatlimab among the current treatment options available for melanoma. More information is also necessary regarding the intercranial activity of nivolumab plus relatlimab, as well as the role of biomarkers for this combination therapy.

“These data further validate nivolumab plus relatlimab as a treatment option for patients with advanced melanoma and support the benefit of dual checkpoint inhibition [in the first-line setting],” Long concluded.

Reference

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). J Clin Oncol. 2022;40(suppl 36)360385. doi:10.1200/JCO.2022.40.36_suppl.360385