Nivolumab Plus Relatlimab Demonstrates Improved OS, ORR in Untreated Metastatic or Unresectable Melanoma

Treatment with nivolumab (Opdivo) and relatlimab resulted in better overall survival (OS) outcomes coupled with numerically improved response rates compared with nivolumab alone for patients with untreated metastatic or unresectable melanoma, according to findings from the phase 2/3 RELATIVITY-047 trial (NCT03470922) that were presented as part of the American Society of Clinical Oncology (ASCO) Plenary Series.¹

Notably, the media OS was not reached (NR) in the combination arm (95% CI, 34.20-NR) compared with 34.10 months (95% CI, 25.23-NR) in the single-agent arm (HR, 0.80; 95% CI, 0.64-1.01; P = .0593). Corresponding rates of objective response were 43.1% and 32.6%.

Additionally, updated data continued to show sustained progression-free survival (PFS) benefit in this patient population. “The PFS favored the nivolumab/relatlimab combination for all stratification factors,” Georgina Long, AO, BSc, PhD, MBBS, FRACP, FAHMS, co-medical director and chair of melanoma medical oncology and translational research at the Melanoma Institute Australia, said during a presentation of the data.

Relatlimab is a human LAG-3 antibody that acts on exhausted T cells by restoring the effector function. “With the addition of nivolumab and relatlimab, the exhausted phenotype is reversed, and the activated tumor cell ultimately results in tumor cell death.”

Previous results of the trial that were published in the New England Journal of Medicine showed that PFS was improved with the combination of nivolumab and relatlimab vs nivolumab alone (HR, 0.75; 95% CI, 0.62-0.92; P = .006).² The data presented herein served as a follow-up to those data.

The global, randomized, double-blind trial enrolled patients with untreated unresectable or metastatic melanoma with an ECOG performance status of 0 or 1. Patients were stratified based on LAG-3 and PD-L1 expression, BRAF mutational status, and American Joint Committee on Cancer (AJCC) version 8 M staging. Those who enrolled (N = 714) were randomized 1:1 to receive either 480 mg of nivolumab plus 160 mg of relatlimab every 4 weeks or the nivolumab backbone alone every 4 weeks. The primary end point is PFS by blinded independent central review (BICR), with key secondary outcomes including overall survival (OS) and overall response rate (ORR) by BICR.

Baseline characteristics were well balanced between the 2 groups, according to Long. Of note, 38.9% of patients had M1C disease, 25.8% had M1A, 24.2% had M1B, and 2.4% had M1D. Additionally, 66.9% of patients had an ECOG performance status of 0. Long also noted that 36.1% of patients had elevated serum lactate dehydrogenase levels. LAG-3 expression was greater than or equal to 1% in 75.2% of patients and PD-L1 expression was <1% in 59.0%.

OS rates in the combination and single-agent arms were 77.0% (95% CI, 72.2%-81.1%) vs 71.6% (95% CI, 66.6%-76.0%), respectively, at 12 months; 63.7% (95% CI, 58.1%-68.7%) vs 58.3% (95% CI, 52.7%-63.4%) at 24 months; and 55.8% (95% CI, 49.8%-61.4%) vs 48.8% (95% CI, 42.7%-54.7%) at 36 months. OS benefit was maintained regardless of LAG-3 and PD-L1 expression, BRAF mutation status, and AJCC stage.

Subsequent therapies were administered in 40.8% of those in the combination arm and 42.6% of those in the monotherapy arm. In the former, 12.4% of patients received BRAF and/or MEK inhibitors and 32.7% received systemic therapies such as PD-(L)1 and/or CTLA-4 inhibitors (11.8%), nivolumab/ipilimumab (Yervoy; 4.2%), and nivolumab alone (4.2%). Additionally, 14.6% of patients underwent radiotherapy and 7.0% underwent surgery. In the control group, 14.8% of patients received subsequent BRAF and/or MEK inhibitors and 34.5% received systemic agents such as PD-(L)1 and/or CTLA-4 inhibitors (15.9%), nivolumab/ipilimumab (6.7%), and nivolumab alone (5.6%). Investigators also reported that 12.3% and 8.1% of patients underwent radiotherapy and surgery, respectively.

The ORR in the combination cohort was comprised of 16.3% complete responses (CRs) and 26.8% partial responses (PRs). Moreover, 17.2% achieved stable disease and 29.6% experienced progressive disease. In the comparator arm, the ORR was made up of 14.2% CRs and 18.4% PRs, with a stable disease rate of 16.4%, and a progressive disease rate of 41.5%. Patients receiving relatlimab had a disease control rate (DCR) of 62.8% (95% CI, 57.6%-67.8%) vs 50.7% (95% CI, 45.4%-56.0%) with control therapy. The median duration of response (DOR) was not reached in either arm.

After a median follow up of 19.3 months, updated results indicated a median PFS of 10.22 months (95% CI, 6.51-14.75) in the combination arm vs 4.63 months (95% CI, 3.48-6.44) in the nivolumab alone arm (HR, 0.78; 95% CI, 0.64-0.94). The PFS rates at 12 months were 48.0% (95% CI, 42.5%-53.4%) and 36.9% (95% CI, 31.7%-42.1%), respectively; rates at 24 months were 38.5% (95% CI, 32.7%-44.2%) and 29.0% (95% CI, 23.8%-34.4%).

Grade 3/4 adverse effects (AEs) occurred in 43.4% of those in the combination group and 35.1% of those in the monotherapy group. Any-grade and grade 3/4 treatment-related AEs (TRAEs) occurred in 83.7% and 21.1% of in those experimental group, respectively, compared with 72.4% and 11.1% in the comparator group. Any-grade and grade 3/4 TRAEs led to therapy discontinuation in 15.2% and 9.0% of those in the combination group, respectively, vs 7.2% and 3.6% of those in the single-agent arm.

The most common any-grade TRAEs that occurred in 10% or more of patients in the experimental cohort were pruritus (24.5%), fatigue (23.4%), and rash (16.6%); common grade 3/4 TRAEs were fatigue (1.4%), diarrhea (1.1%), arthralgia (0.8%), and rash (0.8%). Common any-grade TRAEs in the comparator arm included pruritus (16.4%), rash (13.4%), and fatigue (13.1%); grade 3/4 TRAEs included pruritis (0.6%), rash (0.6%), and diarrhea (0.6%).

Additionally, grade 3/4 immune-mediated AEs included hepatitis (4.2%), adrenal insufficiency (1.7%), and diarrhea/colitis (1.4%) in the combination group. In the single-agent group, common grade 3/4 immune-mediated AEs were and hepatitis (1.7%), rash (1.4%), and diarrhea/colitis (1.4%) in the.

References

1. Long GV, Hodi FS, Lipson EJ, et al. Relatlimab and nivolumab vs nivolumab in previously untreated metastatic or unresectable melanoma: overall survival and response rates from RELATIVITY-047 (CA224-047). Presented at ASCO Plenary Series; March 15, 2022; virtual.
2. Tawbi HA, Schadendorf D, Lipson EJ, et al. Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. N Engl J Med. 2022;386(1):24-34. doi:10.1056/NEJMoa2109970