Nivolumab Plus Relatlimab Induces Durable Responses in Advanced Melanoma

The combination of nivolumab (nivolumab) and relatlimab (Opdualag) demonstrated clinical benefit with a manageable safety profile in patients with advanced melanoma who have progressed on prior PD-L1 or PD-1 inhibitors, regardless of PD-L1 and LAG-3 expression, according to findings from the ongoing phase 1/2a RELATIVITY-020 trial (NCT01968109).¹

At a clinical cutoff date of January 4, 2021, and a minimum follow-up of 19.4 months, among evaluable patients, the overall response rate (ORR) by blinded independent central review (BICR) was 12.0% (95% CI, 8.8%-15.8%) in patients who had progressed on 1 prior PD-1 inhibitor (D1; n = 351) and 9.2% (95% CI, 5.2%-14.7%) in those who had progressed on at least 1 prior PD-1/PD-L1 inhibitor (D2; n = 163).

“Among patients with advanced melanoma who had progressed following anti–PD-1-based therapy, nivolumab plus relatlimab triggered durable tumor regressions and had a manageable safety profile,” Evan J. Lipson, MD, of Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland, said to OncLive^®.

“Nivolumab and...relatlimab...have been shown to be a safe and effective treatment option in heavily pretreated patients with advanced melanoma. [In RELATIVITY-020], nivolumab and relatlimab were found to have a manageable, consistent safety profile, and did not result in any treatment-related deaths,” lead study author Paolo A. Ascierto, MD, of Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale,” in Naples, Italy, said to OncLive^®.

Previously, the phase 2/3 RELATIVITY-047 trial (NCT03470922), which investigated a fixed-dose combination of nivolumab, a PD-1 inhibitor, plus relatlimab, a LAG-3 inhibitor, vs nivolumab monotherapy in patients with previously untreated advanced melanoma, demonstrated a significantly improved median progression-free survival (PFS) with the combination over nivolumab alone, at 10.2 months (95% CI, 6.5-14.8) vs 4.6 months (95% CI, 3.5-6.4; HR, 0.78, 95% CI, 0.6-0.9) at a median follow-up of 19.3 months. Additionally, the median ORR by BICR was 43.1% (95% CI, 37.9%-48.4%) in patients who received the combination vs 32.6% (95% CI, 27.8%-37.7%) in those who received nivolumab alone.² The findings from RELATIVITY-047 supported the March 2022 FDA approval of fixed-dose relatlimab plus nivolumab in patients at least 12 years of age with unresectable or metastatic melanoma.

The open-label, dose-escalation and cohort-expansion RELATIVITY-020 trial evaluated the efficacy, safety, and tolerability of relatlimab monotherapy and relatlimab plus nivolumab in patients with advanced solid tumors. Part D of this trial investigated the efficacy and safety of relatlimab plus nivolumab in patients with advanced melanoma who had progressed during or within 3 months of 1 PD-1–containing regimen (D1) or at least 1 PD-1/PD-L1–containing regimen (D2).¹

To enroll in RELATIVITY-020, patients needed to have a histologically or cytologically confirmed metastatic and/or unresectable solid malignancy. Patients were eligible for part D if they had advanced unresectable or metastatic melanoma and disease progression while on PD-L1 or PD-1 inhibitors.

In part D1, patients needed to have received 1 prior PD-1 inhibitor, specifically nivolumab or pembrolizumab (Keytruda), in the advanced/metastatic setting, and progressed on this agent within 3 months of receiving the last dose. Patients who had received prior CTLA-4–containing regimens, including CTLA-4 inhibitors combined with PD-1 inhibitors, were allowed. Patients with BRAF-mutant disease were also allowed if they had received and progressed on 1 prior line of a BRAF inhibitor in the advanced/metastatic setting. However, patients were excluded if they had received prior LAG-3 or PD-L1 inhibitors, or if they had received adjuvant or neoadjuvant PD-1/PD-L1 inhibitors. All patients in D1 needed to have an ECOG performance status (PS) of 0 or 1.

In part D2, patients could have received multiple prior lines of PD-1 or PD-L1 inhibitors. Patients who had received prior adjuvant or neoadjuvant PD-1 inhibitors could enroll if they progressed on those agents during treatment or within 6 months of their last adjuvant dose or if they subsequently progressed on additional PD-1 therapy for metastatic disease. Patients could have received multiple prior lines of BRAF inhibitors, but patients with BRAF-mutant disease were not required to have progressed on these agents. All patients in D2 needed to have an EGOG PS of 0 to 2.

In total, 518 patients (D1, n = 354; D2, n = 164) received nivolumab plus relatlimab. Patients in D1 received 240 mg of nivolumab and 80 mg of relatlimab once every 2 weeks as a single-agent vial (n = 189; D1 once every 2 weeks) or were randomized 1:1 to receive 480 mg of nivolumab and 160 mg of relatlimab once every 4 weeks as a single-agent vial (n = 83) or once every 4 weeks as a fixed-dose combination (n = 82; D1 once every 4 weeks). Patients in D2 received 480 mg of nivolumab and 160 mg of relatlimab once every 4 weeks as a single-agent vial.

The primary end point in part D was safety, measured by the rates of adverse effects (AEs); serious AEs; and AEs leading to treatment discontinuation, death, and laboratory abnormalities. The coprimary end point in D1 once every 2 weeks was ORR by BICR per RECIST v1.1 criteria in patients with LAG-3 expression. The coprimary end point in D1 once every 4 weeks was safety, measured by the incidence of hypersensitivity or infusion-related reactions within 2 days after dosing. An additional coprimary end point was the safety of 240 mg of nivolumab plus 80 mg of relatlimab once every 2 weeks relative to 480 mg of nivolumab plus 160 mg of relatlimab once every 4 weeks.

In D1 and D2, 53.3% and 58.5% of patients had received at least 2 and at least 3 prior lines of therapy, respectively. In D1 and D2, 39.3% and 59.8% of patients had received prior CLTA-4 inhibitors, 16.1% and 23.8% of patients had received prior BRAF inhibitors, and 30.2% and 49.4% had received prior chemotherapy, respectively.

The median duration of treatment was approximately 16 weeks (range, 2-160) in the single-agent vial arms and 19.8 weeks (range, 4-128) in the fixed-dose combination arm.

In D1, the ORR by BICR was 14.1% (95% CI, 9.6%-19.8%) in patients with LAG-3 expression of at least 1% and 5.4% (95% CI, 1.8%-12.2%) in those with LAG-3 expression of less than 1%. The ORR by BICR was 15.7% (95% CI, 10.0%-23.0%) in patients in D1 with PD-L1 expression of at least 1% and 8.2% (95% CI, 4.3%-13.8%) in those with PD-L1 expression of less than 1%.

In patients in D1 with and without prior CLTA-4 exposure, the ORR by BICR was 11.7% (95% CI, 6.8%-18.3%) and 12.1% (95% CI, 8.1%-17.3%), respectively. In patients in D1 with and without prior BRAF or MEK inhibitors, the ORR by BICR was 13.5% (95% CI, 5.6%-25.8%) and 12.5% (95% CI, 1.6%-38.3%), respectively.

In patients in D1 with M1c disease, the ORR by BICR was 13.9% (95% CI, 4.7%-29.5%) in those with brain metastases and 8.1% (95% CI, 4.7%-12.9%) in those without brain metastases. In patients in D1 with lactate dehydrogenase levels greater than or lower than the upper limit of normal, the ORR by BICR was 10.2% (95% CI, 6.0%-15.8%) and 13.7% (95% CI, 9.1%-19.6%), respectively.

The confirmed disease control rates by BICR were 40.5% and 39.9% in D1 and D2, respectively.

The median duration of response was not reached (NR; 95% CI, 12.9-NR) in D1 and 12.8 months (95% CI, 6.9-12.9) in D2. In D1, the 6- and 12-month response rates were 92.3% (95% CI, 78.0%-97.5%) and 70.9% (95% CI, 53.5%-82.7%), respectively. In D2, the 6- and 12-month response rates were 84.6% (95% CI, 51.2%-95.9%) and 52.7% (95% CI, 23.4%-75.5%), respectively.

The median PFS by BICR was 2.1 months (95% CI, 1.9-3.5) in D1 and 3.2 months (95% CI, 1.9-3.6) in D2, with 6-month PFS rates of 29.1% (95% CI, 24.2%-34.1%) and 27.7% (95% CI, 20.5%-35.4%) and 12-month PFS rates of 21.4% (95% CI, 17.0%-26.1%) and 16.0% (95% CI, 10.0%-23.0%) in D1 and D2, respectively.

The median overall survival (OS) was 14.7 months (95% CI, 12.4-16.9) in D1 and 17.1 months (95% CI, 13.4-21.0) in D2, with 12-month OS rates of 56.0% (95% CI, 50.6%-61.1%) and 60.0% (95% CI, 52.0%-67.0%) in D1 and D2, respectively.

Key pharmacokinetic parameters were similar between patients who received the combination as a single-agent vial and those who received it as a fixed-dose combination. An approximately 50% sLAG-3 level decrease occurred at day 29 in the D1 once every 4 weeks cohorts. The investigators observed no difference between sLAG-3 change from baseline to day 15 in the D1 once every 4 weeks cohorts. Treatment with the combination led to an approximately 2-fold increase in serum interferon-gamma levels compared with those at baseline in both D1 once every 4 weeks cohorts.

Any-grade treatment-related AEs (TRAEs) occurred in 67.5% of patients in D1 and 68.9% of patients in D2. Grade 3/4 TRAEs occurred in 15.0% of patients in D1 and 12.8% of patients in D2. The incidence of any-grade TRAEs leading to treatment discontinuation was 5.1% and 4.3% in D1 and D2, respectively.

In D1, the most common immune-mediated AEs were rash (7.3%), hypothyroidism or thyroiditis (5.9%), and diarrhea or colitis (5.4%). In D2, the most common immune-mediated AEs were rash (8.5%), hypothyroidism or thyroiditis (4.3%), and hepatitis (4.3%).

The incidence of treatment-related hypersensitivity or infusion-related reactions was 8.5% (n = 16) in the D1 once every 2 weeks cohort, 3.6% (n = 3) in the D1 once every 4 weeks single-agent vial cohort, and 7.3% (n = 6) in the D1 once every 4 weeks fixed-dose combination cohort. No grade 3/4 instances of hypersensitivity or infusion-related reactions occurred.

One patient in D1 developed grade 3 myocarditis. No treatment-related deaths occurred in part D.

“The combination [of nivolumab and relatlimab] expands the treatment options for this patient population,” Lipson concluded.

Editor’s Note:Dr Lipson reports consulting or advisory roles with Bristol Myers Squibb, Novartis, MacroGenics, Merck, Sanofi/Regeneron, Genentech, Odonate Therapeutics, Eisai, Natera, Instil Bio, Nektar, OncoSec, Pfizer, Rain Therapeutics, Regeneron, CareDX, and Immunocore; and has received research funding from Bristol Myers Squibb (Inst), Merck (Inst), and Sanofi/Regeneron (Inst).

Dr Ascierto reports stock and other ownership interests in PrimeVax; consulting or advisory roles with Bristol Myers Squibb, Roche/Genentech, Merck Sharp & Dohme, Novartis, Array BioPharma, Merck Serono, Pierre Fabre, Incyte, MedImmune, AstraZeneca, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, OncoSec, Nouscom, Takis Biotech, Lunaphore Technologies, Seattle Genetics, iTeos Therapeutics, Medicenna, Bio-Al Health, ValoTx, Replimune, and Bayer; research funding from Bristol Myers Squibb (Inst), Roche/Genentech (Inst), Array BioPharma (Inst), Sanofi (Inst), and Pfizer (Inst); and has received travel accommodations from Merck Sharp & Dohme, Pfizer, Bio-Al Health, and Replimune.

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. Published online February 13, 2023. doi:10.1200/JCO.22.02072
2. Long GV, Hodi SF, 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(36):360385. doi:10.1200/JCO.2022.40.36_suppl.360385