Nivolumab/Relatlimab Yields Long-Lasting Activity in Pretreated Melanoma

Nivolumab (Opdivo) plus relatlimab (Opdualag) produced a manageable safety profile and long-lasting clinical activity in patients with advanced melanoma that has progressed following prior treatment with anti–PD-L1 regimens, according to findings from the phase 1/2a RELATIVITY-047 trial (NCT01968109).

"Response rates appeared to be enriched among patients with tumors expressing PD-L1 or LAG-3; however, responses were observed regardless of PD-L1 and LAG-3 expression (1% cutoff)," according to the authors of the phase 1/2a RELATIVITY-047 trial.

The objective response rate (ORR) by blinded central independent review (BICR) was 12.0% (95% CI, 8.8%-15.8%) for a cohort of patients who received only 1 prior line of anti–PD-L1 therapy (D1) and 9.2% (95% CI, 5.2%-14.7%) in a cohort of patients who received 1 or more lines of anti–PD-L1 therapy (D2). Additionally, the median duration of response (DOR) was not reached (NR; 95% CI, 12.9-NR) in D1 and 12.8 months (95% CI, 6.9-12.9) in D2.

“Response rates appeared to be enriched among patients with tumors expressing PD-L1 or LAG-3; however, responses were observed regardless of PD-L1 and LAG-3 expression (1% cutoff),” the study authors stated. Additionally, the results suggested “that LAG-3 and PD-L1 may not be appropriate as sole markers for treatment selection.”

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 rate in each respective cohort was 29.1% (95% CI, 24.2%-34.1%) and 27.7% (95% CI, 20.5%-35.4%) in the D1 and D2 cohorts, respectively, and the 12-month PFS rate was 21.4% (95% CI, 17.0%-26.1%) and 16.0% (95% CI, 10.0%-23.0%).

Investigators of the phase 2/3 RELATIVITY-020 trial evaluated nivolumab plus relatlimab among patients with histologic or cytologic confirmation of an advanced solid malignancy. Part D of the trial specifically included patients with advanced unresectable or metastatic melanoma and documented disease progression while on a prior anti–PD-L1 regimen.

In Part D1, patients who only received 1 prior line of anti–PD-L1 therapy received 240 mg of nivolumab and 80 mg of relatlimab once every 2 weeks as a single-agent vial or were randomly assigned 1:1 to receive 480 mg of nivolumab and 160 mg of relatlimab once every 4 weeks as a single-agent vial or fixed-dose combination. In part D2, patients received 480 mg of nivolumab and 160 mg of relatlimab once every 4 weeks.

The primary end point of the trial was safety and ORR per RECIST v1.1 criteria. Other efficacy end points included disease control rate (DCR), DOR, PFS, and overall survival (OS).

In Part D1, patients who received only 1 line of prior anti–PD-1 therapy and had documented, unequivocal disease progression within 3 months after the last dose of a PD-1 regimen were eligible for enrollment. Part D2 allowed patients who received multiple prior lines of anti–PD-1 therapy to enroll on the trial.

With a minimum potential follow-up of 19.4 months, the pooled D1 population included 354 patients and D2 included 164 patients. The median duration of nivolumab and relatlimab 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 arms. 

Investigators noted that baseline patient characteristics were comparable across the D1 pooled population and 3 D1 cohorts. In the D1 pooled cohort, 53.3% of patients received 2 or more prior lines of therapy and 58.5% of those in D2 had 3 or more lines of prior therapy. In the pooled D1 and D2 populations, respectively, 39.3% and 59.8% received prior anti–CTLA-4 therapy, 16.1% and 23.8% received BRAF inhibitor therapy, and 30.2% and 49.4% received prior chemotherapy.

The median 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. In each respective group, the 12-month OS rate was 56.0% (95% CI, 50.6%-61.1%) and 60.0% (95% CI, 52.0%-67.0%).

The confirmed DCR was 40.5% (95% CI, 35.3%-45.8%) in D1 and 39.9% (95% CI, 32.3%-47.8%) in D2. The confirmed DCR of 12 weeks or more was 38.7% (95% CI, 33.6%-44.1%) and 37.4% (95% CI, 30.0%-45.3%) in each respective group.

In D1 pooled, ORR by BICR was 11.7% (95% CI, 6.8%-18.3%) for patients with prior CTLA-4 exposure and 12.1% (95% CI, 8.1%-17.3%) for those without prior exposure. Additionally, ORR for patients who did and did not receive prior BRAF or MEK inhibitors was 13.5% (95% CI, 5.6%-25.8%) and 12.5% (95% CI, 1.6%-38.3%), respectively.

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

“…Nivolumab and relatlimab efficacy was observed regardless of the presence of controlled brain metastases, lactate dehydrogenase, and prior therapy with or without a CTLA-4 inhibitor…or a BRAF/MEK inhibitor,” the study authors stated.

Grade 3 or 4 treatment-related adverse effects (TRAEs) occurred in 15.0% of patients in D1 and 12.8% of those in D2. These TRAES included fatigue in 1 patient and diarrhea in 5 patients in the D1 cohort as well as diarrhea in 1 patient in D2. Serious grade 3 or 4 TRAEs occurred in 26.3% of those in the in D1 cohort and 32.3% of patients in the D2 cohort. Moreover, grade 3/4 TRAEs led to treatment discontinuation in 8.2% and 7.9% of patients in each respective group.

The most frequent any-grade immune-mediated AEs in the D1 pooled and D2 populations, respectively, included rash (7.3% and 8.5%), hypothyroidism or thyroiditis (5.9% and 4.3%), and diarrhea or colitis (5.4% and 2.4%).

Reference

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