Combo more than doubles PFS in RELATIVITY-047

The combination of relatlimab and nivolumab was found to more than double progression-free survival (PFS) in patients with previously untreated metastatic or unresectable melanoma compared with nivolumab alone, according to the results of a phase II-III, double-blind, randomized trial published in The New England Journal of Medicine.

The combination targets two immune checkpoints—lymphocyte-activation gene 3 (LAG-3) and programmed death 1 (PD-1).

“Relatlimab is a first-in-class human IgG4 LAG-3–blocking antibody that binds to LAG-3 and restores the effector function of exhausted T cells,” Hussein A. Tawbi, MD, PhD, from the Department of Melanoma Medical Oncology, Division of cancer Medicine, University of Texas MD Anderson Cancer Center, in Houston, and colleagues wrote. They added that the relatlimab-nivolumab combo’s efficacy was previously demonstrated in a phase I-II dose escalation trial in patients who were either relapsed or were refractory to nivolumab, a PD-1-blocking antibody, alone.

Nivolumab is the current standard of care for patients with melanoma, Tawbi and colleagues noted. The current trial, dubbed RELATIVITY-047, randomized 714 patients to either the combination therapy (n=355) or nivolumab alone (n=359). Median follow-up was 13.2 months at database lock on March 9, 2021. Trial randomization took place from May 2018 through December 2020.

Progression-free survival was the primary outcome; overall survival and objective response were the secondary endpoints. The combination therapy consisted of a fixed dose of 160 mg relatlimab and 480 mg nivolumab, which was compared to 480 mg nivolumab alone.

The median age of the trial participants was 63; less than half were women; 50% had metastasis stage M1a/b, while 38.9% stage M1c; most (70.4%) had cutaneous nonacral melanoma; and 66.9% were ECOG performance status 0.

“The median progression-free survival was 10.1 months (95% confidence interval [CI], 6.4 to 15.7) with relatlimab–nivolumab as compared with 4.6 months (95% CI, 3.4 to 5.6) with nivolumab (hazard ratio for progression or death, 0.75 [95% CI, 0.62 to 0.92]; P=0.006 by the log-rank test),” Tawbi and colleagues wrote. “The percentage of patients with progression-free survival at 12 months was 47.7% (95% CI, 41.8 to 53.2) with relatlimab– nivolumab and 36.0% (95% CI, 30.5 to 41.6) with nivolumab.

The other findings of the RELATIVITY-047 trial include:

  • A prespecified exploratory analysis found the combination therapy outperforming nivolumab across key subgroups, with the median PFS longer for patients with LAG-3 expression of 1% or more. Still, the combination therapy group did better overall regardless of LAG-3 expression.
  • Patients with PD-L1 expressions of 1% or more had similar outcomes in both groups—15.7 months (95% CI, 10.1-25.8) in the relatlimab–nivolumab group and 14.7 months (95% CI, 5.1 to not reached) in the nivolumab group (hazard ratio for progression or death, 0.95 [95% CI, 0.68-1.33]).
  • For patients with PD-L1 expression of less than 1%, those in the relatlimab-nivolimab group had a median PFS of 6.4 months (95% CI, 4.6-11.8) compared with 2.9 months in the nivolumab group (95% CI, 2.8 to 4.5; hazard ratio, 0.66 [95% CI, 0.51-0.84]).
  • The combination therapy was beneficial regardless of BRAF mutation status.

Of note, 65.8% (470) of the patients—237 in the combination arm and 233 in the nivolumab arm—discontinued treatment, mainly due to disease progression (36.3% and 46.0%, respectively).

The median duration of treatment for the relatlimab-nivolumab arm and the nivolumab arm was 5.6 months and 4.9 months, respectively, and the median time to discontinuation was 8.3 months (95% CI, 6.5-11.0) and 6.5 months (95% CI, 5.5-9.2), respectively.

The study authors also summarized treatment-related adverse events:

  • Infusion-related adverse reactions occurred in 5.9% of the combination group compared to 3.6% of those receiving nivolumab alone.
  • 18.9% of the combination group and 9.7% of the nivolumab group experienced grade 3 or 4 adverse events.
  • Increased levels of lipase, alanine aminotransferase, aspartate aminotransferase, and fatigue (all less than 2%) were the most common grade 3 or 4 treatment-related adverse events in the relatlimab–nivolumab group.
  • 14.6% in the relatlimab-nivolumab group versus 6.7% of the nivolumab group discontinued treatment because of any grade adverse events.
  • Three deaths in the combination group were considered treatment related compared with two deaths in the nivolumab group.
  • Immune-mediated adverse events in the relatlimab-nivolumab group included hypothyroidism or thyroiditis in 18% of the patients, rash in 9.3%, and diarrhea or colitis in 6.8%.
  • Myocarditis was found in 1.7% of the relatlimab-nivolumab group.

Combination immune therapy has been a boon for bolstering survival time for patients to nearly 50% at five years, noted Adam E. Frampton, FRCS, FRSB, PhD, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Sciences, University of Surrey, and Shivan Sivakumar, MRCP, PhD, the Department of Oncology, University of Oxford, and the Department of Oncology, Oxford University Hospitals, both in the U.K., in an accompanying editorial.

“Outcomes can still be further improved, and evaluating new immune checkpoint targets is an attractive possibility,” Frampton and Sivakumar wrote.

Tawbi and colleagues noted that: “The phase III CheckMate 067 trial showed the benefit of dual checkpoint inhibition with a CTLA-4 inhibitor and PD-1 inhibitor over monotherapy with a CTLA-4 inhibitor, with long-term data confirming durable disease control and improved overall survival with dual checkpoint inhibition. These results led to approval of the combination immunotherapy by the Food and Drug Administration and widespread adoption as standard of care in the first-line treatment of metastatic melanoma. The trial reported here shows a significantly longer median progression free survival with dual checkpoint inhibition of LAG-3 and PD-1 than with PD-1 inhibition monotherapy. These results suggest that dual checkpoint inhibition should be considered as a treatment option over PD-1 inhibition monotherapy as first-line therapy.”

The editorialists wrote that the Checkmate trial showed “a staggering median overall survival of 72.1 months,” but added that while the PFS times 11.5 in the Checkmate 067 compared with 10.1 in RELATIVITY-047 are similar “the safety profile of relatlimab-nivolumab appears more favorable than that of nivolumab-ipilimumab, with grade 3 or 4 treatment-related adverse events reporting in 18.9% of patients who received relatlimab–nivolumab as compared with 59% of patients who received nivolumab–ipilimumab.”

They added that longer follow-up will give more information about the overall survival of patients with high LAG-3 versus low LAG-3 expression. “Perhaps patients with low LAG-3 would derive more benefit from receiving anti-PD-1 and anti-CTLA-4 as first-line therapy, followed by anti-LAG-3 as second-line therapy,” Frampton and Sivakuma wrote. Nonetheless the relatlimab-nivolumab combination is another addition to the “immunotherapeutic arsenal, which will create more options in the treatment landscape for advanced melanoma.”

  1. The combination of relatlimab and nivolumab was found to more than double progression-free survival (PFS) in patients with previously untreated metastatic or unresectable melanoma compared with nivolumab alone.

  2. The combination targets two immune checkpoints—lymphocyte-activation gene 3 (LAG-3) and programmed death 1 (PD-1).

Candace Hoffmann, Managing Editor, BreakingMED™

This study was funded by Bristol Myers Squibb.

Tawbi reported relevant relationships with Bristol Myers Squibb, Genetech, GlaxoSmithKline,Karyopharm Therapeutics, Merck Sharp & Dohme, and Novartis.

Sivakumar reported relevant relationships with Bristol Myers Squibb.

Frampton disclosed no relevant relationships.

Cat ID: 26

Topic ID: 78,26,730,105,11,26,935,192,925