Relatlimab plus nivolumab confers benefit across key subgroups in advanced melanoma
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CHICAGO —Adding relatlimab to nivolumab improved PFS, OS and objective response rates across key subgroups of patients with previously untreated metastatic or unresectable melanoma, according to a study presented at ASCO Annual Meeting.
The results showed superiority of nivolumab and relatlimab-rmbw (Opdualag, Bristol Myers Squibb) over single-agent nivolumab (Opdivo, Bristol Myers Squibb), consistent with findings among the overall population in the randomized phase 2/3 RELATIVITY-047 trial, Hussein A. Tawbi, MD, PhD, co-director of the Brain Metastasis Clinic at The University of Texas MD Anderson Cancer Center, told Healio.
The combination also exhibited a favorable risk-benefit profile.
Study rationale
Tawbi and colleagues conducted the subgroup analyses to gain a better understanding of which subpopulations may benefit from the anti-PD-1 antibody nivolumab and the lymphocyte-activation gene 3 (LAG-3)-blocking antibody relatlimab.
“Anti-PD-1 antibodies have evolved and been developed around the idea of reversing T-cell exhaustion,” Tawbi said. “PD-1 expression on the surface of T cells is a marker of T-cell exhaustion. LAG-3 is another checkpoint that has been shown to be mostly co-expressed on exhausted T cells, as well, and it also negatively regulates effector T-cell function. The idea of inhibiting that checkpoint and trying to increase T-cell effector function has been investigated and shown really remarkable activity in preclinical models.”
The ongoing RELATIVITY-020 study further showed the nivolumab-relatlimab combination, as second-line treatment, induced durable responses and immune activity beyond that generated by PD-1 inhibition alone, Tawbi said.
“With that in mind, RELATIVITY-047 was designed to study that combination in the first line among treatment-naive patients with metastatic melanoma,” he said.
The first 452 patients enrolled in the randomized phase 2/phase 3 trial received either fixed-dose infusion of 160 mg relatlimab plus 480 mg nivolumab or 480 mg nivolumab alone every 4 weeks. The trial halted enrollment for 6 months to assess efficacy, and after an independent data safety monitoring board determined the efficacy threshold had been met, the study reopened as a phase 3 trial and completed enrollment of 714 patients (median age, 63 years).
After median follow-up of 19.3 months, results showed the combination continued to demonstrate significantly improved PFS by blinded independent central review, the primary endpoint, compared with nivolumab alone (median, 10.2 months vs. 4.6 months; HR = 0.78;95% CI, 0.64-0.94). Tawbi and colleagues also reported a 20% improvement in the secondary endpoint of OS (median, not reached vs. 34.1 months), which fell just short of statistical significance, as well as a higher objective response rate (43.1% vs. 32.6%). The results led to FDA approval of the combination in March for patients with unresectable or metastatic melanoma.
“When we presented those data, it became clear that combination therapy is superior to single-agent therapy,” Tawbi said. “We really were interested in looking at whether we could identify any subgroup in which single-agent might still have relevance.”
Key findings
Results showed not only a continued PFS benefit of nivolumab and relatlimab in key subgroups, but also superior OS and ORR rates, although Tawbi stressed the study was not adequately powered for these endpoints.
“Looking at all of the relevant clinical subgroups, and even biomarker subgroups, there was not a single subgroup in which nivolumab and relatlimab was not superior to nivolumab alone,” Tawbi told Healio.
The combination conferred a higher ORR rate among patients regardless of LAG-3 expression ( 1%, 47% vs. 35.3%; < 1%, 31% vs. 24.4%), PD-L1 expression ( 1%, 52.7% vs. 44.9%; < 1%, 36.4% vs. 24.1%) and BRAF status (wild-type, 43.4% vs. 33.6%; mutant, 42.6% vs. 30.9%). Those positive for PD-L1 and LAG-3 had an ORR of 54.5% vs. 44.3%.
“From my perspective, it is a clinically relevant difference,” Tawbi said.
The ORR benefit also was higher with the combination regardless of baseline metastases stage, tumor burden and baseline lactate dehydrogenase.
Almost one-fifth of patients in the overall population (18.6%) had acral or mucosal melanoma, which Tawbi said was good inclusion for the rare subtypes. Among those with acral melanoma, researchers observed an ORR of 30% with nivolumab and relatlimab compared with 11.9% with single-agent PD-1.
“That is still inferior to the overall response of 47% with the combination among patients with cutaneous melanoma, but a decent response rate in an otherwise hard-to-treat population,” he said.
The combination also had a manageable safety profile, with no new safety signals. Grade 3 to grade 4 toxicities occurred among 21% of patients in the combination group vs. 11.1% with nivolumab, which historically has a rate of around 15%.
“It’s not a huge tax of toxicity that’s added [with relatlimab] while you get a pretty consistent benefit for all patients,” Tawbi said.
Implications
Tawbi said the nivolumab-relatlimab regimen has demonstrated better tolerability than nivolumab and ipilimumab (Yervoy, Bristol Myers Squibb) and strong activity compared with nivolumab alone.
“The debate will continue over which populations should be treated with ipilimumab and nivolumab vs. nivolumab and relatlimab until a randomized study is performed,” he said.
“However, ipilimumab and nivolumab continues to be an excellent regimen for patients with active untreated brain metastases, and we will continue to treat that population with that combination until there is evidence that the other combination is active enough in comparison.”
Perspective
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Lucy Boyce Kennedy, MD
The FDA approval of nivolumab plus relatlimab has introduced a new immune therapy option for patients with metastatic melanoma.
RELATIVITY-047 demonstrated a significant improvement in PFS with nivolumab plus relatlimab compared with nivolumab monotherapy. In addition, researchers reported clinically meaningful improvements in OS and ORR, although the study was not powered to assess these endpoints.
Nivolumab plus relatlimab is an important addition to our systemic therapy toolbox for unresectable or metastatic melanoma. The benefit of the combination was seen across all subgroups, suggesting that nivolumab plus relatlimab will largely replace single-agent anti-PD-1 therapy in the first-line setting. In the absence of randomized data comparing the two available combination regimens — nivolumab plus relatlimab or ipilimumab plus nivolumab — selection between these two regimens likely will depend on patient-specific factors and individualized decision-making. Ipilimumab plus nivolumab remains the preferred regimen for patients with active, untreated brain metastases, as we are awaiting data on the intracranial efficacy of nivolumab plus relatlimab. Ipilimumab plus nivolumab also remains favored for patients with poor prognostic factors, such as a high visceral disease burden, based on the high response rates and durable responses reported in CheckMate-067.
As we celebrate the addition of a new class of immune checkpoint inhibitors to our melanoma treatment paradigm, we also acknowledge that immune therapy resistance remains a critical area of unmet need. Data on the activity of nivolumab plus relatlimab in the anti-PD-1 or anti-CTLA-4-refractory setting are limited, and data on the efficacy of nivolumab plus relatlimab in the immune therapy-refractory setting are eagerly anticipated.
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Tawbi HA, et al. Abstract 9505. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
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