Relatlimab/Nivolumab in Melanoma Improves Brain Metastasis–Free Survival

Targeted Oncology: Could you describe the study design of the phase 3 RELATIVITY-047 study (NCT03470922)?

Ahmad Tarhini, MD, PhD: This was a first-line patient population with untreated metastatic melanoma who were randomly assigned 1:1 to a fixed-dose combination of nivolumab at 480 mg and relatlimab at 160 mg [Opdualag]. This was a fixed-dose single infusion on the study given over 60 minutes. Currently, it's used mostly over 30 minutes. We give it over 30 minutes every 4 weeks in our practice. This was compared with nivolumab [Opdivo] 480 mg every 4 weeks as a single infusion. The primary end point was progression-free survival [PFS] by blinded independent central review [BICR], not investigator [assessment]. Secondary end points were overall survival [OS] and the objective response rate [ORR] by BICR.

What are the most recent data presented from this study?

The update presented by Hussein A. Tawbi, MD, PhD, at the American Society of Clinical Oncology Annual Meeting [ASCO] in June was the data lock of October 2023 at a median follow-up of 34 months.

The baseline patient characteristics…compared with CheckMate 067 [NCT01844505], which tested ipilimumab [Yervoy] plus nivolumab. If we look at [patients with] M1C and M1D disease, patients with visceral metastases or treated brain metastases, these were about 41% of the patient population on the study, similar to CheckMate 067. [Approximately] 36% of the patients had more than upper limit of normal for serum lactate dehydrogenase, also comparable with CheckMate 067. Looking at the PD-L1 expression, 59% of patients had PD-L1 [expression] less than 1%...and roughly 61.5% had BRAF wild-type, so [this was] a relatively high-risk patient population.

What do the latest updates to the efficacy end points show?

For the updated primary end point of PFS by BICR, the HR was 0.79 [95% CI, 0.66-0.95]. The median was 10.2 months [for nivolumab/relatlimab] compared with 4.6 months [for nivolumab alone], similar to what was seen in CheckMate 067. There was an exploratory analysis looking at relatlimab/nivolumab vs nivolumab in terms of the landmark PFS rates at 4 years: 30% of patients were progression free with the combination compared with 22% with nivolumab monotherapy.

Looking at the OS analysis, the HR was 0.80 [95% CI, 0.66-0.99]. This was a secondary end point, so it was not statistically significant because the way [the trial] was designed and the hierarchy of testing, but 20% reduction was a clear trend in favor of the combination. Looking the 4- and 5-year OS rates, 52% and 49% of patients alive at 4 and 5 years [vs 43% and 39%, respectively, in the monotherapy arm].

By BICR, the ORR was 44% with nivolumab/relatlimab vs 34% with nivolumab, so roughly 10 percentage points’ difference in response between the combination and monotherapy. The median duration of response was not reached for both. We know with PD-1 based immunotherapy the duration of response is durable. In terms of complete responses, there were 20% and 19%, [respectively].

An interesting analysis that was also presented at ASCO was central nervous system metastasis–free survival. At 4 years, it was 83% with nivolumab/relatlimab compared with 73% with nivolumab, a 10% difference. These are the only data we have in brain metastases with nivolumab/relatlimab. There are ongoing studies testing it similar to the way ipilimumab/nivolumab was tested. But these data are interesting and certainly support testing this in that setting.

What were the safety outcomes at this later follow-up time?

In terms of grade 3 and 4 treatment-related adverse events [TRAEs], there were 22% [with the combination] compared with 12% [with monotherapy]. For grade 3/4 TRAEs leading to discontinuation, it was 10% compared with 4%, and for all grades it was 18% and 10% [respectively]. Treatment-related deaths can happen; there were 4 with nivolumab/relatlimab and 2 with nivolumab.

In terms of hypothyroidism/thyroiditis, it's approximately 19% with nivolumab/relatlimab compared with 15% with nivolumab. Rash was slightly higher at 11% vs 8%. Diarrhea was 7% and 3%, although grade 3 or 4 was only 1.4% [in both arms]. In terms of hepatitis, it was 5.9% grade 3 to 4 [vs 3.1%, respectively]. Adrenal insufficiency was 5.4% [with the combination]; pneumonitis was 3.9% compared with 1.9% with nivolumab, and grade 3/4 was 0.6% in both arms. Hypophysitis [of any grade] was 2.8% compared with 1.1% [respectively], and grade 3/4 were 0.6% and 0.3% [respectively]. Nephritis [occurred in] 2% and 1.4% [respectively].… Myocarditis was also noted on the study; there was 1.7% incidence [of any grade] with nivolumab/relatlimab and 0.6% instance with nivolumab. Troponin elevation was being monitored on the study. Troponin was being detected because it was being tested for, but it’s something to keep in mind with those [patients].

_Reference:

_{Tawbi HA, Hodi SF, Lipson EJ, et al. Nivolumab (NIVO) plus relatlimab (RELA) vs NIVO in previously untreated metastatic or unresectable melanoma (RELATIVITY-047): Overall survival (OS) and melanoma-specific survival (MSS) outcomes at 3 years. J Clin Oncol. 2024;42(suppl 16):9524. doi:10.1200/JCO.2024.42.16_suppl.9524}