Activity and safety of first-line treatments for advanced melanoma: A network meta-analysis

by Selleckchem | Jul 14 2023

Background: Treatment options for advanced melanoma have increased with the US Food and Drug Administration approval of the anti-LAG3 plus anti-PD-1 relatlimab/nivolumab combination. To date, ipilimumab/nivolumab is the benchmark of overall survival, despite a high toxicity profile. Furthermore, in BRAF-mutant patients, BRAF/MEK inhibitors and the atezolizumab/vemurafenib/cobimetinib triplet are also available treatments, making the first-line therapy selection more complex. To address this issue, we conducted a systematic review and network meta-analysis of the available first-line treatment options in advanced melanoma.

Methods: Randomised clinical trials of previously untreated, advanced melanoma were included if at least one intervention arm contained a BRAF/MEK or an immune-checkpoint inhibitor (ICI). The aim was to indirectly compare the ICIs combinations ipilimumab/nivolumab and relatlimab/nivolumab, and these combinations with all the other first-line treatment options for advanced melanoma (irrespective of BRAF status) in terms of activity and safety. The coprimary end-points were progression-free survival (PFS), overall response rate (ORR) and grade ≥3 treatment-related adverse events (≥ G3 TRAEs) rate, defined according to Common Terminology Criteria for Adverse Events.

Results: A total of 9070 metastatic melanoma patients treated in 18 randomised clinical trials were included in the network meta-analysis. No difference in PFS and ORR was observed between ipilimumab/nivolumab and relatlimab/nivolumab (HR = 0.99 [95% CI 0.75-1.31] and RR = 0.99 [95% CI 0.78-1.27], respectively). The PD-(L)1/BRAF/MEK inhibitors triplet combinations were superior to ipilimumab/nivolumab in terms of both PFS (HR = 0.56 [95% CI 0.37-0.84]) and ORR (RR = 3.07 [95% CI 1.61-5.85]). Ipilimumab/nivolumab showed the highest risk of developing ≥ G3 TRAEs. Relatlimab/nivolumab trended to a lower risk of ≥ G3 TRAEs (RR = 0.71 [95% CI 0.30-1.67]) versus ipilimumab/nivolumab.

Conclusion: Relatlimab/nivolumab showed similar PFS and ORR compared to ipilimumab/nivolumab, with a trend for a better safety profile.

Comments:

The systematic review and network meta-analysis aimed to compare the activity and safety of different first-line treatment options for advanced melanoma. The study included randomized clinical trials of previously untreated patients with advanced melanoma, focusing on interventions that involved either a BRAF/MEK inhibitor or an immune checkpoint inhibitor (ICI).

A total of 18 randomized clinical trials involving 9,070 metastatic melanoma patients were included in the analysis. The study compared the ICIs combinations of ipilimumab/nivolumab and relatlimab/nivolumab, as well as these combinations with other first-line treatment options, regardless of the BRAF mutation status of the patients. The primary endpoints measured were progression-free survival (PFS), overall response rate (ORR), and the rate of grade ≥3 treatment-related adverse events (≥ G3 TRAEs).

The results of the analysis showed no significant difference in PFS and ORR between ipilimumab/nivolumab and relatlimab/nivolumab. The hazard ratio (HR) for PFS was 0.99 (95% CI 0.75-1.31), indicating no significant disparity in PFS between the two combinations. The relative risk (RR) for ORR was 0.99 (95% CI 0.78-1.27), suggesting similar response rates.

However, when comparing the ICIs combinations with BRAF/MEK inhibitors triplet combinations, the PD-(L)1/BRAF/MEK inhibitors showed superiority over ipilimumab/nivolumab in terms of both PFS and ORR. The HR for PFS was 0.56 (95% CI 0.37-0.84), indicating a significant improvement in PFS with the triplet combinations. The RR for ORR was 3.07 (95% CI 1.61-5.85), suggesting a substantially higher response rate.

In terms of safety, ipilimumab/nivolumab had the highest risk of developing grade ≥3 treatment-related adverse events (≥ G3 TRAEs). On the other hand, relatlimab/nivolumab showed a trend towards a lower risk of ≥ G3 TRAEs compared to ipilimumab/nivolumab, with an RR of 0.71 (95% CI 0.30-1.67).

In conclusion, the study found that relatlimab/nivolumab had similar efficacy in terms of PFS and ORR compared to ipilimumab/nivolumab, but with a potential advantage of a better safety profile. However, PD-(L)1/BRAF/MEK inhibitors triplet combinations were shown to be superior to ipilimumab/nivolumab in both PFS and ORR. The findings highlight the complexity of selecting first-line therapies for advanced melanoma, especially in BRAF-mutant patients, and provide valuable insights for treatment decision-making.