Immune checkpoint inhibitors as first line in advanced melanoma: Evaluating progression-free survival based on reconstructed individual patient data

Cancer Med. 2023 Feb;12(3):2155-2165. doi: 10.1002/cam4.5067. Epub 2022 Aug 3.


Background: In patients with advanced melanoma, immune-checkpoint inhibitors (ICIs) represent the mainstay for first line treatment. Recently, relatlimab+nivolumab was proposed as a new combination therapy. This review was aimed at summarizing the current data of effectiveness for ICIs. Progression-free survival (PFS) was the endpoint of our analysis.

Methods: After a standard literature search, Phase II/III studies comparing different ICI regimens in previously untreated advanced melanoma patients were analyzed. Patient-level data were reconstructed from Kaplan-Meier curves by application of the IPDfromKM method. These reconstructed datasets were used to perform indirect comparisons between treatments. Standard statistical testing was used, including hazard ratio and medians. A secondary analysis employed the restricted mean survival time.

Results: Six trials were included in our analysis. Information on PFS from these trials was pooled according to the following treatments: nivolumab or pembrolizumab as monotherapy, or in combination with ipilimumab, and relatlimab + nivolumab. Pembrolizumab+ipilimumab showed significantly better PFS compared with the other treatments; nivolumab+ipilimumab ranked second; the other treatments showed a similar survival pattern.

Conclusions: The picture of comparative effectiveness resulting from our analysis is complex. The IPDfromKM method is advantageous because it accounts for the length of follow-up but loses the balance between treatment group and controls determined by randomization. Based on indirect comparisons, the combination of pembrolizumab+ipilimumab showed a particularly high efficacy, and so deserves further investigation. While the effect of between-trial differences in inclusion criteria plays an important role, our results do not support the proposal of relatlimab+nivolumab as a new standard of care.

Keywords: IPDfromKM method; advanced melanoma; individual patient data; ipilimumab; nivolumab; patient data reconstruction; pembrolizumab; progression-free survival; relatlimab; survival meta-analysis.

Publication types

  • Review

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols
  • Humans
  • Immune Checkpoint Inhibitors / therapeutic use
  • Ipilimumab
  • Melanoma*
  • Nivolumab* / therapeutic use
  • Progression-Free Survival


  • relatlimab
  • Nivolumab
  • Ipilimumab
  • Immune Checkpoint Inhibitors