According the primary results of the COMBI-i trial, the addition of PD1 inhibitor spartalizumab to treatment with dabrafenib and trametinib does not improve progression-free survival (PFS) in patients with unresectable or metastatic melanoma. However, specific subgroups of patients might benefit from a combined treatment approach.

 

In the past decade, the emergence of both immune checkpoint inhibitors and targeted therapy have improved the treatment outcomes for patients with unresectable or metastatic melanoma. Despite these advantages, many patients experience disease progression and, therefore, new treatment strategies are needed. Based on promising preclinical data, the phase 3 COMBI-i trial evaluated the effect of combining immune checkpoint inhibition with targeted therapy (i.e. BRAF and MEK inhibition).

At ESMO Virtual 2020, Dr Paul Nathan (Mount Vernon Cancer Centre, UK) presented results of the primary analysis of the COMBI-i trial [1]. In this trial, 532 patients with unresectable or metastatic BRAF-mutated melanoma were randomized 1:1 to treatment with the PD1 inhibitor spartalizumab (440 mg Q4W) plus dabrafenib (150 mg BID) and trametinib (2 mg QD) – the “triplet” – or placebo plus dabrafenib and trametinib – the “doublet”. The primary endpoint of COMBI-i is investigator-assessed progression-free survival (PFS) using RECIST 1.1; significance threshold P<0.025 [equivalent HR <0.801]. Overall survival (OS) is a key secondary endpoint. The primary analysis presented at ESMO is based on a minimum follow-up of 24 months and 312 events (statistical threshold P=0.02497).

Median PFS was 16.2 months in the triplet arm and 12.0 months in the doublet arm (HR 0.82; 95% CI 0.655-1.027; P=0.042). Estimated PFS rates at 12 months were 58% and 50%, respectively, and 44% and 36% at 24 months. So, based on the statistical design of the study, COMBI-i did not met its primary endpoint. Interestingly, the performance of patients receiving the doublet was superior to that historically seen in trials with dabrafenib plus trametinib, Dr Nathan remarked. Additional subgroup analyses revealed a trend to more benefit of triplet versus doublet in patients with high LDH levels, more metastatic sites, and a high tumour mutational burden. As could be expected, triplet therapy was related to more treatment-associated adverse events and a higher number of dose modifications (interruptions or discontinuations of dabrafenib and trametinib) compared with double therapy.

Commenting on the results of COMBI-i, Dr Bartosz Chmieowski (University of California, Los Angeles, USA) compared COMBI-i with KEYNOTE-22 and IMspire150 [2]. These trials also evaluated the effect of adding a checkpoint inhibitor to BRAF/MEK-inhibition. Although the PFS curves of all 3 studies are fairly comparable, only IMspire150 met its endpoint [3,4]. This means that minimal differences in patient populations (LDH levels, number of metastases) and differences in the statistical design of the trials are important determinants for a “positive” or “negative” result in these trials. In addition, Dr Chmielowsky challenged the rationale of these trials. It is known that treatment with a BRAF inhibitor is associated with increased expression of melanoma antigens and an increase in CD8+ T cell infiltrate in the tumour. Therefore, it would be better to evaluate the benefit a targeted therapy added to a checkpoint inhibitor rather than to evaluate the benefit of checkpoint inhibitor added to targeted therapy. In the STARBOARD trial the latter design will be tested (pembrolizumab plus encorafenib/tremelimumab versus pembrolizumab).

 

  1. Nathan P, et al. Spartalizumab plus dabrafenib and trametinib (Sparta-DabTram) in patients (pts) with previously untreated BRAF V600–mutant unresectable or metastatic melanoma: Results from the randomized part 3 of the phase III COMBI-i trial. ESMO 2020 Virtual Meeting, abstract LBA43
  2. Chmielowski B. Mastering the art of the management of patients with metastatic melanoma. ESMO 2020 Virtual Meeting, Presentation ID 4816.
  3. Ascierto PA, et al. Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma. Nat Med. 2019; 25: 941-946.
  4. Gutzmer R, et al. Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAF V600 mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2020; 395:1835-1844.

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