Triplet combinations offer more options but complicate melanoma treatment

GlobalData Healthcare 13 May 2020 (Last Updated May 13th, 2020 16:37)

Triplet combinations offer more options but complicate melanoma treatment

At the 2020 annual American Association for Cancer Research (AACR) conference on 27-28 April, a new option for the treatment of metastatic melanoma patients with BRAFV600 mutations was presented.

Specifically, the addition of the PD-L1 inhibitor Tecentriq (atezolizumab) to a doublet therapy, consisting of the BRAF inhibitor Zelboraf (vemurafenib) and the MEK inhibitor Cotellic (cobimetinib), all marketed by Roche, led to a significant improvement in progression-free survival (PFS) over just the doublet therapy in the IMspire150 Phase III study.

At a median follow-up of 18.9 months, the investigator-assessed PFS was 15.1 months for the Tecentriq + Zelboraf + Cotellic group versus 10.6 months for the placebo + Zelboraf + Cotellic group (hazard ratio: 0.78, p = 0.025). The addition of Tecentriq resulted in a similar proportion of serious adverse events (33.5% for the triplet versus 28.8% for the doublet).

Interestingly, the median duration of response (DOR) was 21 months for the triplet versus 12.6 months for the doublet, strongly suggesting that a subset of patients derive great benefit from the addition of Tecentriq, while the rest of the patients should remain on doublet therapy only. The mature overall survival (OS) data available upon a future analysis will be of great importance.

In the absence of a compelling OS advantage for the triplet, physicians may show a preference for the oral doublet combination because it is safer and more easily administered, instead of introducing additional hospital visits for the administration of intravenous Tecentriq.

A doublet combination of a BRAF and a MEK inhibitor is a frequent option for metastatic, BRAFV600-mutant melanoma. Novartis’ Tafinlar + Mekinist (dabrafenib + trametinib) and Array Biopharma’s Braftovi + Mektovi (encorafenib + binimetinib) were Food and Drug Administration (FDA)-approved in 2014 and 2018 respectively. Since then, the Tafinlar + Mekinist doublet has achieved blockbuster status, highlighting the sales potential of similar combinations.

The combination of Braftovi + Mektovi was approved on the basis of a PFS of 14.9 months, which will create additional requirements to demonstrate that the addition of a premium-priced anti-PD-L1 agent to an anti-BRAF/MEK doublet provides sufficient benefits to warrant approval and reimbursement.

Competition in the first-line melanoma treatment landscape has been significant, including from the blockbuster combination of Bristol-Myers Squibb’s Yervoy + Opdivo (pembrolizumab and nivolumab) and is expected to rise further with the introduction of additional immunotherapy agents.

For example, Merck’s Keytruda (pembrolizumab) is being tested in combination with Novartis’ doublet in the KEYNOTE-022 trial, which had reported a PFS benefit of 6.2 months with the addition of Keytruda as of last analysis. Other late-stage trials for triplets include the COMBI-I and TRIDeNT trials, which include testing the addition of spartalizumab or Opdivo to the Tafinlar + Mekinist doublet.

An FDA approval in melanoma treatment is typically reliant upon an improvement in PFS or relapse-free survival. A high standard set by the combination of Yervoy + Opdivo, shown in the CheckMate 067 trial to offer over 50% five-year OS, is expected to result in uncertain adoption of new agents in the first line. Key opinion leaders interviewed by GlobalData have agreed that triplet therapies are important for first-line therapy in BRAF-mutant melanoma.

However, without head-to-head testing with the most aggressive regimen and additional biomarker testing, physicians will be uncertain about how to choose the most effective therapy. Relevant questions that remain unanswered include whether the use of next-generation BRAF and MEK inhibitors will further enhance PFS and which patients benefit most from the addition of immunotherapy.