A phase III study evaluating a combination of a Novartis AG anti-PD-1 candidate with the well-established BRAF/MEK inhibitor combo in first-line unresectable or metastatic BRAF V600 mutant melanoma missed its primary endpoint of progression-free survival, leaving the company without a clear alternative to competitor Roche Holding AG’s triplet for the indication, approved in July.

The investigational anti-PD1-1 spartalizumab was the big variable in the study, given either in combination with the BRAF inhibitor Tafinlar (dabrafenib) and the MEK inhibitor Mekinist (trametinib) or withheld in an arm that substituted a placebo for it alongside the BRAF/MEK inhibitor combo.

"What's probably happening is that targeted therapy is, in some way, inhibiting the immunotherapy. Otherwise, you would have gotten at least an additive advantage," University of California San Francisco professor Adil Daud told BioWorld. Daud, a melanoma expert who was a senior researcher in the KEYNOTE-001 and KEYNOTE-006 studies, was not involved with the Novartis study.

Called COMBI-i, the study sought to explore the potential benefit of combining the two major approaches in melanoma medicine today: targeted therapy and immunotherapy. While the former offers high response rates, it's beset by relatively short duration of response. The latter flips the picture, yielding lower response rates but longer duration of response. Whether a combination could offer the best of both worlds for treatment-naive patients with advanced BRAF-mutated melanoma, or at least some additive improvement was in question – though not wholly unknown.

Two earlier studies, KEYNOTE-022 and IMSpire150 explored a similar question. In KEYNOTE-022, researchers tested the efficacy of the PD-1 inhibitor Keytruda (pembrolizumab) in combination with Tafinlar and Mekinist in participants with advanced melanoma. Though that study showed some signs of efficacy for the triplet, it failed to reach statistical significance on overall response rate.

IMSpire150, a study using Roche's Tecentriq (atezolizumab) as the anti-PD1 asset alongside its MEK inhibitor Cotellic (cobimetinib) and its BRAF inhibitor Zelboraf (vemurafenib), painted a different picture. The triplet demonstrated enough benefit to PFS for patients with BRAF V600 mutation-positive advanced melanoma to win a label expansion for that indication from the FDA in July. However, some researchers took issue with the study's reliance on investigator-assessed PFS as its primary endpoint instead of more rigorous measure of centrally-assessed PFS.

As for COMBI-i, though it didn't reach its primary endpoint, "the study’s findings give us valuable insights into the role the investigational immunotherapy spartalizumab may play in future cancer therapy combinations and underscore the previously established importance of Tafinlar + Mekinist for these patients,” said John Tsai, Novartis' head of global drug development and chief medical officer. However, a representative of the company declined to provide any examples of those insights.

Future efforts in the indication will likely focus on different types of combinations, as well as trying to understand what's went wrong with the targeted therapy/immunotherapy approach, Daud said. "My guess is that people will focus on using more intensive immunotherapy or more intensive targeted therapy." Genomic sequencing, used alongside a baseline regimen of ipilimumab and nivolumab, followed by the potential combination of new medicines with BRAF/MEK regimens could also be explored, he said.

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