Array Biopharma’s combination win in melanoma puts it commercially behind, but perhaps clinically ahead of, Novartis and Roche. Progression-free survival of 14.9 months for the binimetinib and encorafenib doublet is numerically better than that of marketed competitors from the two Swiss groups, but the smaller biotech will be coming late to a market that looks limited.
Combinations of Mek and Braf inhibitors have had difficulty expanding from skin cancer into other indications, and even in melanoma their use is restricted to those patients with a BRAF mutation. Still, this is forecast to be a $2bn market in 2022, and Array shares rose 55% in expectation that the Colorado-based group will grab a share of it.
The three-arm Columbus study compared the Array combination versus two single agents, Roche’s Braf inhibitor Zelboraf and Array’s encorafenib alone. The 14.9 month PFS survival over the 7.3 months recorded by Zelboraf patients was statistically significant, although the doublet failed to show a statistically significant benefit over encorafenib monotherapy.
In a conference call today Array executives did not shed much light on that puzzling latter result, other than to say that the “magnitude of effect” data would be important for regulators to consider – the difference between the combination and encorafenib arms just missed statistical significance at a p value of 0.051.
Much of the rest of the data will be held back for presentation at a medical meeting, with chief executive Ron Squarer saying the group was targeting the Society for Melanoma Research conference in Boston in early November. These data will include details on adverse events, where a more tolerable combination could prove to have an advantage over the Novartis and Roche pairings, which carry with them skin, liver, cardiovascular and pulmonary toxicities.
Regulatory submissions for Array's combination are expected in 2017.
Shape of the market
While Mr Squarer and fellow executives were reluctant to make the comparison with the competing combinations, it should not escape anybody’s attention that Novartis’s Mekinist/Tafinlar combination achieved an 11.4 month PFS outcome and the Roche Zelboraf/Cotellic combination 9.9 months. Caution should be used when making cross-trial comparisons, of course, but it seems safe to say Array's product should be at least competitive on efficacy.
What Array is competing for is another question. With immuno-oncology agents Opdivo, Yervoy and Keytruda dominating this indication, regardless of biomarker status, the targeted agents like Braf, Raf and Mek inhibitors will be fighting over a limited number of patients. Array chief operating officer Andrew Robbins acknowledged today that there was a “slight weight in favour of immuno-oncology as first-line” even in the population eligible for a Mek and Braf or Raf inhibitor.
Thus Columbus contains a prespecified subgroup analysis of patients that have been previously treated with immunotherapies, data that will be released as part of subsequent analyses.
Meanwhile, Array’s ambitions outside melanoma remain enthusiastic despite the failure of its second Mek inhibitor, selumetinib, in lung cancer. The colorectal cancer trial Beacon CRC with Erbitux was announced earlier this year, for which the FDA issued a special protocol assessment earlier this month, and will complete enrolment in 2018. It is one of the few trials outside of melanoma for agents in these classes.
Immunotherapy has been the dominant theme of oncology for several years, although groups like Array persist in advancing targeted agents. Wise companies know that they need to identify how these will be used in this new context. Array’s combination is showing impressive signs against its direct competitors, but physicians will want to consider where it fits best in a sequence that includes Opdivo and Keytruda.