Colorectal cancer could see Array stand alone at last

The group’s Braftovi/Mektovi combo shows the potential of a targeted approach in colorectal cancer, so where is the competition?

This year’s biggest catalyst for Array Biopharma, readout of the Beacon CRC trial, fell short of expectations, but yesterday’s 23% share price climb reflected its importance: Array showed that the Braf mutation is a factor in colorectal cancer, and that this disease subtype can be treated with a biomarker-driven therapy.

At a stroke this could transform the group from an originator of projects that achieve greatness in other companies’ hands to a bona fide drug developer in its own right. It is surprising that neither of the other major Braf inhibitor players, Novartis and Roche, have given colorectal cancer much thought, but this might now change.

Like Array both the Swiss companies boast Braf/Mek inhibitor combinations that are approved for melanoma. The Braf mutation is present in around 60% of melanomas, but in colorectal cancer it far rarer, amounting to some 10% of cases; perhaps economic considerations have deterred interest in colorectal cancer, as it is problematic to set two different prices for the same therapy.

Striking gold

And perhaps Array, a latecomer to this space, is happy to deprioritise melanoma. It had worked hard to find a niche in which its combo, Braftovi plus Mektovi, might work, and having earlier licensed out its most promising assets it struck gold in colorectal cancer (In sticking to the knitting has Array given up too much?, January 31, 2019).

Beacon CRC had tested Braftovi on top of Erbitux, with or without Mektovi, versus Erbitux plus chemo, in second or third-line colorectal cancer. The long-awaited interim analysis showed that both the triplet and doublet beat control in extending overall survival, the primary efficacy endpoint, and overall response rate.

These measures were hit with high statistical significance, but failed to meet expectations. Beacon CRC’s safety lead-in showed 15.5 months of OS, and some had expected ORR above 30%; in the event, the triplet yielded 9.0 months and 26.1% respectively.

That said, in an area with few realistic options there can be no doubt about the clinical significance of the result. Braftovi/Mektovi already has US compendia listing for Braf-positive colorectal cancer, meaning that a reimbursement mechanism is in place, and that the Beacon CRC data could immediately boost off-label prescribing.

Interestingly enough, Novartis’s own Braf/Mek combo, Tafinlar/Mekinist, also boasts compendia listing in Braf-mutant colorectal cancer on the basis of phase II data showing 9.1-month OS and a 21% ORR. However, a quarter of these study subjects were first line, so the Beacon CRC dataset, in a more severe population, seems stronger and should help Array establish dominance here.

Most tellingly of all, however, Novartis has not carried out any phase III work since generating the mid-stage data three years ago, suggesting that colorectal cancer is not a commercial focus. And even that is more than Roche has done with its combo, Zelboraf/Cotellic, outside melanoma. Zelboraf plus irinotecan and an anti-EGFR drug like Erbitux carries US compendia listing for Braf-mutant colorectal cancer.

Marketed Braf/Mek inhibitor combinations
Company Braf inhibitor Mek inhibitor Braf+ melanoma Braf+ colorectal cancer
Novartis (ex Glaxo) Tafinlar Mekinist Approved 2014 Triplet with Vectibix (NCT01750918)
Triplet with PDR001 (NCT03668431)
Roche/Exelixis Zelboraf Cotellic Approved 2015 Zelboraf/irinotecan/Erbitux (NCT02164916)
Array (ex Novartis) Braftovi Mektovi Approved 2018 Beacon CRC (NCT02928224*)
Anchor CRC (NCT03693170)
NB: all trials phase II except if marked *.

The irony of how Array came to own its combo will be lost on few investors: Novartis had had rights to Mektovi, but handed these back, plus Braftovi and $85m, when Array alleged that the Swiss firm’s ownership of Mekinist/Tafinlar put it in an anticompetitive situation.

The sellside expects Braftovi/Mektovi to generate $1.2bn of revenue by 2024, according to EvaluatePharma, $702m of which will come from colorectal cancer. Attention now turns to Array’s first-line Anchor CRC study, which reads out mid-2020.

It is possible that Braf-mutant colorectal cancer is simply too small a use for Novartis and Roche to bother with, but even if the Beacon CRC results spur renewed development Array has an important first-mover advantage. It must make the most of this, and Anchor CRC holds the key to consolidating its position.

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