Braftovi outdoes Tafinlar in colorectal cancer

The rollercoaster story of Braftovi, a BRAF inhibitor originated and then given away by Novartis, has just seen another success, with the US FDA granting it accelerated approval as part of an Erbitux and chemo combination for first-line BRAF-mutated colorectal cancer.

The drug, now owned by Pfizer, therefore has four US-approved indications, with the front-line colorectal cancer nod coming after an approval in second-line BRAF-positive disease was granted four years ago. This is notable in light of Novartis's decision to focus on the rival BRAF inhibitor Tafinlar, which never got approved for this cancer type.

The basis for Braftovi's first-line approval is the Breakwater study, where an Erbitux plus chemo combo scored a 61% response rate, versus 40% for chemo with or without Avastin. The trial has additional cohorts, including Braftovi and Erbitux alone, and will evaluate PFS (primary) and OS (secondary) endpoints, which will presumably be used to back full approval.

It does not include Pfizer's MEK inhibitor Mektovi, which had been studied as part of a Braftovi/Mektovi/Erbitux triplet in the second-line Beacon-CRC trial, but which was found to add nothing to the Braftovi/Erbitux doublet that ultimately got a US green light in 2020. Braftovi plus Mektovi is separately approved for BRAF-mutant melanoma and NSCLC.

In those last two settings Braftovi/Mektovi competes against Novartis's BRAF inhibitor Tafinlar and MEK inhibitor Mekinist. Pfizer's nine-month 2024 sales of Braftovi, with or without Mektovi, rose 26% to $437m, while Novartis reported nine-month Tafinlar/Mekinist revenues of $1.5bn (+9%).

Changes of ownership

All four assets have undergone various changes of ownership, and their development suggests that first in class isn't necessarily best in class, at least not in every indication.

Tafinlar and Mekinist were originated by GSK, and were first approved in 2013, but ended up at Novartis through a 2014 asset swap that included GSK's marketed oncology portfolio and Novartis's vaccines business. At the time the Swiss firm's earlier-stage pipeline also included the project later named Braftovi, as well as Mektovi, the latter through a licensing deal with Array Biopharma.

To satisfy antitrust concerns over the GSK deal, which would otherwise have resulted in Novartis having two BRAF and two MEK inhibitors, Novartis ended the Array deal, handing Mektovi back to Array along with an $85m payment. If that weren't generous enough, it then sold the in-house developed Braftovi to Array for a "de minimis" payment.

Later in 2015 Array licensed ex-US rights to both molecules to Pierre Fabre for $30m up front and up to $425m in development and commercialisation milestones. But the big payoff came in June 2019, when Pfizer acquired Array for $11.4bn, citing the potential of Braftovi and Mektovi as a key reason for the move.

It's true that Novartis remains ahead in melanoma, and that Mektovi appears to have no value in colorectal cancer, given the ambiguous result of the triplet in Beacon-CRC. But the colorectal setting is clearly the one where Pfizer has the best chance to make headway on its rival, and its first-line approval is another step on this path.

Selected trials of Braftovi and Mektovi

Source: OncologyPipeline.