Amgen looks for Five Prime payback

One of the main reasons why Amgen paid $1.9bn for Five Prime Therapeutics in March 2021 was the anti-FGFR2b MAb bemarituzumab. Four years on, with bema set to deliver its first pivotal results imminently, the company will find out whether its investment was worth it.

The study in question, Fortitude-101, involves first-line gastric cancer that overexpresses FGFR2b, testing bema plus mFolfox6 chemo versus mFolfox6 alone, and is expected to deliver OS data, its primary endpoint, soon. Given that rival FGFR approaches have been associated with toxicity, another question will be whether specific targeting of FGFR2b can improve matters.

One biotech also homing in on specific FGFR subtypes is Tyra Biosciences, though its lead, TYRA-300, hits FGFR3 and has impressed in bladder cancer. Bema is of special interest because it affords Amgen the chance to be first in class; according to OncologyPipeline only two other industry assets hit FGFR2b specifically, and both lag bema in development.

Optimism

Optimism behind Fortitude-101, and the likely reason why Amgen pulled the acquisition trigger on Five Prime, centres on the phase 2 Fight trial, a controlled study in a small population of FGFR2b-expressing, first-line gastric cancer patients.

Fight yielded its first results in 2020, with bema plus chemo cutting risk of death by 42% versus chemo, and of progression or death by 32%. Final analysis was presented at ESMO-GI in 2023, showing median OS of 19.2 months versus 13.5 months (HR=0.77).

Corneal adverse events were especially notable, being seen at any grade in 67% and 10% of bema combo and control cohorts respectively; the rate of drug discontinuation owing to any treatment-emergent AEs was 41% for bema and just 5% for chemo alone, and such matters will clearly be in focus when the phase 3 trial reads out.

Interestingly, Fight was originally designed as a phase 3 study, but it was converted to a phase 2 in a much smaller population (155 rather than 548 patients), mainly to learn more about the importance of FGFR2b expression.

Notably, Fight enrolled patients with any 2+/3+ staining for FGFR2b by immunohistochemistry, but the benefit was most pronounced in subjects with FGFR2b overexpression in ≥10% of tumour cells, where a hazard ratio for OS of 0.52 was seen. Because of this Fortitude-101 mandates ≥10% FGFR2b expression, and the Fight data give a benchmark for the phase 3 trial to hit.

How big?

One consideration, should bema reach the market, is the need for FGFR2b diagnosis – unlikely to be a burden given how widespread testing already is for other genetic mutations/alterations and overexpressions.

But how big could the FGFR2b gastric cancer market be? Amgen has long claimed that a third of front-line gastric cancer patients overexpress FGFR2b, but the number will be smaller if restricted only to the high (≥10%) expressers.

The underlying all-comers gastric cancer population is important too, given that this market is significantly larger in China than in the US. In China Zai Lab holds bema rights, under a deal with Five Prime that predates the Amgen acquisition, and it's Zai Lab that is responsible for coordinating Chinese hospitals participating in Fortitude-101.

Speaking to ApexOnco in January Zai Lab said gastric cancer comprised 400,000-500,000 patients per year in China, and that ≥10% FGFR2b expressers still amounted to about 100,000. "We see this as a billion dollar opportunity on an annual basis in China," said Josh Smiley, chief operating officer, adding that bema could thus become Zai Lab's biggest-selling oncology drug.

As for the competition, BeiGene's BG-C137 and Allink's ALK201 are in early human trials, but unlike bema both are ADCs.

Projects specific for FGFR2b

Source: OncologyPipeline.