Five Prime looks to turn a corner

With Five Prime’s stock surging 300% overnight the company will be hoping to put a disastrous three years behind it. The reason for the sudden enthusiasm lies in survival data with bemarituzumab, a wholly owned asset the group had touted last year, but which until now had little to back up the hype.

The findings, in the Fight trial in first-line stomach cancer, position the company’s lead project as the first mover in a new approach, FGFR2B inhibition, with little competition. Of course they come with caveats, and the stock move has to be seen in the context of a share price that had lost 90% of its value since 2016.

The collapse in 2016/17 was triggered by disappointing data with cabiralizumab, an anti-CSF-1R MAb partnered with Bristol Myers Squibb. A restructuring and C-suite sweep-out followed (Five Prime moves towards subprime, January 16, 2019). Five Prime’s phoenix-like rise sees it valued at $800m, which by today’s standards seems undemanding.

Taking the Fight

The spotlight now falls on bemarituzumab. Fight was the first large trial in front-line gastric/gastroesophageal junction cancer to screen for FGFR2B overexpression, which the company says accounts for 30% of non-Her2-driven cancers of this type; according to last year’s investor pitch this amounts to 56,870 addressable patients.

Fight combined bemarituzumab with chemo, and compared its progression-free survival versus chemo alone as primary endpoint; overall survival was a secondary measure. Both showed a statistically significant effect, according to the study’s design, with median PFS improving 2.1 months to 9.5 months, and median OS not yet reached but showing a 42% reduction in risk of death.

This is where the caveats begin, however. Five Prime revealed that the p value threshold for this trial was 0.2, and according to this both measures succeeded, with p=0.073 and 0.027 respectively. Had Fight used the more common definition of statistical significance of 0.05 the study would have been a bust, since its primary endpoint would have missed this stricter threshold.

The group defended its design, saying this was not uncommon for a small phase II study; it said it had not designed Fight as a registrational study, and had only been hoping to see a survival trend. As such, the seemingly positive data appear to have come as a big surprise.

Questions

If Five Prime now seeks to raise cash, potential investors will question why the upper bound of the confidence interval for PFS is above 1.0, and why 34% of bemarituzumab subjects discontinued because of an adverse event versus just 5% in the control group. And nothing has been said about baseline patient characteristics, an imbalance in which could account for the apparent benefit.

A further spanner in the works is that the front-line setting is set to change, with Merck & Co and Bristol both recently claiming successes with anti-PD-1 antibodies, though histology and biomarkers complicated data interpretation (Esmo 2020 – double win complicates the gastric cancer picture, September 21, 2020).

If FGFR2B is indeed implicated in gastric cancer competing companies should take note. EvaluatePharma data reveal several with assets against this target, though apparently none with specificity at the 2B subtype. While bemarituzumab is an antibody most are small molecules; Incyte’s Pemazyre, which hits FGFR1/2/3, is marketed for cholangiocarcinoma.

Five Prime also claims that FGFR2B is overexpressed in subgroups of squamous NSCLC, triple-negative breast, ovarian and pancreatic cancers. For now, however, its focus must be on designing a phase III gastric cancer study with a primary endpoint of OS.

Selected clinical assets with activity at FGFR2
Project	Company	Target	Type
Marketed
Pemazyre	Incyte	FGFR1, 2 & 3	Small molecule
Phase II
E7090	Eisai	FGFR1, 2 & 3	Small molecule
Debio 1347	Debiopharm/Roche	FGFR1, 2 & 3	Small molecule
HMPL-453	Hutchison China Meditech	FGFR1, 2 & 3	Small molecule
ABSK091	Abbisko Therapeutics	FGFR1, 2 & 3	Small molecule
Bemarituzumab	Five Prime/Zai Lab	FGFR2B	Antibody
Phase I
3D-185	3D Medicines	FGFR1, 2 & 3, CSF1R	Small molecule
DS-1123	Daiichi Sankyo	FGFR2	Antibody
RLY-4008	Relay Therapeutics	FGFR2	Small molecule
PRN1371	Sanofi (ex Principia)	FGFR1, 2, 3 & 4	Small molecule
Source: EvaluatePharma & company statements. https://www.evaluate.com/vantage/articles/news/trial-results/five-prime-looks-turn-corner