Verastem spoils its ASCO bounce

Avutometinib, a Roche castoff that Verastem acquired for just $3m, remains a volatile asset. Pancreatic cancer data in an ASCO abstract unveiled on 23 May initially sent Verastem’s shares up 45% in the aftermarket, but an unpleasant update on the project’s filing plans in a different setting brought the stock down to earth today.

The shares closed down 66% after Verastem said its rolling US submission for avutometinib plus defactinib in second-line serous ovarian cancer was being limited only to patients with KRAS-mutated disease, reducing the addressable population. Not only that, but the response rate in the phase 2 Ramp-201 study backing this accelerated approval filing has fallen from 45% to 27%.

The reason for the KRAS-mutant restriction is clear, as it’s these patients who have driven most of the efficacy in Ramp-201. Verastem has now revealed that ORR in KRAS-mutant disease was 37%, versus just 15% in wild-type patients.

This is all a far cry from last year’s ASCO, when the company’s press release trumpeted a 45% ORR (13/29 patients) in Ramp-201, an improvement on the 28% figure contained in the abstract. That caused Verastem's stock to surge 126%, and made it one of the winners of ASCO 2023.

A key part of the filing plan is the confirmatory phase 3 Ramp-301 study of the avutometinib combo in second-line serous ovarian cancer patients. This got under way last October, and curiously continues to enrol KRAS wild-type patients as well as those with KRAS-mutant disease.

ASCO 2024

In mid-2020 Verastem bought avutometinib, a dual RAF/MEK inhibitor then known as CKI27, from Roche’s Chugai unit for $3m after it was deemed to have disappointed as monotherapy. Before this morning’s bombshell there was hope that the project’s ASCO data would again boost Verastem.

This year’s ASCO poster concerns the separate Ramp-205 study in first-line pancreatic ductal adenocarcinoma, where avutometinib plus defactinib, Abraxane and chemo yielded a 75% response rate among eight evaluable subjects. Sellside analysts cite a 23% ORR for Abraxane plus gemcitabine alone as a benchmark in this setting.

However, two of the five avutometinib responses remained unconfirmed at the 24 January cutoff, and toxicity was notable: among the 18 safety-evaluable patients grade ≥3 treatment-related adverse events included liver enzyme elevations in 17% and sepsis in 11%, while one patient discontinued owing to febrile neutropenia and a bilirubin increase.

This is an updated version of a story published earlier.