Sutro’s folate challenge to Immunogen hits a problem

 When does disclosure of a best-in-class drug profile warrant a share selloff? When it is accompanied by questions about the way data were generated, apparently, along with concerns about lack of a therapeutic window.

A case in point is Sutro, which yesterday released an update from an ovarian cancer trial of its folate receptor α antibody-drug conjugate STRO-002. This caused Wells Fargo to trumpet STRO-002’s profile as “best-in-class” – the project is a challenger to Immunogen’s similarly acting mirvetuximab soravtansine, which recently scored in a similar setting – but today Sutro stock opened off 25%.

On the face of it the Sutro update was upbeat: in a pretreated ovarian cancer population not enriched for FRα expression there was a 33% overall response rate to STRO-002, comprising 19% in a 4.3mg/kg cohort and 47% in 5.2mg/kg. Immunogen’s Soraya trial had shown 32% of relapsed ovarian cancer patients responding to mirvetuximab, but this was a FRα-high population.

A cross-trial comparison gives Sutro the efficacy edge, therefore, notwithstanding some subtle differences; 63% and 65% of the patients given STRO-002 had relapsed on Avastin and a Parp inhibitor respectively, versus 100% and 48% in Soraya, for instance. Sutro said ORR was 40% for >25% FRα expressers, and 13% for those at or below the 25% threshold, but even targeting only the former would give STRO-002 70% of the population.

What’s the dose?

Toxicity is a concern, however. Neutropenia is a major problem, with 60% of patients experiencing it at grade 3 or above, and there was one death from febrile neutropenia, in a patient on 5.2mg/kg of STRO-002.

Sutro said a protocol amendment had been implemented to require any 5.2mg/kg patient experiencing grade 4 neutropenia to have their dose cut to 4.3mg/kg. Crucially, however, 5.2mg/kg is the group’s “go-forward” dose for a pivotal study, based on the dose response it claims to have demonstrated.

The key question, therefore, is whether a therapeutic window exists for STRO-002; Sutro claims that responses on 5.2mg/kg are maintained even if the dose is subsequently reduced.

And is there even a dose response? Sutro’s data show some inconsistency as to when they were generated: at the stated November 8 cutoff of the substantive dataset there were three and four confirmed remissions in the 4.3mg/kg and 5.2mg/kg cohorts, respectively.

It is only after post-cutoff follow-up of five additional unconfirmed responses said to be “of interest” that a more convincing dose response emerged: one 4.3mg/kg remission was actually deemed a stable disease, but all four 5.2mg/kg responses were confirmed as real PRs.

Source: Sutro presentation.

Such details aside, it is clear that lack of safety is now the biggest concern surrounding STRO-002.

Not that mirvetuximab has a clean profile itself, of course: in Soraya blurred vision was a common adverse event, and treatment-related AEs led to dose reductions in 19% of patients, dose delays in 32%, and discontinuations in 7%. Immunogen plans to file this quarter, but investors will recall mirvetuximab's 2019 failure in an all-comers population.

Bullish Wells Fargo analysts glossed over STRO-002’s safety profile, while those at Berenberg called its side effects manageable but stopped short of the best-in-class assessment, merely calling the Sutro project competitive against mirvetuximab.

Wells Fargo could still be right. STRO-002 could be the best in a class where toxicity scuppers both assets.

https://www.evaluate.com/vantage/articles/news/trial-results/sutros-folate-challenge-immunogen-hits-problem