The Revolution is here, and it’s... confusing

Revolution Medicines was punished last year following the first data with its pan-KRAS inhibitor RMC-6236 at ESMO, and the group has caused confusion with another update.

True, the phase 1 data presented in pretreated pancreatic cancer, a hard-to-treat disease, look promising. But the company pooled second and third-line patients for some endpoints, while splitting out these populations for others, in addition to giving various cuts of the ORR endpoint without giving important detail on responses or survival by dose.

Such lack of clarity is relevant given Revolution's move to head straight into phase 3, with studies in both pancreatic and non-small cell lung cancers slated to start this year. There were more details of pivotal pancreatic plans: the Rasolute-302 study, as it’s now known, will enrol 460 patients and test RMC-6236 at 300mg once daily.

It was also surprising how Revolution presented the data; the results weren't pre-released for analysis ahead of its conference call on Monday, and there was still no issued press release at the time this story was published.

The group's stock initially opened down, but then recovered, and ended the day up 2%. Revolution's share price has climbed around 20% since it said on 8 July that it would be releasing data.

Dose response?

Given the move into phase 3 one question is how a 300mg dose specifically might perform, as Monday's update didn’t break down responses by dose. 

Instead, Revolution presented pooled data with 160-300mg. Revolution said that, among these doses, it hadn’t seen any “clear patterns” in terms of dose response. The phase 1 study evaluated RMC-6236 dosed as low as 10mg and as high as 400mg, so presumably the latter has been abandoned because of toxicity.

Tolerability is another issue that reared its head when Revolution presented data at ESMO, with rash looking particularly problematic. This was the case again, although the company noted no discontinuations due to treatment-related adverse events. In phase 3 Revolution plans prophylactic oral antibiotic administration to prevent rash.

The phase 1 study enrolled patients with second-line or later RAS-mutant solid tumours. It excluded patients with KRAS G12C mutations, owing to the availability of the G12C inhibitors Lumakras and Krazati; in any case, G12C mutations are seen in less than 2% of pancreatic patients, Revolution says.

The company uses G12X to refer to other G12 mutations, such as G12D or G12V. The study also included subjects with other mutations, such as G13X and Q61X.

Revolution presented several cuts of ORR, but these were largely in line with the 20% seen at ESMO. Specifically, among 79 G12X patients who’d received RMC-6236 at least 14 weeks before the May cutoff date, the ORR was 20%. This rose to 21% if all RAS mutants were included. And response rates increased if only patients with longer follow-up were included.

However, this analysis only included 97 patients out of 127 included in the safety cohort. Presumably 30 weren't evaluable or didn't have 14 weeks or more of follow-up. 

The evolving pancreatic cancer dataset with Revolution’s RMC-6236

Notes: *efficacy data given for 160-300mg/day; **efficacy data given for 80-400mg/day; ^5/9 responses confirmed; ^^2/5 responses across NSCLC & PDAC confirmed. Source: company presentation & ESMO.

On the harder endpoint of PFS, where RMC-6236 impressed, 118 of 127 patients were apparently evaluable, of whom 104 were G12X mutants. 

Revolution cut its data here based on line of disease, and in second-line patients it claimed an 8.1-month median PFS among 42 G12X mutants, and 7.6 months among all 56 RAS mutants. As a benchmark, the company cited a 2.0-3.5 median PFS with current standard-of-care chemotherapy.

Median PFS dropped to 4.2 months in third-line or later patients with G12X mutations. As for a benchmark here the company noted median PFS of 1.9 months with chemo, but for this cohort Revolution didn’t reveal data on other RAS mutants.

Rasolute

Next, Revolution will have to prove its project trumps chemo in a controlled trial. Rasolute-302 will enrol patients with second-line pancreatic cancer, with G12X mutants making up the “core” study population, but it will also allow patients with other RAS mutations, and RAS wild-types with no other actionable mutations.

Co-primary endpoints are PFS and OS, and PFS data are due in the first half of 2026. During its conference call Revolution stopped short of saying it might seek accelerated approval based on PFS, noting only that this would depend on the FDA, and that it was committed to full approval based on OS.

The company did disclose that it would seek an all-comers label – 92% of pancreatic patients have RAS driver mutations and 85% have RAS G12X mutations, according to Revolution.

The company also hopes to test RMC-6236 in first-line pancreatic cancer.

With other groups including Pfizer recently getting in on the pan-KRAS act Revolution’s haste to get phase 3 started might be understandable. But investors that have driven the company’s market cap up to $7.6bn will have to hope that it hasn’t rushed its dose-finding efforts.