Triple meeting 2023 – Revolution’s KRAS revolution promise draws fans

Revolution Medicines has long claimed that its RAS(ON) inhibitors could have the edge over existing RAS(OFF)-targeting KRAS drugs. On Friday the group presented data at the Triple Meeting backing these claims, with responses seen with its G12C inhibitor RMC-6291 in patients who had previously been treated using this mechanism.

There are several caveats: the data are early and in just a handful of patients, and several responses remain unconfirmed. There was also an 11% rate of grade 3 QTc prolongation, and this side effect will no doubt be watched closely in future trials. But excitement over Revolution’s potential sent its stock up 24% on Friday, making the group one of very few winners of the meeting.

With the group also reporting results on its multi-RAS inhibitor RMC-6236 at the Triple (EORTC-NCI-AACR) meeting, and with more to come on that project this weekend at ESMO, Revolution will hope to consolidate on these gains. The company has plenty of cash in hand since its acquisition of EQRX in August.

RAS(ON) > RAS(OFF)?

Revolution is taking a different approach versus more established players in KRAS inhibition, targeting the GTP-bound form of RAS, or RAS(ON). According to the company, it is RAS(ON) signalling that drives uncontrolled cell growth. Thus, Revolution says, its candidates could be differentiated from the incumbent KRAS blockers, Amgen’s Lumakras and Mirati’s Krazati.

The latest data, from 37 patients in a phase 1 trial of RMC-6291 with a cutoff date of October 5, raise hopes that this might indeed be the case.

Probably the most exciting finding is from 10 NSCLC patients previously treated with a G12C inhibitor: in this cohort there was a 50% partial response rate, although one response remains unconfirmed.

Meanwhile, in seven KRAS inhibitor-naive NSCLC patients the ORR was 43% (two unconfirmed responses), and among 20 KRAS inhibitor-naive colorectal cancer patients it was 40% (three unconfirmed responses).

These numbers stack up well against previously reported results with Lumakras and Krazati – particularly in colorectal cancer, where the main promise of KRAS inhibitors has so far seemed to be as part of a combination with Erbitux or Vectibix.

However, the asset to beat now appears to be Roche’s G12C newcomer divarasib.

Cross-trial comparison of single-agent KRAS G12C inhibitors

*Includes unconfirmed responses; others are confirmed only. Source: Triple Meeting, product labels, NEJM & Lancet Oncology.

As for potential side effects, Revolution said all QTc prolongations were asymptomatic with no cardiac sequelae reported, although one patient discontinued following this adverse event. Mirati’s Krazati has a warning for QTc prolongation, showing that this need not be an impediment to approval, however. 

And Revolution said RMC-6291 wasn't associated with the liver toxicity signal been seen with Lumakras and Krazati, something that will need to be borne out in larger studies.

Multi-RAS

The Triple Meeting data on Revolution’s multi-RAS inhibitor, RMC-6236, were limited to pharmacokinetic results. However, ESMO abstracts dropped over the weekend detailing clinical activity in 14 patients in a phase 1 study. These patients received once-daily doses of 80mg and 120mg – the trial has taken dosing up to 400mg once daily.

As of a cutoff date of April 24, the ORR was 36%, with responses seen in two of 10 pancreatic cancer patients, and three of four NSCLC patients. Three of the responses remain unconfirmed, although the abstract didn't break this down by cancer type.

This trial is noteworthy because it excluded patients with G12C mutations. G12D mutants made up 51% of the overall trial population, but other mutations were represented, including G12V, G12R, G12A, and G12S.

This makes the results difficult to benchmark, because of the lack of other data in G12D and other mutants. However, ESMO will see the first clinical results with a KRAS G12D inhibitor, Jiangsu Hengrui’s HRS-4642, during a late-breaker session on Sunday.

The G12D pipeline is becoming increasingly crowded; indeed, Revolution recently began a first-in-human trial of its candidate, RMC-9805, which also targets RAS(ON).

Revolution still has a lot to prove if it is to disrupt the KRAS inhibitor market, but it appears to be off to a good start.