Triple meeting 2024 – Revolution shows selective KRAS promise

Ahead of the Triple meeting, a big question whether Revolution Medicines’ KRAS G12D-selective inhibitor, RMC-9805, could buck the disappointing trend seen with this class of drugs – and the answer appears to be yes.

Revolution cited an overall response rate of 30% in second-line or later pancreatic cancer – an impressive result in this underserved disease, although several responses still need to be confirmed. If this number holds up, RMC-9805 will look better on a cross-trial basis than Astellas’s G12D degrader ASP3082, which recently produced an ORR of 19% in relapsed pancreatic cancer.

RMC-9805’s safety profile also looks cleaner than both ASP3082 and Revolution’s own pan-KRAS inhibitor, RMC-6236. The company is now evaluating a combination of RMC-9805 and RMC-6236, with the hope of producing deeper KRAS inhibition; it also has plans to combine RMC-9805 with other agents.

KRAS G12D is on

Revolution’s projects are designed to hit the GTP-bound (active) forms of KRAS, also known as its “on” state. According to the company, it’s the on state that drives uncontrolled cell growth.

This might explain why the company appears to have had more success than Astellas in targeting KRAS G12D, although there are plenty of reasons to be cautious about RMC-9805.

Cross-trial comparison of KRAS G12D-selective agents in pancreatic cancer

Note: *denominator includes PDAC pts receiving 1,200mg QD or 600mg BID at least 14 weeks before cutoff date, includes confirmed or pending PRs; **denominator includes PDAC pts receiving ≥1 dose of 300–600mg ASP3082 with ≥1 non-missing post-baseline assessment, includes 1 unconfirmed response; ^denominator includes 48 pts treated with 300-600mg doses. Source: EORTC-NCI-AACR & OncologyPipeline.

One is the relatively small number of patients involved in the efficacy analysis. As of the cutoff date of 2 September, the phase 1 study has treated 179 patients with various tumour types, and 104 patients with pancreatic ductal adenocarcinoma (PDAC). However, Revolution zoomed in on 40 PDAC patients receiving the go-forward daily dose of 1,200mg.

Another caveat is the number of unconfirmed responses. Among these subjects, the group claimed a 30% ORR, with 12 responses – but a look at the waterfall plot shows only six of these have been confirmed; Revolution's number also includes patients with unconfirmed responses who are still on treatment and may yet be confirmed. No swimmer’s plot was presented at the Triple (EORTC-NCI-AACR) symposium.

During a conference call to discuss the data on Friday, Revolution execs noted that, based on their experience so far with both RMC-9805 and RMC-6236, most patients who respond end up being confirmed, but this will need to be borne out in future.

In addition, no absolute numbers on side effects were given, only the incidence of treatment-related adverse events occurring in 10% of patients or more. These didn’t look too problematic, although 27% and 20% of patients receiving 1,200mg daily had low-grade nausea and diarrhoea respectively.

Rash, which has been an issue with RMC-6236, was seen in 10% of patients on 1,200mg daily, with none at grade 3. Meanwhile, ALT increases occurred in 6% of patients (1% at grade 3), and AST increases in 4% (none at grade 3). There were no treatment-related grade 4 or 5 adverse events, dose-limiting toxicities or discontinuations.

Meanwhile, Astellas’s active doses of ASP3082 (300-600mg) led to AST increases in 13% of patients, 4% at grade 3. There were also dose-limiting toxicities, including liver enzyme elevations. Despite this, Astellas is dosing higher in the hope of producing more consistent degradation.

The latest data suggest that any problems for Revolution’s combination efforts could come from its pan-KRAS project RMC-6236, rather than RMC-9805. At the Triple meeting, the group presented incremental PDAC data with the former from a phase 1 trial that read out in July; notably, 48% of patients suffered diarrhoea, and 43% nausea, while 91% experienced rash.

RMC-6236 is ahead, with the phase 3 Rasolute-302 PDAC trial recruiting, but RMC-9805 might have become the one to watch.