AACR 2025 – Revolution shows lung promise

Last year Revolution Medicines’ selective KRAS G12D inhibitor zoldonrasib showed early promise in pancreatic cancer, and now the project has done the same in non-small cell lung cancer. A phase 1 trial, presented at AACR on Sunday, found a 61% overall response rate in relapsed KRAS G12D-mutant NSCLC.

There are caveats about the data, including small patient numbers and the fact that over half of the responses are unconfirmed. But, with all responders remaining on treatment, it’s still possible for unconfirmed responses to be confirmed at some point in the future.

Revolution’s stock rose a relatively muted 4%, although the company’s valuation is already on the rich side, at $7.5bn.

The latest data came from the phase 1 RMC-9805-001 trial of zoldonrasib (previously known as RMC-9805) in second-line or later KRAS G12D-mutant solid tumours. Last October Revolution got a boost from a 30% ORR among 40 patients with pancreatic cancer receiving the go-forward dose of 1.2g daily.

Now, at AACR, Revolution has reported a 61% ORR among NSCLC patients receiving the 1.2g daily dose, at a cutoff date of 2 December 2024. However, only 18 patients were evaluable, out of 28 NSCLC patients receiving this dose. And six of the 11 responses were unconfirmed, although all the responders, plus four patients graded as having stable disease, remain on treatment.

Source: AACR 2025.

If this response rate does hold up, it looks better than the result with Astellas’s G12D degrader ASP3082, on a cross-trial basis. At last year’s ESMO meeting the Astellas project produced an ORR of 23% among 13 NSCLC patients, and has broadly been seen as disappointing, also being linked with dose-limiting toxicities – although development continues.

Meanwhile, the RMC-9805-001 trial of zoldonrasib found no grade 4 or 5 treatment-related adverse events with the 1.2g dose, and only 2% of subjects experienced a grade 3 TRAE, according to the latest safety update in 90 patients.

Revolution might have the edge through its targeting of 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.

Zoldonrasib is already being combined with other therapies in the phase 1/2 RMC-LUNG-101 NSCLC trial, while it’s also being tested alongside Revolution’s pan-RAS inhibitor daraxonrasib (formerly known as RMC-6236).

In the meantime the KRAS G12D sector has become crowded, although Bristol Myers Squibb recently dropped out of the running, canning MRTX1133.