Revolution pushes home its pan-KRAS advantage

In a field growing as fast as KRAS inhibition it pays to move fast, and if, like Revolution Medicines, you happen to be armed with $1.85bn in the bank you can afford to do so too.

This could be Revolution’s thinking as the company confirmed plans to push its pan-KRAS inhibitor RMC-6236 into two phase 3 studies this year. The group clearly wants to move before this space becomes as crowded as KRAS G12C inhibition; though at present there are only a couple of other companies with multi-KRAS approaches in human studies, OncologyPipeline reveals over a dozen clamouring for attention in preclinical trials.

Revolution’s enthusiasm is driven by data it presented at last year’s ESMO conference, where the multi-KRAS inhibitor RMC-6236 showed clear potential to treat late-line non-small lung and pancreatic cancers harbouring various KRAS mutations that weren’t G12C. This came with caveats of an unclear dose-response pattern and some worries about rash toxicity.

Announcing full-year financials yesterday Revolution repeated the headline phase 1 findings, citing response rates of 38% (30% confirmed) and 20% (11% confirmed) respectively in non-G12C KRAS-mutant NSCLC and pancreatic ductal adenocarcinoma. This study only began in mid-2022, since when Revolution has initiated two other early trials investigating RMC-6236 combinations.

Phase 3 next

The group's next big move will be the start of two phase 3 studies. Logically, given the phase 1 signal, these will pit RMC-6236 against lung and pancreatic cancers.

The aim is to begin the NSCLC trial this year, enrolling over 400 patients with RAS mutations who have failed on PD-(L)1 blockade and platinum chemo but are naive to RAS inhibition, including G12C-targeting drugs. The core population will have G12 mutant NSCLC, with potential for expansion into KRAS G13 and Q61 too. The trial will measure PFS and OS versus docetaxel.

The pancreatic adeno study will consider similar KRAS biomarkers, and use similar key survival endpoints versus physician’s choice chemo. The aim is to enrol over 500 second-line, RAS inhibitor-naive patients, and start this phase 3 trial “potentially in 2024”.

280Bio and others

If this puts RMC-6236 on an unusually fast track then a desire to move before the competition is a likely reason for the haste.

Apart from Revolution only one other company, 280Bio, has a pan-KRAS inhibitor in the clinic; 280Bio is the US subsidiary of China’s Shanghai Yingli, and presented a poster at last year’s AACR showing that the molecule YL-17231 overcame resistance in KRAS-mutant tumours resistant to G12C inhibition. Two phase 1 trials, one in the US and the other in China, began last October.

A couple of other clinical-stage approaches are worth mentioning. Firstly, Quanta Therapeutics, a private US biotech backed by Sofinnova, AbbVie and others, is developing molecules it describes as multi-KRAS inhibitors that have a preference for a particular subtype. The “G12D-preferring” QTX3034 is just entering phase 1 in KRAS G12D-positive solid tumours.

And secondly Black Diamond is testing a RAF inhibitor, BDTX-4933, in various cancers, including non-G12C KRAS mutated NSCLC. The company recently told ApexOnco that BDTX-4933 seems to lock RAS into an inactive conformation, being a “RAF inhibitor that serves as a RAS clamp”, admitting that its study was a risky bet and that it was proceeding cautiously.

But what’s apparent is that beyond the handful of clinical players is a wave of pan-KRAS inhibiting assets, including degraders as well as inhibitors. At least two of these, from Lilly and BeiGene, could enter the clinic this year, so Revolution might not have the space largely to itself for much longer.

Inhibitors with pan-KRAS potential

Source: OncologyPipeline.