ESMO 2023 – Revolution sets the bar in pan-KRAS inhibition

First the good news for fans of Revolution Medicines: the first clinical data on it’s multi-RAS inhibitor RMC-6236 raise the possibility that KRAS-blocking therapy could be extended beyond its current frontier, patients with G12C mutations.

But there are several caveats to the results, in late-line non-small lung and pancreatic cancers in a phase 1 trial. Efficacy has slipped since the abstract was released, there was no dose-response relationship, and several remissions remain unconfirmed. 

Then there is the question of tolerability: rash was seen very commonly, while gastrointestinal side effects were also high.

G12D mutant promise

The early-stage study of RMC-6236 excluded patients with KRAS G12C mutations, owing to the availability of other G12C blockers like Lumakras and Krazati. Nearly half of the patients in the phase 1 trial had G12D mutations; other well-represented mutations included G12V and, in pancreatic cancer in particular, G12R.

Patients had received a median of two and three prior therapies in NSCLC and pancreatic cancer respectively. 96% of the NSCLC patients had already been treated with checkpoint inhibitors.

Clinical activity was evaluated in patients who had received the first dose of RMC-6236 at least eight weeks before the cutoff date of 12 October.

In NSCLC, an ORR of 38% among 40 evaluable is less impressive than the 75% detailed in the ESMO abstract – although the latter came from just four patients, so perhaps this slippage isn't surprising.

The ORR in pancreatic cancer was lower, at 20%, but the discussant, Dr Elena Garralda of the Vall d´Hebron Institute of Oncology in Barcelona, noted the greater unmet need here.

The evolving dataset with Revolution’s RMC-6236 in phase 1

Note: efficacy data given for evaluable pts receiving ≥80mg/day; *12/15 responses confirmed; **5/9 responses confirmed; ^2/5 responses across NSCLC & PDAC confirmed. Source: ESMO.

Perhaps more worrying is an unclear pattern of responses across daily RMC-6236 doses of 80mg to 400mg. 

When asked about this the study’s presenter, Memorial Sloan Kettering Cancer Center’s Dr Kathryn Arbour, noted that many patients on the higher doses had not been treated for as long as some of those on the lower doses, suggesting that efficacy in some high-dose patients has yet to emerge. 

The dose-escalation and optimisation portion of the study is ongoing; Revolution also plans to evaluate RMC-6236 monotherapy in other tumour types. 

Tolerability with KRAS inhibitors has also been an important consideration, and RMC-6236 appears to be no different. On the plus side, liver enzyme elevations, a stumbling block with the G12C blockers, do not look like a problem with the Revolution agent. 

But there was an 81% incidence of rash, and high rates of GI side effects. Garralda noted that, although these were mainly low grade, they were “pretty relevant”.

She added that long-term tolerability still needed to be determined, and added that this would be particularly important when considering potential combination therapy with RMC-6236. 

No comparison

It's hard to benchmark these data, given the lack of results so far in KRAS mutants beyond G12C. But, as G12D mutations were particularly well represented in Revolution’s study, one relevant comparator could be Jiangsu Hengrui’s G12D inhibitor HRS-4642. That project’s late-breaking abstract had already disappointed, and full data at ESMO today were no better, with just one partial response among 18 solid tumour patients.

Maybe things will become clearer as more clinical data become available on pan-RAS inhibitors. Revolution is well ahead here, however; Garralda noted that the next most advanced candidate came from Astellas, which is planning an IND this year.