Triple meeting 2024 – can Revolution succeed where others stumbled?

KRAS G12D inhibition has so far disappointed, but it should soon become apparent whether Revolution Medicines can buck this trend, with initial clinical data on its G12D-selective project RMC-9805 set to be presented at the upcoming EORTC-NCI-AACR congress.

The conference, also known as the Triple meeting, will also feature a variety of RAS and RAF-targeting assets, including Boehringer Ingelheim’s multi-KRAS contender BI 3706674, also set to yield its first-in-human results.

G12D 

G12D is said to be the most common KRAS driver mutation, being found in around 40% of pancreatic ductal adenocarcinoma (PDAC), 15% of colorectal cancer (CRC) and 5% of non-squamous NSCLC patients. 

However, efforts to hit this target have so far fallen short: at ESMO 2023, Jiangsu HengRui’s inhibitor HRS-4642 produced a 6% ORR among 18 patients, while at this year’s ESMO Astellas’s degrader ASP3082 showed an 8% ORR across various 65 solid tumour patients, although Astellas highlighted better results in PDAC (ORR 19% in 27 patients) and NSCLC (23% in 13 subjects).

Revolution’s RMC-9805 is being tested alone and in combination with the pan-KRAS inhibitor RMC-6236 in a phase 1 trial in KRAS G12D-mutant solid tumours. The Triple meeting title promises data in PDAC, so there should be a chance for a cross-trial comparison against ASP3082.

G12D is becoming a crowded area, with Roche, Lilly, and AstraZeneca recently taking projects into the clinic.

Multi-RAS

Revolution’s multi-RAS blocker RMC-6236 will also feature at the conference, although this will merely involve updated results from a phase 1 study that’s previously been presented.

Perhaps more eagerly awaited here will be data on Boehringer’s BI 3706674, which has become the focus of that group’s KRAS research. The phase 1 study is enrolling patients with gastric and oesophageal cancers, while Revolution has so far reported data with RMC-6236 in PDAC and NSCLC.

One thing to watch out for will be rash, which has proven problematic with the Revolution project.

Alterome’s ALTA-3263 also hits various KRAS mutations – over 90%, according to the company – and the Triple meeting will see data in G12V, G12D and G12C cancer models.

Selected RAS presentations from 2024 EORTC-NCI-AACR symposium

There will also be preclinical data on BridgeBio Oncology’s BBO-10203, a PI3Kα:RAS breaker claimed to be a novel approach to PI3Kα/AKT inhibition that could avoid hyperglycaemia. While BBO-10203 is the only project of this specific class in development, according to OncologyPipeline, AstraZeneca has an approved AKT inhibitor, Truqap, while alpha-specific PI3K inhibition is looking increasingly crowded.

BBO-10203 recently started its first-in-human trial, Breaker-101.

Much further ahead is the pan-RAF inhibitor and Novartis cast-off naporafenib, which its new owner Erasca recently took into phase 3. Investors will get a first look at the phase 1 Seacraft-1 data that spurred this decision; naporafenib is being given alongside Mekinist to solid tumour patients with RAS Q61X mutations.

The 2024 EORTC-NCI-AACR symposium takes place in Barcelona on 23-25 October.