Triple meeting 2024 – can Revolution succeed where others stumbled?
The group will present the first clinical data on its KRAS G12D-selective project RMC-9805.
The group will present the first clinical data on its KRAS G12D-selective project RMC-9805.
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
Project | Mechanism | Company | Abstract |
---|---|---|---|
Late-breaking posters, 23 Oct | |||
RMC-6236 | RAS (on) multi inhibitor | Revolution Medicines | 514LBA |
NST-628 | Pan-RAF-MEK glue | Nested Therapeutics | 519LBA |
KRAS plenary, 23 Oct | |||
BI 3706674 | KRAS-multi inhibitor | Boehringer Ingelheim | NA |
Clinical trial plenary, 24 Oct | |||
Naporafenib + Mekinist | Pan-RAF inhibitor + MEK inhibitor | Erasca (ex Novartis) | 2 |
New drugs plenary, 25 Oct | |||
ALTA3263 | KRAS dual on/off inhibitor | Alterome Therapeutics | 8 |
BBO-10203 | PI3Kα:RAS breaker | BridgeBio Oncology | 9 |
Late-breaking plenary, 25 Oct | |||
RMC-9805 | RAS (on) G12D-selective inhibitor | Revolution Medicines | 502LBA |
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.
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