Revolution sees a new pan-KRAS challenger

Revolution Medicines, which until now has had a relatively unopposed path in pan-KRAS inhibition, will soon face a formidable competitor: Pfizer’s challenger, PF-07934040, is to enter its first-in-human study next month, according to a just revealed listing on the clinicaltrials.gov registry.

Pfizer is also moving fast with a tetravalent LTβR agonistic antibody, PF-07329640, which it only unveiled at a February R&D event, but which is already in phase 1. Here, however, there is virtually no industry competition, according to OncologyPipeline, whereas pan-KRAS inhibition could soon see Lilly and BeiGene join Pfizer in challenging Revolution.

Revolution has moved fast with its multi-KRAS inhibitor, RMC-6236, backed by its nearly $2bn cash balance. However, while the company has mooted the start this year of two phase 3 trials with this project, specifically in lung and pancreatic cancers, neither has yet begun.

Pfizer appears to be taking a broad approach to initial testing of PF-07934040, whose phase 1 trial will include a range of cancers with almost any KRAS mutation. The only restriction is G12C-mutant NSCLC that’s already been treated, most likely with either of the two marketed drugs – Amgen’s Lumakras or Bristol Myers Squibb’s Krazati.

Last year Lilly and BeiGene unveiled preclinical pan-KRAS assets that they expect to take into the clinic in 2024. Boehringer Ingelheim has been active here too, currently with the “KRAS-multi” project BI 3706674, after discontinuing earlier work on pan-KRAS:SOS1 inhibition.

Recently disclosed first-in-human studies*

Notes: *projects newly listed on the clinicaltrials.gov database between 30 May and 7 Jun 2024; **excludes previously treated NSCLC patients with KRAS G12C.

Other recently disclosed first-in-human trial initiations include that of KaliVir’s oncolytic virus VET3-TGI. This modality is in focus since the flotation of CG Oncology and promising data presented last week by Replimune, and KaliVir claims that VET3-TGI is differentiated by additionally encoding IL-12 and a TGF-β inhibitor.

The private Swiss biotech Opna Bio is taking OPN-6602, a dual inhibitor of p300 and CBP, into the clinic in multiple myeloma. This becomes its third clinical asset, after the CSF1R/TRK inhibitor OPN-7486 and the BET inhibitor OPN-2853, for which Opna is now seeking development and commercialisation partners.

Meanwhile, Chengdu Baiyu’s PARP7 inhibitor BY101921 and Insilico/Fosun’s QPCTL inhibitor ISM8207 have just appeared on clinicaltrials.gov, though they have been listed on Chinese clinical study registries, and in the OncologyPipeline database, since January and March respectively.

Such mechanisms show a variety of novel approaches being taken into the clinic, and among these Pfizer’s PF-07329640 should be of interest. This molecule was highlighted at Pfizer’s oncology innovation day in February as a possible combo partner for checkpoint blockade, and its mechanism involves binding to and having an agonistic effect on LTβR, the lymphotoxin β receptor.

The idea is that activating LTβR induces the formation of tertiary lymphoid structures, which have been reported to enhance response to anti-PD-1 therapy. The only other related project is M300, which conditionally agonises LTβR by co-engaging FAP, and is in preclinical development at the private UK biotech Mestag Therapeutics.