Roche expands in KRAS

It wasn’t widely known that, in addition to the phase 3 KRAS G12C inhibitor divarasib, Roche also had a KRAS G12D project. But clinicaltrials.gov has just revealed the entry of the Swiss group’s GDC-7035, a molecule with the latter mechanism, into its first-in-human study.

Roche will be hoping to avoid the disappointments of Jiangsu HengRui and, more recently, Astellas, with inhibition of G12D, which is thought to be an even more prevalent KRAS mutation than the now extremely crowded G12C subtype. New listings on the clinicaltrials.gov registry also reveal the entry of yet another anti-PD-L1 x VEGF bispecific, hot on the heels of Akeso/Summit’s ivonescimab.

Enthusiasm around dual PD-(L)1 and VEGF blockade built during the recent World Lung and ESMO conferences, and much is riding on Summit’s $500m bet on this mechanism. Two other companies have made somewhat smaller bets here, BioNTech and Instil Bio, and the positive data generated so far might be prompting others to look at licensing opportunities.

Clinicaltrials.gov reveals the private Chinese biotech Convalife to be a PD-L1 x VEGF player with a molecule coded CVL006, which hadn’t been disclosed previously, but which is now to start a phase 1 solid tumour study. Convalife recently struck a deal with Shanghai Henlius over a generic version of Puma’s Nerlynx, and is also working on PARP and PI3K inhibitors.

G12D

In KRAS G12D, meanwhile, disappointment abounds, with ESMO data on Astellas’s degrader ASP3082 adding to underwhelming results with HengRui’s inhibitor HRS-4642 a year earlier.

Now Roche is getting in on the act with GDC-7035 in a phase 1 study in KRAS G12D-mutated solid tumours. Despite the disappointments seen so far, companies continue piling into KRAS G12D, with Lilly’s LY3962673 and AstraZeneca’s AZD0022 starting phase 1 recently; the prospect of pan-KRAS inhibition, from Revolution most notably, but also from Lilly, Pfizer and BeiGene, hangs over this space.

Recently disclosed first-in-human studies*

Note: *projects newly listed on the clinicaltrials.gov database between 24 Sep and 3 Oct 2024.

Recent first-in-human initiations include another private Chinese company, Danatlas Pharmaceutical, which is progressing the PARG inhibitor DAT-2645 into a phase 1 study in tumours with DNA damage repair mutations. 

OncologyPipeline notes just eight other PARG inhibitors in the industry pipeline, of which one, Ideaya’s IDE161, has yielded early phase 1 data comprising two partial responses by Recist 1.1, in BRCA-mutant colorectal and endometrial cancers, among five subjects with HRD-mutated solid tumours. 858 Therapeutics’ ETX-19477 started phase 1 in May.

Elsewhere, the prospects for ROR1 inhibition continue to look uncertain, but despite this Huadong Medicine recently took an ADC with this mechanism, HDM2005, into human trials.

Notwithstanding Merck & Co’s $2.8bn acquisition of VelosBio, Lyell’s anti-ROR1 Car-T approach LYL797 has underwhelmed. There was even worse news from Oncternal Therapeutics, which last month ended all clinical activity and put itself up for sale; that company had been a prominent ROR1 player, with the Car-T therapy ONCT-808, but signs of clinical activity plus T cell persistence were marred by a patient death at the highest dose.