HengRui goes pivotal in KRAS G12D

Despite crowding in KRAS G12D inhibition, Jiangsu HengRui’s HRS-4642 is set to become only the second such project to go into phase 3. A pivotal Chinese trial, testing a chemo combo in first-line KRAS G12D-mutant pancreatic cancer, will start in December, according to a recent listing on clinicaltrials.gov.

Adding chemo looks like the sensible way to go. At this year’s ESMO, a Chinese phase 1 study showed only “modest” efficacy with HRS-4642 monotherapy, with an ORR of 25% in relapsed pancreatic cancer patients at the go-forward dose. Adding chemo in the front line boosted the ORR to 63%.

The upcoming phase 3 trial will test HRS-4642 plus Abraxane and gemcitabine, versus Abraxane and gemcitabine alone, with co-primary endpoints of PFS and OS.

More coming

The only other KRAS G12D inhibitor in phase 3, according to OncologyPipeline, is GenFleet’s Verastem-partnered VS-7375 (GFH375). Again, the pivotal study is Chinese, but this time testing monotherapy versus chemo in relapsed G12D-mutated pancreatic cancer.

Verastem has said it hopes to start US registrational trials in PDAC and NSCLC next year. In January the company exercised its option to license VS-7375 for an undisclosed fee, after working with GenFleet since 2023 on RAS-targeting projects.

Others have also revealed pivotal plans for next year, although clinicaltrials.gov listings have yet to emerge. The most high-profile is the RAS specialist Revolution Medicines, although that group has been fairly vague about its intentions. All it has disclosed is that it will begin “one or more” pivotal trials of its G12D and G12C-selective projects, zoldonrasib and elironrasib respectively, “either as monotherapy or in a drug combination”.

Astellas has been more concrete, saying it plans to take its G12D degrader ASP3082 into phase 3 in pancreatic cancer by March 2026, while a pivotal NSCLC is in the planning stages. That project initially failed to impress at ESMO 2024, but produced more promising efficacy results in relapsed NSCLC at this year’s Triple meeting.

And a relative latecomer, Incyte, also hopes to join the party. That group’s INCB161734 impressed in relapsed pancreatic cancer at ESMO, and a first-line chemo combo trial is in the works.

KRAS G12D-targeting projects in late-stage development

Source: OncologyPipeline.