ESMO 2025 – Incyte impresses in KRAS G12D

KRAS G12D is a crowded space, but Incyte looks like it might be able to compete here with INCB161734, according to first-in-human data presented at ESMO over the weekend, in relapsed pancreatic cancer.

The discussant, Dr Ignacio Garrido-Laguna of the University of Utah, called a 34% overall response rate with the go-forward dose of INCB161734, 1,200mg daily, “remarkable”. However, this number included unconfirmed responses, and Incyte will have to replicate this early promise in bigger studies.

The company plans to prioritise a combination of INCB161734 plus chemo in first-line pancreatic cancer, and a pivotal trial could start in 2026, Mizuho analysts noted.

They added that Incyte will concede the second-line pancreatic space to more advanced rivals, such as Revolution Medicines. That company’s selective G12D inhibitor, zoldonrasib, has produced an ORR of 30% in relapsed pancreatic cancer – a number that also includes unconfirmed responses.

Incyte is thought to be developing another G12D inhibitor, INCB186748, although it hasn’t confirmed the mechanism of this project.

HengRui improvement

There were also updates from other KRAS G12D blockers at ESMO, including Jiangsu HengRui’s HRS-4642, and GenFleet and Verastem’s GFH375 (VS-7375).

HRS-4642 produced disappointing data two years ago, with just one partial response among 18 solid tumour patients.

However, that was at doses of up to 300mg; at ESMO this year, the same Chinese study spurred a more impressive 25% confirmed ORR, among 12 pancreatic cancer patients given 1,200mg every two weeks. Still, Garrido-Laguna dubbed this response rate “modest”.

In a separate ESMO session, HengRui also reported a 63% confirmed ORR with a HRS-4642-chemo combo in first-line pancreatic cancer. This result could make the project more relevant, according to the discussant.

HengRui also has another shot on the KRAS G12D goal, with HRS-6093.

GenFleet waning

Finally, GenFleet and Verastem reported updated results on Sunday with GFH375 from a Chinese phase 1/2 study in pancreatic cancer. ORR was 41%, down from 52% at ASCO. Garrido-Laguna said this was “still remarkable activity”, but sounded a note of caution about its location.

Investors will no doubt want to see data from Verastem’s US phase 1/2, which began in June. In January, Verastem exercised its option to license GFH375 for an undisclosed fee; the companies have been working together since 2023 on RAS-targeting projects.

KRAS G12D inhibitors in pancreatic cancer at ESMO 2025

Note: *confirmed & unconfirmed responses; **confirmed responses. Source: ESMO 2025.