HengRui Advances KRAS G12D Inhibitor HRS-4642 to Phase 3 Trial in Pancreatic Cancer
核心洞察
Jiangsu HengRui (搜索)'s KRAS G12D (搜索) inhibitor HRS-4642 will become only the second such project to enter phase 3 trials, with a pivotal Chinese study starting in December 2024.
The phase 3 trial will test HRS-4642 combined with Abraxane and gemcitabine versus chemotherapy alone in first-line KRAS G12D (搜索)-mutant pancreatic cancer (搜索) patients.
Early clinical data showed modest monotherapy efficacy with 25% response rate, but combination with chemotherapy boosted response rates to 63% in first-line treatment.
Jiangsu HengRui (搜索) is advancing its KRAS G12D (搜索) inhibitor HRS-4642 into a pivotal phase 3 trial in pancreatic cancer (搜索), positioning the Chinese pharmaceutical company as only the second player to reach late-stage development in this competitive oncology space. The registrational trial is set to begin in December 2024, according to recent listings on clinicaltrials.gov.
Phase 3 Trial Design and Strategy
The upcoming phase 3 study will evaluate HRS-4642 in combination with Abraxane (nab-paclitaxel) and gemcitabine versus the chemotherapy doublet alone in first-line KRAS G12D (搜索)-mutant pancreatic cancer (搜索) patients. The trial features co-primary endpoints of progression-free survival (PFS) and overall survival (OS).
This combination approach reflects lessons learned from early clinical experience with HRS-4642. Data presented at ESMO 2024 from a Chinese phase 1 study demonstrated only "modest" efficacy with HRS-4642 monotherapy, achieving a 25% objective response rate (ORR) in relapsed pancreatic cancer (搜索) patients at the recommended dose. However, when combined with chemotherapy in the first-line setting, the ORR improved substantially to 63%.
Competitive Landscape in KRAS G12D Inhibition
HengRui joins a select group advancing KRAS G12D (搜索) inhibitors toward registration. GenFleet (搜索)'s Verastem-partnered VS-7375 (GFH375) represents the only other KRAS G12D inhibitor currently in phase 3 development. That Chinese pivotal study is testing monotherapy versus chemotherapy in relapsed G12D-mutated pancreatic cancer (搜索).
Verastem exercised its option to license VS-7375 in January 2024 for an undisclosed fee, following a collaboration with GenFleet (搜索) since 2023 on RAS-targeting projects. The company has indicated plans to initiate US registrational trials in pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC (搜索)) in 2025.
Broader RAS Pipeline Developments
The KRAS G12D (搜索) space is experiencing significant momentum, with multiple companies announcing pivotal trial plans for 2025. Revolution Medicines, a leading RAS specialist, has disclosed intentions to 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 provided more concrete timelines, planning to advance its G12D degrader ASP3082 into phase 3 pancreatic cancer (搜索) trials by March 2026, with a pivotal NSCLC (搜索) study also in development. The project initially showed disappointing results at ESMO 2024 but demonstrated more promising efficacy in relapsed NSCLC at the Triple meeting.
Incyte represents another emerging competitor, with its INCB161734 showing impressive results in relapsed pancreatic cancer (搜索) at ESMO. The company is developing a first-line chemotherapy combination trial.
HengRui's RAS Portfolio
HengRui was notably the first company to present human data with a G12D inhibitor through HRS-4642, though initial results were considered disappointing. The company maintains an active RAS development program, recently initiating a phase 1 trial of another G12D blocker, HRS-6093 (搜索). HengRui also has a G12C inhibitor, HRS-7058, which is expected to present its first clinical data at ESMO.
The advancement of HRS-4642 to phase 3 represents a significant milestone for HengRui's oncology pipeline and underscores the intense competition in targeting KRAS mutations, which represent some of the most common oncogenic drivers in solid tumors.