Early Clinical Data Show KRAS Inhibitors Can Work in Cholangiocarcinoma

Most of the KRAS inhibitors that have produced clinical data in biliary tract cancer so far target KRAS G12C, a mutation found in only a minority of patients with KRAS-mutant disease. KRAS G12D is the most common KRAS alteration in this setting, which makes early data for G12D-directed agents especially notable.

In an interview with CancerNetwork® surrounding the 2026 Chicago Cholangiocarcinoma Symposium, Chih-Yi “Andy” Liao, MD, reviewed the early-phase KRAS inhibitor data emerging in cholangiocarcinoma. He described results with the KRAS G12C inhibitors adagrasib (Krazati), divarasib, and calderasib (MK-1084), including findings from KRYSTAL-1 (NCT03785249) and from studies presented at the 2025 European Society for Medical Oncology (ESMO) Congress.^1-3 Liao emphasized that G12C-directed agents apply to only a minority of patients with biliary tract cancer.

Liao then turned to the first clinical data for a KRAS G12D inhibitor in this setting, GFH375 (VS-7375), a KRAS G12D ON/OFF inhibitor evaluated in a phase 1/2 study conducted in China and presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting.⁴ He noted that the cohort included a patient with a complete response. Liao said the data tell us KRAS inhibitors can work in cholangiocarcinoma, but that the clinical trials are just getting started, and he encouraged patients to participate in them.

Liao is an associate professor of Medicine, associate director of Gastrointestinal Oncology, and co-director of the Neuroendocrine Tumor program at University of Chicago School of Medicine.

Transcript:

CancerNetwork: What are some of the most relevant KRAS agents in cholangiocarcinoma?

Liao: Right now, we don’t have a lot of data, but there are some early-phase trials that have read out. For example, the KRYSTAL-1 study of adagrasib that we talked about had a response rate of 41.7%, which is very promising.¹ Another is divarasib. There is a phase 1/2 study that was presented at [the 2025 ESMO Congress]; for [patients with] biliary tract cancer, the response rate was 23%, and [median] progression-free survival was 7.2 months.² Another is calderasib, based on the phase 1 KANDLELIT-001 study [NCT05067283], which was also presented at ESMO last year and showed a response rate of 64% for cholangiocarcinoma.³ These are all KRAS G12C inhibitors, and KRAS G12C is really the minority. Only a minority of patients with biliary tract cancer have this mutation.

KRAS G12D is the most common KRAS mutation that we see in biliary tract cancer, and it was only very recently, at [the 2026 ASCO Annual Meeting] a few months ago, that we got the first clinical trial data, from a phase 1/2 study [NCT06500676] conducted in China, for a drug called GFH375, which is being developed in the US as VS-7375.⁴ This is a KRAS G12D ON/OFF inhibitor. We learned preliminary phase 1/2 data. They treated 20 patients in this cohort, and the response rate was 40%, including 1 patient with a complete response, and the median progression-free survival was 6.2 months. These are very exciting data that tell us these KRAS inhibitors can definitely work in cholangiocarcinoma, but the clinical trials are just getting started, so we encourage all our patients to participate in these trials; we also eagerly await the results.

References

1. Pant S, Yaeger R, Spira AI, KRYSTAL-1: activity and safety of adagrasib (MRTX849) in patients with advanced solid tumors harboring a KRASG12C mutation. J Clin Oncol. 2023;41(suppl 36):425082. doi:10.1200/JCO.2023.41.36_suppl.425082
2. Krebs MG, Lee C-H, Ami EB, et al. Single-agent divarasib experience in patients with KRAS G12C-positive pancreatic adenocarcinoma (panc), cholangiocarcinoma (cholangio), and other solid tumors. Ann Oncol. 2025;36(suppl 2):S569-S570. doi:10.1016/j.annonc.2025.08.1496
3. Simonelli M, Rojas CI, Dziadziuszko R, et al. MK-1084 monotherapy in participants (Pts) with KRAS G12C–mutated advanced solid tumors: activity and safety in the phase I KANDLELIT-001 study. Ann Oncol. 2025;36(suppl 2):S568-S569. doi:10.1016/j.annonc.2025.08.1495
4. Zhu L, Deng Y, Zong H, et al. Preliminary efficacy of GFH375 in patients with advanced cholangiocarcinoma or colorectal cancer harboring KRAS G12D mutation. J Clin Oncol. 2026;44(suppl 16):3008. doi:10.1200/JCO.2026.44.16_suppl.3008