GENFIT reported positive Phase 1b results for GNS561 plus trametinib in KRAS-mutated cholangiocarcinoma, showing favorable safety, no dose-limiting toxicities, and early antitumor activity. Phase 2 is planned for the second half of 2026.
Written By: Kirti Kumbar, M. Pharm (QA)
Reviewed By: Pharmacally Editorial Team
GENFIT has reported positive Phase 1b results for its investigational therapy GNS561 in combination with the MEK inhibitor trametinib for patients with advanced KRAS-mutated cholangiocarcinoma (CCA).
The open-label, multicenter study (NCT05874414) demonstrated favorable safety and tolerability, while early efficacy signals supported continued clinical development in a patient population with limited treatment options after failure of standard therapies.
About GNS561 and Cholangiocarcinoma
Cholangiocarcinoma is a rare and aggressive cancer arising from the bile ducts. Most patients are diagnosed at an advanced stage, leaving few effective treatment options and resulting in poor long-term survival.
GNS561 is a first-in-class investigational lysosomotropic small molecule that inhibits palmitoyl-protein thioesterase 1 (PPT1). By disrupting lysosomal function and blocking autophagy, the drug interferes with key cancer cell survival pathways. Combining GNS561 with trametinib targets both autophagy and MAPK signaling, a strategy expected to enhance antitumor activity in KRAS-mutated tumors.
Phase 1b Results Support Continued Development
The Phase 1b dose-escalation study enrolled 19 patients with advanced KRAS-mutated cholangiocarcinoma who had progressed after one or two prior standard-of-care treatment lines. Patients received escalating doses of GNS561 alongside trametinib.
The combination demonstrated a favorable safety profile across four dose cohorts. Investigators reported no dose-limiting toxicities, supporting further dose escalation and continued clinical evaluation.
Preliminary efficacy findings also showed encouraging signs of clinical activity. Approximately half of treated patients achieved stable disease at Week 6, while one patient maintained disease control through Week 30. Although the dataset remains limited, these findings suggest the combination may provide meaningful disease stabilization in a heavily pretreated population.
Based on these results, GENFIT will expand the Phase 1b study with additional higher-dose cohorts to further characterize safety and efficacy. The expansion will run alongside preparations for Phase 2, which remains scheduled to begin during the second half of 2026. The recommended Phase 2 dose and final study design are expected to be confirmed later this summer.
Clinical Implications
Principal investigator Dr. Mark Yarchoan, Associate Professor of Oncology at Johns Hopkins Medicine, said the consistency of clinical findings as additional patients entered the study strengthens confidence in the emerging safety and efficacy profile of the combination. He noted that advanced KRAS-mutated cholangiocarcinoma remains an area of substantial unmet medical need and that the encouraging activity observed supports continued investigation of dual inhibition of autophagy and MAPK signaling.
Regulatory Path Forward
GENFIT acquired full intellectual property rights to GNS561 in early 2025 after initially licensing regional development and commercialization rights from Genoscience Pharma in 2021. If ongoing dose escalation confirms these early findings, the upcoming Phase 2 study will further evaluate the combination’s potential as a new treatment option for patients with advanced KRAS-mutated cholangiocarcinoma.
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About the Writer
Kirti Kumbhar (LinkedIn) is an M.Pharm graduate with experience in Quality Assurance at Lupin Limited and a strong interest in clinical research, regulatory affairs, and Trial Master File (TMF) management. She has developed knowledge of regulatory documentation, quality systems, compliance, and healthcare research through her professional experience. Passionate about clinical development and continuous learning, Kirti is committed to supporting high-quality healthcare documentation, regulatory excellence, and research-driven healthcare advancements.