On June 23, 2026 GENFIT (Euronext: GNFT), a biopharmaceutical company dedicated to improving the lives of patients with rare and life-threatening liver diseases, reported positive Phase 1b results for GNS561 in combination therapy in patients with heavily pretreated cholangiocarcinoma, demonstrating a favorable safety and tolerability profile and early signs of antitumor activity.
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Clinical trial context and objective
CCA is a rare and aggressive bile duct cancer, often diagnosed at an advanced stage. It is associated with a high unmet medical need, driven by limited treatment options and poor prognosis. GNS561 is an investigational small molecule targeting PPT1, leading to autophagy inhibition and lysosomal dysfunction, thereby disrupting cancer cell survival mechanisms. By blocking autophagy, GNS561 aims to promote cancer cell death and may enhance sensitivity to other treatments. Its combination with a MEK inhibitor is intended to unlock synergistic potential by simultaneously targeting autophagy and MAPK signaling pathways. In the Phase 1b study, patients with advanced KRAS mutated CCA, who have previously failed one or two lines of prior standard of care therapies, were enrolled to evaluate the safety and tolerability of GNS561 when given in combination with trametinib, a MEKi.
Clinical results and next steps
The initial part of the Phase 1b study has been completed as planned, with 19 patients enrolled across four cohorts evaluating increasing doses of GNS561. A favorable safety and tolerability profile was observed, with no dose-limiting toxicities (DLT) reported, supporting continued clinical development. Continued signals of antitumor activity were also noted in this heavily pretreated population, with approximately half of patients achieving Stable Disease (SD) at Week 6, including one patient maintaining this status up to Week 30. While based on a limited dataset, these findings contribute to shaping the emerging clinical profile of the combination. On this basis, GENFIT has decided to expand the Phase 1b study with additional cohorts at higher dose levels. This expansion, intended to further strengthen the clinical dataset, does not alter the planned transition to Phase 2, which remains on track for initiation in the second half of 2026. The recommended Phase 2 dose and study design are expected to be finalized over the summer.
Dr. Mark Yarchoan, Associate Professor of Oncology at Johns Hopkins Medicine (Baltimore, MD, USA), principal investigator of the program, commented: "Advanced KRAS-mutated cholangiocarcinoma remains an area of high unmet medical need, particularly in patients who have progressed after prior therapies. What is notable in these data is the consistency of the signal as additional patients have been treated, which helps reinforce the initial findings. Combined with a favorable safety and tolerability profile and signs of activity, these results support continued clinical investigation of this combination strategy targeting autophagy and MAPK signaling pathways."
Details available on ClinicalTrials.gov (NCT05874414) cover both the Phase 1b and planned Phase 2 components of this open-label, multicenter study, and will be updated upon initiation of Phase 2.
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ABOUT CHOLANGIOCARCINOMA
Biliary tract cancer (BTC) is the second most common primary liver malignancy diagnosed globally. Cholangiocarcinoma (CCA) is a type of BTC and represents approximately 15% of all primary liver tumors and 3% of gastrointestinal cancers. Based on its anatomical origin, CCA is best classified anatomically as intrahepatic (iCCA) or extrahepatic (eCCA), which is comprised of perihilar (pCCA) and distal (dCCA) CCA. Early diagnosis is a major challenge as most patients with early-stage disease do not have symptoms due to limited biliary obstruction. Rather, patients characteristically manifest symptoms related to their underlying cirrhosis, a condition present in some patients with CCA. Taken together, the majority of patients with CCA are diagnosed with advanced disease, often precluding potentially curative therapies. There are limited therapeutic options for this aggressive disease. The 5-year survival rates drop to 5-15% in the advanced and unresectable settings. The only potentially curative treatment remains surgical resection. Unfortunately, at the time of first diagnosis, only about 25% of the patients are eligible for surgery. Moreover, even after curative intent surgery, the clinical outcomes are disappointing, with 5-year survival rates of 7% to 20%.
ABOUT GNS561
GNS561 is a first-in-class investigational lysosomotropic agent with a novel mechanism of action. When combined with Mitogen-Activated Protein Kinase Kinase (MEK) inhibitors, GNS561 targets complementary pathways critical for cancer cell survival and proliferation, resulting in potent antitumor activity. The combination is being developed as a potential breakthrough therapy for patients with advanced solid tumors. In December 2021, we licensed the exclusive rights from Genoscience Pharma to develop and commercialize the investigational treatment GNS561 in CCA in the United States, Canada and Europe, including the United Kingdom and Switzerland. In early 2025, GENFIT completed the acquisition of the full intellectual property rights for GNS561 from Genoscience Pharma, expanding upon the limited rights initially obtained through the 2021 license.
(Press release, Genfit, JUN 23, 2026, https://ir.genfit.com/news-releases/news-release-details/genfit-positive-phase-1b-data-gns561-combination-therapy-heavily [SID1234668912])