On December 10, 2025 GENFIT (Euronext: GNFT), a biopharmaceutical company dedicated to improving the lives of patients with rare and life-threatening liver diseases, reported encouraging preliminary Phase 1b data from its CCA clinical trial evaluating GNS561 in combination.
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Clinical trial context and objective
CCA is a rare and aggressive cancer of the bile ducts, often diagnosed at an advanced stage. The unmet medical need is characterized by strong limitations in current treatments and poor prognosis. GNS561 is an investigational small molecule that targets PPT1, leading to autophagy inhibition and lysosomal dysfunction, which disrupt cancer cell survival mechanisms. By blocking autophagy, GNS561 aims to promote cancer cell death and may enhance sensitivity to other treatments. Combining GNS561 with a MEKi aims to unlock synergistic potential by simultaneously targeting autophagy and MAPK signaling pathways. In the on-going Phase 1b study, patients with advanced KRAS mutated CCA who have previously failed one or two lines of prior standard of care therapies are enrolled to evaluate the safety and tolerability of GNS561 when given in combination with trametinib, a MEKi, and to identify the recommended doses of the combination to be administered in Phase 2.
Preliminary results
The analysis evaluated 9 patients with measurable disease at baseline, 4 of them reaching tumor assessment at week 6. At this point, the combination therapy demonstrated:
Disease stabilization observed in all 4 evaluated patients, who had all shown disease progression during previous treatment;
Tumor shrinkage in a subgroup of patients with the best response showing a 20% reduction approaching the partial response (PR) threshold.
Achieving disease control and tumor reduction in such heavily pretreated patient population with advanced CCA is a significant signal of antitumor activity.
Clinical Impact
The results to date show a potential to address a critical unmet medical need in oncology. Patients with advanced solid tumors who have progressed on multiple prior therapies have limited treatment options and poor prognoses. The ability of the investigational drug GNS561 associated with a MEKi to achieve disease control in this challenging patient population would represent a significant advance. The consistent pattern of disease stabilization observed across all evaluated patients, combined with objective tumor shrinkage in a subgroup of heavily pretreated patients, suggests the combination has the potential to provide meaningful clinical benefit. Optimization of dosing and patient selection could lead to further improvement in response rates.
Dr. Mark Yarchoan, Associate Professor of Oncology at John Hopkins Medicine (Baltimore, MD, USA), principal investigator of the program, commented: "Advanced KRAS-mutated cholangiocarcinoma remains a formidable clinical challenge, and the emerging activity seen in this initial study is encouraging. Because MEK inhibition alone has historically shown limited efficacy in this setting, the early signs of benefit with dual targeting of autophagy and MAPK signaling provide meaningful rationale for continued evaluation of this combination strategy."
Pascal Prigent, Chief Executive Officer of GENFIT, added: "These early results suggest a potential breakthrough for patients with limited options, and we are committed to advancing this program rapidly to individuals impacted by cholangiocarcinoma. We will also explore GNS561 potential in combination with other agents and in other tumors where autophagy inhibition plays a central role."
Next development steps
Phase 1b dose escalation will continue as planned to confirm the activity signal, with new data for the next patient cohorts expected in 1Q26. These results will be used to establish the recommended Phase 2 combination doses, with completion expected in 1H26. Phase 2 initiation is targeted for 2H26.
(Press release, Genfit, DEC 10, 2025, https://ir.genfit.com/news-releases/news-release-details/genfit-gns561-shows-promising-antitumor-activity-combination [SID1234661343])