95MO - Tinengotinib in patients with advanced, fibroblast growth factor receptor (FGFR) inhibitor refractory/relapsed cholangiocarcinoma

Background

FGFR inhibitors (FGFRi) have a proven role for the management of FGFR-altered cholangiocarcinoma (CCA) after chemotherapy. However, disease progression occurs in 6-8 months. Secondary polyclonal mutations in the FGFR2 kinase domain represent a prominent acquired resistance mechanism. Tinengotinib was identified as a novel FGFRi with high potency to a variety of FGFR2 kinase domain mutations and has shown promising clinical results in CCA pts who have progressed on prior FGFRi. Here, we present pooled data from three trials.

Methods

Pts received tinengotinib orally once daily for 28 days per cycle. Pooled analyses of treatment-related adverse events (TRAEs), overall response rate (ORR), disease control rate (DCR), and median progression-free survival (mPFS) in the stratified CCA population were performed.

Results

A total of 73 advanced CCA pts were enrolled between Dec 2019 - Mar 2023. Median age was 60 years (24-81), 60% were female, 100% pts had ≥ 1 prior therapy including 47% pts with prior FGFRi, 97% had stage IV disease at screening. TRAEs were reported in 63 (86.3%) pts. 28 (38.4%) were Grade (G) 1-2, 32 (43.8%) were G3, 3 (4.1%) were G4, no G5 was observed. The most common TRAEs (≥20%) were hypertension (43.8%, G3 19.2%), stomatitis (32.9%, G3 4.1%), diarrhea (30.1%, G3 4.1%) and palmar-plantar erythrodysesthesia (24.7%, G3 2.7%). Among 58 evaluable pts, the ORR and DCR were 20.7% and 75.9%, respectively. In 29 pts with FGFR2 alteration who received prior FGFRi, the ORR and DCR were 34% and 89.7%, respectively. 21 pts who acquired resistance to prior FGFRi had ORR of 38.1%, DCR of 95.2% and mPFS of 6.90 months (95%CI, 4.90-9.20). 10 pts who developed FGFR2 kinase domain mutations (N549D/H/K/T, V564F/I/L, E565A/G/K) detected by liquid biopsy at baseline had ORR of 50%, DCR of 90% and mPFS of 7.03 months (95%CI, 0.95-11.86).

Conclusions

These pooled results suggest that tinengotinib has a manageable toxicity profile in CCA pts. Notable clinical benefit was noted with tinengotinib in FGFR-altered CCA pts with acquired resistance to prior FGFRi. A global phase III clinical trial is planned to further evaluate the efficacy and safety of tinengotinib for CCA with FGFRi resistance.

Clinical trial identification

NCT03654547, NCT04742959, NCT04919642.

Editorial acknowledgement

Legal entity responsible for the study

TransThera Sciences (Nanjing), Inc.

Funding

TransThera Sciences (Nanjing), Inc.

Disclosure

M. Javle: Financial Interests, Personal, Advisory Role: QED Therapeutics, Oncosil, Incyte, Mundipharma, AstraZeneca, Merck, EMD Serono, Basilea Pharmaceutical; Financial Interests, Personal, Other: Rafael Pharmaceuticals, Incyte, Pieris Pharmaceuticals, Merck, Merck Serono, Novartis, Seagen, BeiGene, QED Therapeutics, Bayer, TransThera Biosciences. C. Liao: Financial Interests, Personal, Advisory Board: Incyte, AstraZeneca, Lantheus, Eli Lilly, Transthera, Ipsen; Financial Interests, Personal, Trial Chair: BMS. C. Fountzilas: Financial Interests, Institutional, Research Grant: Pfizer Inc, Taiho Oncology, Merck Sharp & Dohme Corp., National Comprehensive Cancer Network; Financial Interests, Institutional, Local PI: Seattle Genetics, Inc., TransThera Biosciences, AstraZeneca, Aravive, Inc., Merck Sharp & Dohme Corp., Puma Biotechnology, Kadmon, Astellas Pharma, Pfizer Inc, Dragonfly Therapeutics, MedImmune, LLC., Hoosier Cancer Research Network, Incyte Corporation, Rafael Pharmaceuticals, Kinex Phamaceuticals, Syndax Pharmaceuticals, SWOG, National Cancer Institute, Erythech Pharma, Lilly, Corcept Therapeutics, Ipsen, CG Pharmaceuticals, Biomea Fusion, Bellicum, Amgen Inc.; Non-Financial Interests, Institutional, Other, Principal Investigator on upcoming clinical trial evaluating biomarker for treatment selection in pancreatic cancer: Valar Labs. D. Li: Financial Interests, Personal, Other, Consulting Fees: AstraZeneca, Eisai, Exelixis, Genentech, Ipsen Biopharmaceuticals, Merck, QED, Servier, DelCath, TerSera Therapeutics; Financial Interests, Institutional, Research Grant: Brooklyn Immunotherapeutics, AstraZeneca. M.S. Pelster: Financial Interests, Institutional, Other, Consulting: AstraZeneca, Bayer, CytomX, Daiichi Sankyo, Ipsen, Novartis, Pfizer, Seagen; Financial Interests, Institutional, Local PI: Agenus, Arcus Biosciences, Astellas, BeiGene, BioNTech, Bristol Myers Squibb, Codiak Biosciences, Eisai, Gilead, Gritstone Oncology, HiberCell, Immune-Onc Therapeutics, Leap Therapeutics, Novartis, OncXerna Therapeutics, Panbela Therapeutics, Revolution Medicines, Surface Oncology, SQZ Biotechnologies, Translational Genomics, TransThera Sciences, ZielBio, 1200 Pharma. S.A. Piha-Paul: Financial Interests, Personal, Advisory Role: CRC Oncology; Financial Interests, Institutional, Research Funding: AbbVie, Aminex, Biomarin, Boehringer Ingelheim, Bristol Myers Squibb, Cerulean Pharma, Chugai Pharma, Curis, Five Prime Therapeutics, Genmab, GSK, Helix BioPharma, Incyte, Jacobio, MedImmune, Medivation, Merck Sharp & Dohme, Novartis, Pieris Pharmaceuticals, Pfizer, Principa Biopharma, Puma Biotechnology, RAPT Therapeutics, Seagen, Taiho Oncology, Tesaro, TransThera Biosciences, Amphivena Therapeutics, Alkermes, Daiichi Sankyo, Lilly, ABM, Acepodia, ENB Therapeutics, Gene Quantum, Silverback Therapeutics, NIH/NCI, Cyclacel, F-Star, HiberCell, Immunomedics, Lytix Biopharma, Gilead Sciences, Phanes Therapeutics, Purinomia, ZielBio, Hengrui Pharmaceutical, Replimune, Synlogic, Epigenetix, Immorna, Jiangsu Simcere Pharmaceutical Co. Ltd., Nectin Therapeutics. All other authors have declared no conflicts of interest.