TransThera Sciences announced the publication of translational studies demonstrating tinengotinib's efficacy against cholangiocarcinoma (CCA) with acquired resistance to FGFR inhibitors in Annals of Oncology, a high-impact journal with an impact factor of 56.7. The research, co-authored by Dr. Peng Peng, Vice President at TransThera, represents a significant advancement in understanding and overcoming FGFR resistance mechanisms.
Addressing Critical Resistance Mechanisms
Cholangiocarcinoma is an aggressive bile duct cancer frequently driven by FGFR2 fusion and rearrangement, which can be targeted with inhibitors like pemigatinib and futibatinib. However, resistance commonly develops due to acquired FGFR2 mutations, creating an urgent need for next-generation therapies.
The published study utilized multimodal analyses to develop a comprehensive model characterizing the biology of acquired resistance, informing the rational design of next-generation FGFR inhibitors. According to the research, novel FGFR inhibitors should be small, high-affinity compounds capable of binding to the active form of FGFR.
Breakthrough Structural and Functional Data
The article disclosed for the first time the co-crystal structure of tinengotinib with the FGFR2 kinase domain, revealing its unique binding mode. Kinetic studies demonstrated tinengotinib's higher affinity compared to first-generation FGFR inhibitors, while in vitro and in vivo studies confirmed its activity against clinically acquired FGFR2 resistance mutations. The research also included a case report demonstrating clinical efficacy, establishing tinengotinib as a second-generation FGFR inhibitor meeting all the criteria for overcoming resistance.
Largest Clinical Dataset Analysis
Dr. Lipika Goyal, Director of Gastrointestinal Oncology at Stanford Cancer Center and the study's principal investigator, emphasized the research's comprehensive scope: "The study represents a comprehensive analysis of acquired resistance to FGFR inhibitors using circulating tumor DNA, biopsy, rapid autopsy, pharmacokinetic, and in vitro and in vivo data. It represents the largest collection of primary patient data on acquired FGFR resistance, with analysis of nearly 500 clinical samples."
Dr. Goyal highlighted the collaborative nature of rare cancer research, stating, "Research in rare cancers like CCA relies on the collective efforts of numerous teams working together, and we highly appreciated the translational studies of tinengotinib by TransThera, which validated the principles of developing next-generation FGFR inhibitors highlighted in this publication."
Clinical Development and Regulatory Recognition
Tinengotinib is an internally discovered, global phase III multi-kinase inhibitor that targets FGFRs and VEGFRs, mitotic kinases Aurora A/B, and Janus kinases (JAK). The compound has demonstrated potential efficacy across various solid tumors in ongoing clinical trials in the US and China.
The drug has received significant regulatory recognition, including Orphan Drug Designation and Fast Track Designation from the FDA for CCA treatment, Breakthrough Therapy Designation from China's NMPA, and Orphan Drug Designation from the EMA for biliary tract cancer treatment.
Dr. Peng from TransThera expressed optimism about the clinical impact: "We are delighted that TransThera's discovery be part of the fundamental research in the field of overcoming FGFR refractory. Currently tinengotinib is undergoing a pivotal phase 3 study globally and we hope to bring novel treatment option to CCA patients."
Implications for Future Treatment
The study's findings provide crucial insights into resistance mechanisms and validate the design principles for next-generation FGFR inhibitors. Dr. Goyal concluded, "We believe this study will be a substantial contribution to the field that will advance our understanding of acquired resistance to FGFR inhibitors."
The comprehensive analysis of nearly 500 clinical samples represents the most extensive dataset on acquired FGFR resistance to date, potentially informing the development of additional therapies for this challenging indication.
