European Medicines Agency Grants Orphan Drug Designation to Tinengotinib for Biliary Tract Cancer


Tinengotinib has been awarded orphan drug designation from the European Medicines Agency for use in select patients with biliary tract cancer.

EMA grants orphan drug designation to tinengotinib | Image Credit: © Rasi -

EMA grants orphan drug designation

to tinengotinib | Image Credit: © Rasi


The European Medicines Agency has granted an orphan drug designation to tinengotinib, a next-generation FGFR inhibitor, for the treatment of patients with biliary tract cancer.1

Moreover, agencies in the European Union have authorized the phase 3 FIRST-308 study (NCT05948475), which is evaluating the safety and efficacy of the agent compared with physician’s choice of treatment in patients with FGFR-mutated cholangiocarcinoma who are refractory to or relapsed on chemotherapy and FGFR inhibition.2 The trial received prior authorizations in the United States, South Korea, and Taiwan region.

“We are very delighted to have achieved the significant regulatory progresses for tinengotinib in global development at various countries and regions,” Jean Fan, MD, chief medical officer of TransThera Sciences, stated in a press release. “These milestones are not only the recognition by global regulatory authorities of the potential clinical benefit of tinengotinib to treat CCA patients, but also a reflection of the company’s international regulatory capabilities and unwavering commitment to bringing innovative therapies to global patients.”

Ten to 15% of adult patients with advanced intrahepatic cholangiocarcinoma, and 1% to 2% of those with advanced extrahepatic disease, will develop FGFR alterations.3 Although first-generation FGFR inhibitors like pemigatinib and fubatinib have received regulatory approval for use in patients with advanced cholangiocarcinoma harboring FGFR2 fusions or rearrangements following systemic chemotherapy, these patients typically experience progression within 6 to 9 months. These patients are also known to develop acquired resistance mutations.

Tinengotinib has been shown to have strong potency against several FGFR2 kinase domain mutations. Compared with other approved agents, tinengotinib has a small structure with high binding affinity and active conformation binding. Data from several phase 1/2 studies (NCT03654547, NCT04742959, NCT04919642) have demonstrated the agent’s clinical activity in patients with FGFR-altered metastatic cholangiocarcinoma who were heavily pretreated with chemotherapy and FGFR inhibitors.4

In the 41 patients with FGFR2-altered cholangiocarcinoma, the ORR with the agent was 29%; the disease control rate (DCR) and clinical benefit rate (CBR) were 90% and 42%, respectively. The median progression-free survival (PFS) was 5.98 months (95% CI, 5.26-9.10). In patients with FGFR inhibitor–relapsed/refractory cholangiocarcinoma (n = 36), tinengotinib elicited an ORR of 31% with a DCR of 92% and a CBR of 44%. In this group, the median PFS was 6.01 months (95% CI, 5.26-9.10). In patients with cholangiocarcinoma and FGFR2 kinase domain mutations (n = 16), the respective ORR, DCR, and CBR were 44%, 94%, and 63%. The median PFS was 6.90 months (95% CI, 2.86-13.44) in this group.

The open-label, randomized, global, multicenter, phase 3 FIRST-308 study is recruiting patients with histologically or cytologically confirmed, FGFR2-positive cholangiocarcinoma or adenocarcinoma of biliary origin who have radiological evidence of unresectable or metastatic disease.3 All patients must have received 1 or more prior lines of chemotherapy and 1 FDA-approved FGFR inhibitor. They also need to be at least 18 years of age, have an ECOG performance status of 0 or 1, and acceptable organ function.

If they previously received 2 or more FGFR inhibitors, had uncontrolled hypertension, or known brain or central nervous system metastases that have progressed within 28 days before the start of study treatment, they were excluded.

For part A, participants (n = 200) will be randomly assigned 2:2:1 to receive tinengotinib at a daily dose of 10 mg (n = 20) or 8 mg (n = 20), or physician’s choice of 5-fluororacil (5-FU) plus leucovorin and oxaliplatin or 5-FU plus leucovorin and irinotecan (n = 10). Stratification factors include geographic region (North America, Europe, and other), previous lines of chemotherapy (1 vs ≥2), and physician’s choice of treatment. The following end points will support part B dose selection: adverse effects (AEs; primary end point); and ORR, duration of response (DOR), and pharmacokinetics (PK; secondary end points).

For part B, participants will be randomly assigned 2:1 to receive the selected dose of tinengotinib, which will be jointly selected by an independent data monitoring committee and the trial sponsor (n = 100), or physician’s choice of chemotherapy (n = 50). The primary end point of this portion of the research is PFS, and secondary end points include overall survival, ORR, DOR, AEs, quality of life, and PK.

“Leveraging the regulatory agency's support from the EU in addition to the US and other countries and regions, we will continue to expedite the global clinical development and commercialization of tinengotinib,” Fan added in the press release.1 “We are hopeful that these efforts will enable us to bring this novel drug to patients around the world as quickly as we can.”


  1. TransThera announced global phase 3 clinical trial for cholangiocarcinoma authorized in the European Union and orphan drug designation for tinengotinib to treat biliary tract cancer granted by European Medicines Agency. News release. TransThera Sciences, Inc. March 8, 2024. Accessed March 11, 2024.
  2. Study of tinengotinib vs physician’s choice a treatment of subjects with FGFR-altered in cholangiocarcinoma (FIRST-308). Updated February 26, 2024. Accessed March 11, 2024.
  3. Javle M, Kankeu Fonkoua LA, Mahipal A, et al. 95MO Tingenotinib in patients with advanced, fibroblast growth factor receptor (FGFR) inhibitor refractory/relapsed cholangiocarcinoma. Ann Oncol. 2023;34(suppl 2):S215-S216. doi:10.1016/j.annonc.2023.09.1388
  4. Javle MM, Rimassa L, Goyal L, et al. First-308: Phase III study of tinengotinib versus physician’s choice in patients with FGFR-altered, chemotherapy- and FGFR inhibitor­–relapsed/refractory cholangiocarcinoma. J Clin Oncol. 2024;42(suppl 3):TPS575. doi:10.1200/JCO.2024.42.3_suppl.TPS575
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