Lytgobi (futibatinib)

P2, N=64, Terminated, Taiho Oncology, Inc. | N=168 --> 64 | Completed --> Terminated; The Sponsor decided to discontinue the study due to strategic considerations and not due to any safety-related concerns.

Advanced CCA remains largely inoperable, and combination gemcitabine plus cisplatin (GemCis) chemotherapy remains the standard treatment for patients affected by this disease...The FDA has approved the targeted therapies ivosidenib, pemigatinib, infigratinib, and futibatinib, as well as the immunotherapy durvalumab, for patients with CCA in recent years...While several promising advancements have been made, further research is required to improve outcomes for patients with CCA. This review provides an up-to-date, comprehensive overview of currently approved targeted therapies in CCA, as well as those under investigation.

Pan-FGFR-selective inhibitors (erdafitinib, pemigatinib, and futibatinib) have been developed in clinical practice...FGFR2-selective inhibitor lirafugratinib, FGFR3-selective inhibitors LOXO-435 and TYRA-300, FGFR2/3-selective inhibitor ABSK061, and FGFR4-selective inhibitors are in clinical development. Additionally, novel isoform-selective FGFR-targeting degraders, FGFR2b/FGFR3-selective antibodies, and de novo-designed 'c' isoform-selective proteins provide novel treatment strategies. This review provides an overview of the current FGFR-targeted therapeutics and limitations and evaluates next-generation inhibitor development to guide future research.

P2, N=14, Completed, Mayo Clinic | Active, not recruiting --> Completed

The article provides an overview of genetic alterations that are targetable with current oncological therapies, including FDA-approved inhibitors for FGFR2 (pemigatinib, futibatinib) and IDH1 (ivosidenib), along with inhibitors targeting BRAF, HER2, NTRK, and immunotherapies for MSI-high and TMB-high tumors. Intrahepatic CCA presents a broader spectrum of therapeutic targets, including rare fusions (ALK, RET), compared to perihilar and extrahepatic CCA, which share a poor prognosis and limited therapeutic options with pancreatic cancer. In this regard, intrahepatic CCA may become the "non-small cell lung cancer of gastrointestinal oncology."

P2, N=115, Terminated, Taiho Oncology, Inc. | Completed --> Terminated; Sponsor made a strategic decision to terminate the study considering enrollment challenges for some of the cohorts in the trial.

If the tumour is unresectable, the recommended first-line treatment is cisplatin + gemcitabine + durvalumab a programmed cell death ligand 1 [PD-L1] inhibitor or pembrolizumab a programmed cell death protein 1 [PD-1] inhibitor. The development of targeted therapies has led to these treatments being recommended as second- or third-line therapy for patients with actionable gene alterations, while 5-fluorouracil-based chemotherapy is recommended for those without. Robust data support the use of ivosidenib in patients with IDH1 mutations (phase 3), and phase 2 trials showed efficacy of pemigatinib and futibatinib for patients with FGFR2 gene fusions, trastuzumab deruxtecan and zanidatamab for patients with HER2 overexpression/amplification, and dabrafenib + trametinib for patients with BRAFV600E mutations. It is hoped that wider dissemination of the content from this meeting will improve outcomes of patients with CCA by encouraging earlier referral, increasing the use of early molecular testing, an MDT approach, and maximising the use of targeted therapies. Continued efforts to raise awareness, implement education outreach opportunities, and involve patient advocacy groups are encouraged to improve CCA outcomes.

With a growing incidence of BTC and growing use of targeted therapies for FGFR2 alterations, the emergence of secondary resistance-causing point mutations following treatment with approved inhibitors is becoming increasingly challenging. Beyond selective inhibitors, lenvatinib may represent a viable therapeutic option.

P2, N=53, Active, not recruiting, Taiho Oncology, Inc. | Trial primary completion date: Jul 2025 --> Mar 2026

All AEs were optimally managed with dose modulation. Future studies should focus on identifying the most effective dosages to further enhance treatment safety.

Here, we report a case of FGFR2-rearranged iCCA where the patient achieved a radiographic partial response (PR) to tasurgratinib (a third-line FGFR inhibitor) following prior progression on pemigatinib and futibatinib. More broadly, this report serves as a basis for a current opinion on the evolving landscape of sequential FGFR inhibition in iCCA. We delve into the complexities of acquired resistance, dissect the arguments for and against prolonged FGFR pathway blockade, explore the impact of co-occurring genomic alterations, discuss the controversies, research priorities, and the urgent need for a balanced perspective to guide future clinical practice and trial design in this rapidly advancing but still uncertain field.

Based on CGP analysis, the patient is currently receiving futibatinib, and the lung metastatic lesions have shrunk or partly disappeared. CGP can assist in selecting an appropriate therapeutic strategy when histological differentiation between DCCA and PDAC is challenging.