Pemazyre (pemigatinib)

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.

For adjuvant treatment, capecitabine (based on the BILCAP trial) and S-1 (from the ASCOT trial) have become standard regimens. Neoadjuvant therapy using gemcitabine-platinum combinations and locoregional strategies such as hepatic artery infusion chemotherapy (HAIC) and yttrium-90 radioembolization (Y-90 TARE) have improved resectability and survival outcomes...FGFR2 fusions, IDH1 mutations, and BRAF V600E mutations can be targeted with inhibitors such as pemigatinib, ivosidenib, and dabrafenib-trametinib, respectively, showing promising response rates in clinical trials...Combination strategies involving PD-1 inhibitors with radiotherapy or anti-angiogenic agents are further expanding the potential for treatment. Future efforts should focus on standardizing resectability criteria, expanding access to molecular profiling, and accelerating Phase III trials.

Introduction: Gastrointestinal stromal tumors (GISTs) are primarily driven by mutations in KIT (KIT proto-oncogene receptor tyrosine kinase) or PDGFRA (platelet-derived growth factor receptor alpha), but resistance to tyrosine kinase inhibitors (TKIs) such as imatinib remains a major clinical challenge. Although direct evidence remains limited, particularly regarding DNA repair and polymorphisms, FGFR2-targeted therapies (e.g., erdafitinib, pemigatinib) show potential, especially in combination with TKIs or DNA-damaging agents. Future research should prioritize GIST-specific clinical trials, the development of FGFR2-driven models, and standardized molecular diagnostics to validate FGFR2 as a therapeutic target.

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.

Targeted therapies based on genomic information are limited in the treatment of advanced gastric cancer. Thus, this case suggests that pemigatinib may represent a promising targeted therapy option for patients with advanced gastric cancer harbouring FGFR2 alterations.

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."

Safety was consistent with the overall FIGHT-207 population. Pemigatinib had antitumor activity and a manageable safety profile in patients with CNS tumors.

P2, N=83, Terminated, Incyte Corporation | Completed --> Terminated; Recruitment ceased after a pre-planned futility interim analysis indicated a low probability to confer a clinically meaningful improvement in objective response when compared to currently available therapies. There were no safety related concerns.

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.

P2, N=30, Completed, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Recruiting --> Completed | N=43 --> 30 | Trial completion date: May 2027 --> Sep 2025 | Trial primary completion date: May 2026 --> Sep 2025

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.

In MGMT-unmethylated differentiated GBM cell lines, pemigatinib combined with temozolomide further enhanced radiosensitivity. In vivo, pemigatinib combined with localized irradiation produced the longest median survival compared to either treatment alone in mice bearing orthotopic GSC-derived tumors, although the difference was not statistically significant. These findings support further clinical investigation to validate these preclinical findings and determine the potential role of FGFR inhibition as part of multimodal GBM therapy.