Despite identifying resistance mutations, evidence is insufficient to definitively link a specific alteration to a subsequent drug's efficacy. Biomarkers provide crucial context for clinicians, but do not yet dictate a precise treatment path, highlighting the need for clinical judgment.

A real-world study found that 25% of patients on pemigatinib had extrahepatic cholangiocarcinoma, a subtype where the drug's FGFR2 fusion target is historically rare. This significant deviation from established biology suggests potential issues with physician-abstracted data, such as mislabeling or referral bias, highlighting the need for cautious interpretation of real-world patient cohorts.

Clinicians must recognize that not all genomic tests are adequate for identifying FGFR2 fusions. Amplicon-based NGS panels are not suitable for this purpose. RNA-based sequencing is the recommended approach to avoid missing patients who could benefit from targeted FGFR inhibitors.

When a biliary tract tumor has both an FGFR2 fusion and HER2 positivity, oncologists may prioritize targeting the FGFR2 fusion. They reason that fusions are often early, clonal, and homogenous driver events, making them a more reliable therapeutic target than HER2, which can be expressed heterogeneously.

The technology and breadth of molecular testing panels for GIST are rapidly evolving. A patient whose tumor tested negative for driver mutations in the past should be considered for re-testing with current, broader panels. This may uncover previously undetectable alterations like FGFR translocations and open up new treatment options.

Real-world data for pemigatinib in cholangiocarcinoma showed a higher response rate (59%) than the pivotal FITE-202 trial (36%). This discrepancy likely stems from the lack of standardized, centrally reviewed imaging in real-world settings, which can inflate perceived response. Comparable progression-free survival across both settings supports this interpretation.

The FIGHT-302 trial for FGFR2-rearranged cholangiocarcinoma closed early, like similar trials, because the standard of care evolved faster than patients could be recruited. This highlights a fundamental challenge in studying rare molecular subtypes, requiring alternative trial designs where thousands of patients must be screened to find a few eligible participants.

Despite showing superior progression-free survival over chemotherapy, the FIGHT-302 trial doesn't establish pemigatinib as an automatic first choice or a "slam dunk." It solidifies its role as a strong option, with the final decision depending on patient preferences, tumor characteristics, and a detailed discussion of pros and cons versus chemo-immunotherapy.

Learnings from trials like FIGHT-302 reveal that resistance to targeted therapy occurs both on-target (kinase domain) and off-target (e.g., MAP kinase pathway). The next research frontier is likely not just developing better inhibitors, but combining them with chemotherapy to potentially block multiple resistance pathways simultaneously from the outset.