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.

An individual tumor can have hundreds of unique mutations, making it impossible to predict treatment response from a single genetic marker. This molecular chaos necessitates functional tests that measure a drug's actual effect on the patient's cells to determine the best therapy.

Early studies found FGFR2 fusions in ~15% of patients, skewed by testing heavily pre-treated individuals. As testing moves to the first-line setting, the true prevalence appears to be much lower (5-8%), which has major implications for clinical trial design and prevalence estimates.

The same cancer-driving mutation behaves differently depending on the cell's internal "wiring." For example, a drug targeting a mutation works in melanoma but induces resistance in colorectal cancer due to a bypass pathway. This cellular context is why genetic data alone is insufficient.

Cancers evolve under therapeutic pressure, often developing new resistance mutations. Re-testing the tumor via tissue or liquid biopsy upon progression is essential, as it can identify acquired mutations that make the cancer susceptible to a different, next-generation targeted therapy, extending patient survival.

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.