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.

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 FLORA two study's overall survival benefit was so compelling that clinicians should now default to osimertinib plus chemotherapy for most first-line EGFR-mutant NSCLC patients, only opting out for specific reasons like comorbidities or patient preference.

Even if randomized trials show zongertinib's efficacy is merely comparable to chemoimmunotherapy, its significantly milder safety profile—especially its lack of cardiac toxicity and manageable side effects—is expected to make it the preferred first-line choice. Patient quality of life and tolerability are becoming decisive factors in treatment selection.

Due to a 10-11 month overall survival benefit shown in the FLORA two regimen, leading oncologists now consider osimertinib plus chemotherapy the standard first-line treatment for metastatic EGFR-mutant NSCLC. Monotherapy is reserved only for patients who cannot tolerate or refuse chemotherapy.

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.

For BRAF V600E mutated colorectal cancer, data argues against the common practice of starting with chemotherapy and saving targeted therapy for later. Hitting the specific tumor biology hard and early with combination targeted agents leads to significantly better outcomes, including doubling overall survival.

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.