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.

Real-world data suggests that using one antibody-drug conjugate (ADC) immediately after another is often ineffective. A potential strategy to overcome this resistance is to administer a different class of chemotherapy before starting the second ADC.

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.

By targeting MEK, which is downstream of RAS/RAF in the MAPK pathway, Immuneering's therapy can block a wider range of potential resistance mutations. This preempts the cancer's ability to adapt by mutating upstream proteins, a common failure point for drugs that target RAS directly.

While research pursues mechanism-based strategies (e.g., 4th-gen TKIs) for acquired resistance, recent practical breakthroughs are mechanism-agnostic, like ADCs or chemotherapy combinations. This highlights a pragmatic, broad-spectrum approach to treating progression after frontline osimertinib.

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.

The presence of heterogeneous resistance mutations, some of which may be below detection limits, suggests a new strategy. Using a potent, broad-spectrum combination therapy upfront in the second-line setting, rather than sequential monotherapies, could eradicate more resistant clones and give patients a better chance at long-term survival or even a cure.

New CDK inhibitors that also target CDK2 show great activity in models resistant to current CDK4/6 agents. Instead of being reserved for later use, they are already being tested in frontline trials. The strategy, similar to that of ALK inhibitors in lung cancer, is that using the best drug first may prevent or significantly delay the onset of resistance.

A key strategy for Iterion is combining its Wnt-beta-catenin inhibitor with existing therapies like EGFR-TKIs. Research shows the Wnt pathway is often upregulated as a resistance mechanism to these primary treatments. By blocking this escape route, the combination therapy aims to prevent resistance and improve patient outcomes.