The accelerated FDA approval of Taliso-V for CMET overexpression creates a new treatment category, distinct from previously targeted MET exon 14 skipping mutations. This validates IHC-based protein overexpression as an independent, actionable biomarker, expanding targeted therapy options for a new patient population that previously had none.

The SAVANNAH study showed that targeting MET amplification after TKI failure is only effective with stringent diagnostic criteria (e.g., IHC 3+ in >90% of cells). Lower cutoffs lead to poor outcomes, highlighting the need for precise biomarker testing to select patients for this therapy.

Clinical trials for MET-targeted therapies in NSCLC use varying definitions for MET amplification, including different Gene Copy Number (GCN) or MET-CEP7 ratio cutoffs. This inconsistency makes it challenging to compare drug efficacy and apply trial data directly to clinical practice.

The confirmatory Code Break 200 study for sotorasib demonstrated a statistically significant improvement in progression-free survival (PFS) over docetaxel. However, it failed to show a similar benefit in overall survival (OS), a critical distinction for oncologists weighing long-term patient outcomes.

With a 90% response rate and median progression-free survival approaching four years, taletrectinib is now the preferred frontline treatment for ROS1-positive NSCLC. Its efficacy and manageable safety profile, primarily transient GI toxicity and manageable LFT elevation, surpass older-generation inhibitors.

Despite newer MET TKIs like capmatinib and tipotinib being available, the older drug crizotinib remains a valuable option for NSCLC patients with MET alterations. It is often better tolerated, making it a practical choice for patients who cannot handle the side effects of newer agents.

Contrary to the standard 'TKI-first' approach for driver mutations, a study in MET exon 14 skipping NSCLC suggests a different strategy. Patients with high PD-L1 expression appeared to have better outcomes with first-line chemoimmunotherapy, reserving the targeted therapy for later. This challenges the conventional wisdom of prioritizing the driver mutation over immunotherapy biomarkers in this specific subgroup.

Unlike immunotherapy, neoadjuvant osimertinib yields poor pathologic complete response (pCR) rates. However, it significantly improves major pathologic response (MPR) and survival, suggesting pCR may be the wrong efficacy endpoint for cytostatic EGFR TKIs, which have a different mechanism of action than immunotherapy.

The LEAP-010 trial showed a combination therapy improved tumor response and progression-free survival but failed to improve overall survival, the ultimate measure of benefit. This highlights the risk of relying on surrogate endpoints, which can be misleading, especially when a treatment adds significant toxicity.