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.

The NEOADORA trial showed lower-than-expected pathologic complete response (pathCR) rates for neoadjuvant osimertinib (<10%), even with chemotherapy. This suggests EGFR TKIs primarily halt tumor growth (cytostatic) rather than eradicate tumor cells (cytotoxic), contrasting with the higher pathCR rates seen with chemo-immunotherapy.

When EGFR+ NSCLC transforms to small cell, clinicians often continue the TKI osimertinib alongside chemotherapy. This practice is largely based on expert consensus and the rationale of suppressing any remaining EGFR-driven clones, rather than on definitive clinical trial data showing a clear benefit.

The distinct side effect profiles of pan-RAS inhibitors (rash, mucositis) and G12D-specific inhibitors (GI issues) are driving separate clinical strategies. The G12D drugs' better combinability with chemotherapy contrasts with pan-RAS agents, which may be better suited for monotherapy due to toxicity from blocking normal RAS.

In ROS1-positive NSCLC, starting with older TKIs before newer agents like Repotrectinib dramatically worsens outcomes. Median overall survival has not been reached after 5 years for TKI-naive patients but drops to just 25 months for those pre-treated with another TKI. This starkly quantifies the critical importance of using the most effective treatment first.

Clinicians are becoming more comfortable extrapolating positive adjuvant trial data from established targets like EGFR and ALK to other mutations like ROS1, even without specific Phase 3 evidence. This practice is particularly considered for patients in high-risk settings like locally advanced disease.

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.

While the avutometanib/defactinib combination is newly approved for KRAS-mutated ovarian cancer, its significant toxicity profile—causing up to a third of patients to stop treatment—creates a clear clinical need for agents like specific KRAS inhibitors that may offer similar efficacy with better tolerability.

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.