The COMPEL study showed a near doubling of progression-free survival by continuing osimertinib with chemotherapy after first-line progression. This contradicts findings with first-generation TKIs (like gefitinib) and establishes "TKI continuation" as a new standard of care.

The NeoADURA trial demonstrates that adding osimertinib in the neoadjuvant setting for EGFR-mutated NSCLC results in a 'humongous benefit' in major pathological response and nodal downstaging compared to chemotherapy alone, significantly improving surgical outcomes.

Features like brain metastases or p53 co-mutations are considered high-risk. However, about 75% of patients have at least one such factor, making the "high-risk" profile the norm, not the exception, and reinforcing the need for upfront combination therapy.

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.

Data from the ADAURA trial suggests that EGFR-mutated lung cancer patients with detectable ctDNA before starting adjuvant osimertinib are at very high risk of recurrence. This finding supports considering indefinite, lifelong osimertinib for this subgroup, deviating from the standard three-year duration.

The success of perioperative osimertinib means oncologists cannot choose the optimal strategy (targeted therapy vs. chemoimmunotherapy) for resectable lung cancer without first knowing the patient's EGFR, ALK, and PD-L1 status. This elevates biomarker profiling from a metastatic-setting tool to a critical first step in early-stage disease.

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.

For patients with actionable mutations like EGFR or ALK, targeted therapy is the priority, regardless of PD-L1 score. Starting immunotherapy first in these patients can significantly increase the risk of developing severe pneumonitis (ILD) when they later switch to targeted therapy like osimertinib.

A sobering finding from the LAURA trial was its control arm. EGFR-mutant patients receiving standard "curative-intent" chemoradiation alone had extremely high and rapid relapse rates (PFS ~6 months), highlighting the inadequacy of this standard and underscoring the necessity of adding consolidation osimertinib.