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 standard of care for newly diagnosed EGFR-mutated non-small cell lung cancer has shifted from osimertinib monotherapy to combination regimens. Experts agree that combinations (e.g., osimertinib/chemo) should be the default choice, with monotherapy now reserved for cases with significant tolerability concerns.

When treating EGFR-mutated NSCLC that has progressed on osimertinib, leading oncologists advocate for continuing the TKI even when adding a new agent like datopotamab deruxtecan. This off-label practice is based on strong biological rationale and consistent trial data showing benefit from maintaining EGFR inhibition.

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.

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.

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.

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.

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.

The era of sequential monotherapy is over. Trials like FLORA2 (Osimertinib + chemo) show significant progression-free and overall survival benefits, making intensified upfront treatment the new standard of care for most patients, marking a major paradigm shift in treatment.