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.

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.

The two leading first-line combination therapies for EGFR-mutated NSCLC, FLORA2 and Mariposa, offer similar survival benefits. The decision often comes down to patient preference and managing distinct side effects: hematologic toxicity versus dermatologic issues and thromboembolic events.

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.

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.

For EGFR-mutated NSCLC patients with brain metastases, even numerous ones (>30), potent systemic therapy like osimertinib plus chemotherapy is often initiated first. This can achieve high rates of complete intracranial response, allowing clinicians to delay or entirely avoid whole-brain radiation and its long-term toxicities.

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.

For N2+ EGFR-mutant NSCLC, clinicians now face a choice. Combining neoadjuvant osimertinib with chemotherapy is potent and gets treatment done upfront, but osimertinib monotherapy is better tolerated, reducing the risk of toxicity that could prevent a patient from reaching their planned surgery.