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.

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.

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.

Contrary to expectations from metastatic disease trials like FLAURA2, the NeoAdura study showed that combining chemotherapy with neoadjuvant osimertinib did not yield a better major pathologic response (MPR) than osimertinib alone for resectable EGFR-mutant lung cancer, questioning the role of upfront chemo in this setting.

Despite initial benefits, fewer than 10% of EGFR-mutated NSCLC patients on osimertinib monotherapy survive five years. A significant portion (25-40%) never even receive a second-line treatment, highlighting the limitations of this once-standard approach.

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.

For patients with atypical (non-exon 19/21) EGFR mutations, the treatment landscape has expanded. Recent ASCO guideline updates now recommend three different first-line options—afatinib, osimertinib, and amivantamab with lazertinib—signaling a move away from a one-size-fits-all approach for this diverse patient subgroup.

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.