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 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.

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 lung cancer patients experiencing cardiac toxicity like QTc prolongation with osimertinib, lazertinib presents a viable alternative. Its lower rate of cardiac side effects allows for continued third-generation TKI therapy in a specific patient subset where osimertinib may be contraindicated.

The antibody-drug conjugate datopotamab deruxtecan (Dato-DXd) has an accelerated FDA approval that extends beyond common EGFR mutations. Its label includes activity in patients with uncommon mutations and exon 20 insertions, based on data from the TREPION-Lung studies, broadening its clinical applicability.

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.

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.