The standard first-line treatment for classical EGFR-mutated NSCLC has evolved from osimertinib monotherapy to include two combination strategies: osimertinib plus chemotherapy (FLORA2) and amivantamab plus lazertinib (MARIPOSA). This provides more aggressive options for patients with a higher disease burden or CNS metastases.
In a landscape where identifying a driver mutation typically dictates using a targeted agent first-line, KRAS G12C and NRG1 fusions are notable exceptions. For these mutations, standard chemo-immunotherapy is the initial treatment, with targeted agents reserved for subsequent lines of therapy.
Clinicians must avoid giving PD-1/PD-L1 immunotherapy concurrently with or immediately before the EGFR inhibitor osimertinib due to a significantly increased risk of severe pneumonitis. This is critical when EGFR mutation status is pending, urging caution before starting empiric immunotherapy.
While PD-L1 testing by IHC is standard, the diagnostic workup for metastatic NSCLC must now also include IHC for HER2 and CMET. This is because specific antibody-drug conjugates and other agents are now approved and tied directly to the protein expression levels identified by these tests.