The first-line treatment of EGFR-mutated metastatic non–small cell lung cancer (NSCLC) now requires greater individualization. Contemporary guidelines note that combination regimens are generally preferred, although osimertinib monotherapy remains an option for selected patients in whom tolerability is a priority.

In the first-line setting for classical EGFR-mutated advanced NSCLC, both the FLAURA2 and MARIPOSA trials demonstrated the superior efficacy of combination therapy compared with osimertinib monotherapy. Each trial showed statistically significant and clinically meaningful improvements in progression-free survival, with mature data also showing an overall survival benefit. These results support considering combination regimens as a strong option in the frontline setting.

Adding chemotherapy to osimertinib increases toxicity, particularly myelosuppression with associated cytopenias, as well as diarrhea and skin-related adverse events. In contrast, the amivantamab-plus-lazertinib combination exhibits a distinct toxicity profile that, in our experience, can be more challenging to manage. This includes frequent infusion-related reactions, prominent cutaneous toxicity, and folliculitis. These effects often require substantial supportive care, making the amivantamab-plus-lazertinib regimen quite demanding to manage in the first-line setting.

Other uncommon EGFR mutations, including EGFR exon 20 insertions, constitute a distinct molecular subgroup with unique therapeutic considerations. Data from the PAPILLON trial support chemotherapy plus amivantamab as a preferred first-line approach in this setting. For subsequent lines, zipalertinib is an investigational EGFR TKI that has shown activity specifically in EGFR exon 20 insertion–mutated NSCLC, particularly in patients who were previously treated with platinum-based chemotherapy with or without amivantamab. At the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting, John V. Heymach, MD, PhD, presented results from the primary analysis of the phase 3 WU-KONG28 study of sunvozertinib in the first line for patients with advanced NSCLC with EGFR exon 20 insertion mutations. The trial met its primary end point; however, the comparator was chemotherapy alone, not amivantamab plus chemotherapy. We will continue to monitor investigational and emerging therapies in this area.

Obtaining a biopsy at diagnosis and a rebiopsy at the time of progression remain essential for personalizing therapy in EGFR-mutated NSCLC. The patterns of disease progression can vary widely. In cases of oligoprogression (limited to 1 or up to a few site[s]), local ablative therapies such as radiation are often used. However, in the setting of systemic progression involving multiple sites, we strongly consider a repeat biopsy to identify the underlying resistance mechanism—whether it be a secondary EGFR resistance mutation, MET amplification, histologic transformation, or another targetable alteration.

If no actionable biomarker is identified on rebiopsy, subsequent treatment options are largely dictated by the regimen that was used in the first-line setting. For instance, patients who received amivantamab plus lazertinib in the MARIPOSA study would not be candidates for the MARIPOSA-2 regimen. Similarly, those who progressed on chemotherapy plus osimertinib would not receive the COMPEL regimen.

In practice, many patients progress on first-line osimertinib monotherapy; in this setting, reasonable options include the MARIPOSA-2 or COMPEL regimen. I generally continue the EGFR TKI in the second-line setting to maintain central nervous system penetration and activity.