Would you add immunotherapy to chemotherapy for a patient with metastatic NSCLC, an atypical EGFR mutation, and PD-L1 ≥50% who has progressed on osimertinib?

This is a difficult scenario, and there is no data to guide this. There is good evidence to suggest that patients with the classical mutations do not respond to ICIs regardless of PD-L1 expression. There is one small retrospective analysis that included 7 patients with uncommon mutations (G719X and exon 20 ins). This showed that patients with uncommon EGFR mutations had a slightly better RR to ICI (Yamada et al., PMID 30790471). I personally would try chemotherapy without immunotherapy.

While osimertinib has shown meaningful activity in the most prevalent atypical mutations G719X, L861Q, and S768I, its efficacy is not uniform across all atypical mutations: L861Q is associated with higher response rates and longer survival, while G719X and S768I show moderate benefit. (Choet al., PMID 31825714) For the case presented, platinum-based chemotherapy, with or without amivantamab, can be considered. The addition of amivantamab to chemotherapy has demonstrated improved progression-free survival compared to chemotherapy alone but is associated with increased hematologic and EGFR/MET-related toxicities. (Bazhenova et al., PMID 39531596)

If amivantamab is not available or appropriate, combinations of immunotherapy with antiangiogenic ...