Immunotherapy in EGFR mutant non-small cell lung cancer: when, who and how?

Mutations in the epidermal growth factor receptor (EGFR) are detected in approximately 15% of lung adenocarcinomas in western countries, with even higher rates noted in Asian patients. The most common alterations that lead to constitutive activation of its tyrosine kinase are in-frame deletions of exon 19 and the L858R mutation in exon 21. Single-agent tyrosine kinase inhibitor (TKI) therapy leads to substantial progression-free survival (PFS) benefit with very manageable toxicity profiles. However, resistance ultimately ensues, including development of a second EGFR mutation such as T790M (seen in 60% of patients who progress after first or second generation TKIs), acquisition of mutations in other receptors (MET) or transformation to more aggressive histology such as small cell lung cancer (approximately 5% of cases). When resistance develops, patients are treated with systemic chemotherapy and ultimately succumb to the disease, hence the need for more effective therapies.