Prolonged response to osimertinib in EGFR exon 20 insertion and SETD2 loss-of-function mutation in advanced NSCLC: a molecular paradox

Introduction: EGFR exon 20 insertions represent a minority of activating mutations in non-small cell lung cancer (NSCLC), but they are usually associated with resistance to first- and second-generation tyrosine kinase inhibitors (TKIs). Case presentation: A 75-year-old woman, a never-smoker, presented with irritative cough and was diagnosed in February 2020 with stage IV lung adenocarcinoma with bilateral pulmonary and pleural involvement. Next-generation sequencing identified an infrequent EGFR exon 20 insertion (p.Asp770_Asn771insAsnProHis) and a concomitant loss-of-function mutation in SETD2, with no alterations in TP53, RB1 or MET. Discussion: Treatment with osimertinib (80 mg/day) was initiated, achieving a radiologic partial response maintained to date, with more than five years of follow-up and no relevant toxicities. This behavior suggests that certain insertions close to codon 770 may retain sensitivity to third-generation TKIs. Conclusion: This case highlights the value of comprehensive molecular characterization in NSCLC with rare mutations and supports that EGFR exon 20 insertions do not necessarily confer universal resistance to osimertinib, which could have implications for truly individualized selection of systemic treatment in these patients.