Oncologic resilience in EGFR S768I: from oligoprogression to complete response

Introduction: Male patient with a history of heavy smoking (74 pack-year), diagnosed with lung adenocarcinoma harboring the S768I mutation in exon 20 of EGFR, stage IV (cT3N0M1b), due to a single brain metastasis. The finding was incidental during follow-up of a post-COVID-19 pulmonary infiltrate. Case report: Initially, the disease exhibited an oligometastatic phenotype, with no lymph node or distant extrathoracic involvement (except for the brain). The patient received concomitant chemoradiotherapy with cisplatin and vinorelbine as intensive locoregional management. Upon adrenal progression, afatinib was initiated, resulting in three months of progression-free survival. He was then treated with carboplatin-pemetrexed for six months, including maintenance, followed by further disease progression. Serial biopsies of the adrenal metastasis revealed persistence of the S768I mutation with no emergence of secondary resistance (T790M) and a high tumor mutational burden (TMB): 35-38 mut/Mb. Given the lack of effective targeted therapies for S768I and the presence of high TMB, immunotherapy with nivolumab was initiated. After more than two years of treatment, the patient maintains an almost complete morphometabolic response in the lungs, adrenal glands, and central nervous system. Conclusion: This case illustrates the prolonged clinical course of an adenocarcinoma with an atypical EGFR mutation, the limited efficacy of tyrosine kinase inhibitors against S768I, and the potential benefit of immunotherapy in selected subgroups-even in the presence of uncommon EGFR mutations.