Exon 19 deletion mutation and exon 21 L858R mutation are the most prevalent epidermal growth factor receptor (EGFR) mutations that are responsive to EGFR tyrosine kinase in-hibitors (EGFR-TKIs). However, the efficacy of EGFR-TKIs against rare EGFR mutations is debatable. Many patients will eventually develop resistance to EGFR-TKIs over time. Furthermore, there is still no standard protocol for patients developing resistance to Osimertinib, particularly those with rare or complex mutations. Here, we present a lung adenocarcinoma patient with EGFR L747S and L858R double mutations, who responded to Pembrolizumab plus chemotherapy after developing Osimertinib resistance, with a thirteen-month response duration.  This is the first report of the efficacy of Pem-brolizumab plus chemotherapy after Osimertinib resistance on a patient harboring EGFR L747S and L858R double mutations. Our case can serve as a therapy recommendation for patients with comparable rare mutations.

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