Background: Acquired resistance is inevitable in non-small cell lung cancer (NSCLC) patients treated with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). The emergence of EGFR exon 20 C797S is one of the major resistance mechanisms to osimertinib as a third-generation EGFR-TKI. To date, there is no standard of care for NSCLC patients after acquiring EGFR C797S. Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of various types of cancers in the last decade. Whether NSCLC patients with acquired EGFR C797S could benefit from ICIs remains elusive. Case Description: Herein, we reported two cases of EGFR-mutant NSCLC patients who acquired a tertiary EGFR mutation C797S benefited from ICIs. A 28-year-old woman presented with anepithymia and nausea. Chest computed tomography (CT) revealed a mass in the right lung. She was diagnosed with stage IV lung adenocarcinoma (LUAD) with EGFR exon 19 deletion (19del) based on imaging and next-generation sequencing (NGS) findings. She received icotinib followed by osimertinib, then acquired EGFR T790M-cis-C797S. She had low tumor mutation burden (TMB) and achieved partial response (PR) to a programmed cell death-1 (PD-1) inhibitor sintilimab combined with platinum-based doublet chemotherapy as late-line treatment lasting more than 5 months. A 66-year-old man complained with chest tightness, hemoptysis, and back pain. CT scans revealed a mass in the right lung and metastases to the bilateral lungs, liver, adrenal gland, mediastinal lymph nodes, and bone. He was also diagnosed with EGFR 19del-positive LUAD and treated with icotinib followed by osimertinib. He also acquired EGFR T790M-cis-C797S. The patient had low TMB also and benefited from a PD-1 inhibitor camrelizumab combined with platinum-based doublet chemotherapy as late-line treatment with a progression-free survival (PFS) of 8 months. Two cases had no treatment-related adverse events leading to discontinuation of PD-1 inhibitors. Conclusions: Our study provides the first clinical evidence that ICIs combined with platinum-based doublet chemotherapy may be effective treatment options for overcoming resistance mediated by EGFR T790M-cis-C797S. Clinical trials are needed to evaluate the efficacy and safety of PD-1 inhibitors in the treatment of NSCLC patients harboring EGFR T790M-cis-C797S.