Two case reports of non-small cell lung cancer patients harboring acquired T790M--C797S benefit from immune checkpoint inhibitor combined with platinum-based doublet chemotherapy.

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 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 C797S. Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of various types of cancers in the last decade. Whether NSCLC patients with acquired C797S could benefit from ICIs remains elusive.

Case Description: Herein, we reported two cases of -mutant NSCLC patients who acquired a tertiary 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 exon 19 deletion (19del) based on imaging and next-generation sequencing (NGS) findings. She received icotinib followed by osimertinib, then acquired T790M--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 19del-positive LUAD and treated with icotinib followed by osimertinib. He also acquired T790M--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 T790M--C797S. Clinical trials are needed to evaluate the efficacy and safety of PD-1 inhibitors in the treatment of NSCLC patients harboring T790M--C797S.