EGFR-tyrosine kinase inhibitors (TKIs) have revolutionized the treatment for NSCLC. However, acquired drug resistance often occurs after treatment with EGFR-TKIs. EGFR T790M and C797S mutations are the most common resistance mechanism in patients who failed from first- and third- generation EGFR TKI treatments, respectively. However, there is no standard of care for NSCLC harboring EGFR T790M and C797S in-cis. The present case reports a 69-year-old Chinese man with advanced NSCLC harboring EGFR exon 19-deletion, T790M, cis-C797S, and HER2 amplification who was heavily pre-treated. The patient was then given a combination of afatinib and apatinib and achieved a PFS of more than 10 months. This case showed that afatinib plus apatinib may be a promising therapy for patients with EGFR 19Del-T790M-cis-C797S mutant and HER2 amplified NSCLC.