Osimertinib (AZD9291), a third-generation epidermal growth factor receptor (EGFR)-tyrosine-kinase inhibitor (TKI), is useful in the treatment of non-small cell lung cancer who show resistance to first-generation EGFR-TKIs and harbor T790M mutation. Acquisition of resistance to osimertinib due to several mechanisms has been reported. We report the first case of an Indian patient with osimertinib resistance, due to C797S mutation. A 52-year-old nonsmoker man was detected to have metastatic lung adenocarcinoma (Stage IV) with EGFR exon 19 deletion and treated with erlotinib. After 12 months of response with erlotinib, he developed resistance because of the development of T790M mutation. He was started on osimertinib, with which he responded for 20 months. A follow-up positron emission tomography scan showed progressive disease. Subsequent liquid biopsy did not detect any mutation. However, rebiopsy of the lung lesion showed additional C797S mutation (in cis association with T790M). Hence, the patient was diagnosed to have "triple whammy," i.e., triple mutation of exon 19 deletion, T790M, and C797S mutations.