Third-Generation EGFR-TKIs in T790M-Negative NSCLC After First/Second-Generation EGFR-TKI Failure: A Retrospective Study.

PURPOSE: In non-small cell lung cancer (NSCLC) patients resistant to first- or second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), only half develop the T790M mutation and thus qualify for the treatment using third-generation EGFR-TKIs. For T790M-negative patients, chemotherapy is the recommended second-line treatment. We compared the efficacy between third-generation EGFR-TKIs and chemotherapy with or without first/second-generation EGFR-TKIs in T790M-negative patients. PATIENTS: This study included T790M-negative patients with EGFR-mutated advanced NSCLC and progressing after first-line treatment with first- or second-generation EGFR-TKIs. Data on clinical characteristics, disease features, and survival were collected, including general conditions, medical history, imaging, histology, and molecular profiling. RESULTS: Of 82 patients progressing after first- or second-generation EGFR-TKIs without acquiring T790M, 45 received third-generation EGFR-TKIs and 37 received chemotherapy and/or first/second-generation EGFR-TKIs. We found that third-generation EGFR-TKIs led to significantly longer median progression-free survival (mPFS) than other treatments [10.20 months vs. 5.70 months, p = 0.017]. Subgroup analyses indicated that third-generation EGFR-TKIs had similar mPFS to the chemotherapy group but were significantly superior to first/second-generation EGFR-TKIs with or without chemotherapy (10.20 months vs. 4.80 months, p < 0.001; 10.20 months vs. 3.30 months, p = 0.004). The median overall survival (mOS) for patients treated with third-generation EGFR-TKIs and with non-third-generation therapy was 39.80 months (95% CI 23.14 to 56.46) and 32.40 months (95% CI 18.71 to 46.09), p = 0.408, respectively. CONCLUSIONS: Third-generation EGFR-TKIs significantly improved mPFS in T790M-negative patients with EGFR-mutated advanced NSCLC and resistant to first-line treatment with first- or second-generation EGFR-TKIs. TRIAL REGISTRATION: ChiCTR2500096109.