BackgroundThis study investigated molecular testing, treatment patterns, and prognosis in Chinese patients who progressed from first-line (1 L), epidermal growth factor receptor -tyrosine kinase inhibitors (EGFR-TKIs) therapy, highlighting limited real-world data on clinical practice.MethodsConsecutive eligible patients were prospectively enrolled in 16-centers in China. The primary endpoints were second-line (2 L) treatment patterns and clinical outcomes, including median progression-free survival (mPFS) and median overall survival (mOS) from 2 L treatment.ResultsOverall, 300 patients were enrolled in the study, and among them, 291 patients were included in the Full Analysis Set, and 213(73.2%) underwent molecular testing, after progression from 1 L therapy. 30.5% (65/213) had tissue samples, while 66.7% (142/213) had plasma samples. In tissue and plasma samples, T790M positive rates were 53.8% and 43.7%, respectively. mPFS and mOS for patients with T790M positive who received third generation (3 G) EGFR-TKIs as 2 L therapy were 14.7 months and 32.0 months, respectively. The mPFS for patients with T790M negative who received 3 G EGFR-TKIs, prior EGFR-TKIs plus local therapy, and chemotherapy as 2 L therapy were 7.6 months, 10.2 months, and 4.9 months, respectively. The corresponding mOS for these patients were 21.2 months, 16.6 months, and 15.0 months, respectively. No new safety signal emerged.ConclusionsPatients with acquired resistance to first generation (1 G)/second generation (2 G) EGFR-TKIs receiving 3 G EGFR-TKIs, especially T790M positive, showed better clinical outcomes after molecular testing.Clinical trial registrationThe study has been registered at ClinicalTrials.gov (NCT04207775). The PISCES study in Chinese epidermal growth factor receptor mutant, non-small cell lung cancer patients progressing after first-line, epidermal growth factor receptor-tyrosine kinase inhibitors shows that T790M positive patients treated with osimertinib achieved a median overall survival of 32 months, highlighting the importance of molecular testing to guide effective second-line therapy.