Pattern of resistance on first-line EGFR-directed therapy in EGFR-positive metastatic non-small cell lung cancer.

e20660 Background: Resistance to EGFR- tyrosine-kinase inhibitors (TKI), both intrinsic and acquired, presents a major challenge in EGFR mutant non-small-cell lung cancer (NSCLC), with the T790M mutation being the most common acquired resistance mechanism. Data on resistance patterns in the Indian population remains limited. Methods: This post hoc analysis of a Phase III trial conducted at Tata Memorial Centre, Mumbai, India, included 350 patients with advanced EGFR-mutant NSCLC. Patients were randomized to receive either gefitinib alone (n=176) or gefitinib with chemotherapy (pemetrexed and carboplatin, n=174). The primary objective was to identify resistance mechanisms following progression. Secondary objectives included comparing resistance patterns between the two arms and assessing progression rates and outcomes. At progression, histological and molecular evaluation was done with RTPCR, ALK IHC and/or NGS at physician discretion. Results: Of the 275 patients (78.6%) with progressive disease (PD), 206 were included in the final analysis after excluding those without histological or molecular data. Histological transformation to small cell carcinoma (SCLC) occurred in 12 patients (6%), with various EGFR mutation statuses. T790M mutations were identified in 44 of 119 patients (37%) in the gefitinib arm and 17 of 87 patients (19%) in the gefitinib plus chemotherapy arm (p = 0.008). New sensitizing mutations were found in 6 patients (5%) in the gefitinib arm and 1 patient (1.1%) in the gefitinib plus chemotherapy arm (p = 0.12), while loss of prior sensitizing mutations was observed in 21 patients (17.6%) and 28 patients (32%) in the respective arms (p = 0.015).Patients with T790M mutations had a progression-free survival 2 (PFS2) of 22.7 months (95% CI: 19.4–27.4), compared to 19.2 months (95% CI: 17.5–22.9) in those without T790M mutations (p = 0.95). Overall survival (OS) was 27.9 months (95% CI: 24.6–34.6) in the T790M group compared to 26.5 months (95% CI: 23.2–30.1) in the non-T790M group (p = 0.75). Conclusions: Emergence of T790M was lower than reported in previous studies, likely due to the addition of chemotherapy to gefitinib. T790M mutations were more prevalent in the gefitinib-alone arm. Histological transformation and loss of sensitizing mutations highlight the importance of repeat biopsy and molecular testing to guide subsequent treatment decisions.