Pattern of resistance on first-line EGFR-directed therapy in EGFR-positive metastatic NSCLC

Resistance to epithelial growth factor receptor gene (EGFR)-tyrosine kinase inhibitors, both intrinsic and acquired, presents a major challenge in EGFR mutant non-small cell lung carcinoma (NSCLC), with the T790M mutation being the most common acquired resistance mechanism. Data on resistance patterns in the Indian population remains limited.

This post hoc analysis of a Phase III trial conducted at Tata Memorial Centre (TMC) in Mumbai, India, included 350 patients with advanced EGFR-mutant NSCLC. Patients were randomised 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 reverse transcription polymerase chain reaction (RT-PCR), anaplastic lymphoma kinase - immunohistochemistry (ALK IHC) and/or next generation sequencing (NGS) at physician discretion.

Of the 275 (78.6%) patients experiencing progressive disease (PD), a total of 206 patients were available for the final analysis after excluding patients without histological/molecular analysis.Histological transformation to small cell lung carcinoma (SCLC) occurred in 12 patients (6%), with various EGFR mutation statuses identified. T790M mutations were observed in 44 (37%) of 119 patients in the gefitinib arm and 17 (19%) of 87 patients in the gefitinib plus chemotherapy arm (p = 0.008). A new sensitising mutation was found in 6 (5%) in the gefitinib arm and in 1 (1.1%) in the gefitinib plus chemotherapy arm (p - 0.12). Loss of prior sensitising mutation was found in 21 (17.6%) in the gefitinib arm and in 28 (32%) in the gefitinib plus chemotherapy arm (p - 0.015).Patients with T790M mutations had a progression-free survival 2 of 22.7 months (95% CI: 19.4-27.4 months), compared to 19.2 months (95% CI: 17.5-22.9 months) in those without T790M mutations (p = 0.95). Overall survival was 27.9 months (95% CI: 24.6-34.6 months) in the T790M group compared to 26.5 months (95% CI: 23.2-30.1 months) in the non-T790M group (p = 0.75).

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 sensitising mutations highlight the importance of repeat biopsy and molecular testing to guide subsequent treatment decisions.