Adding chemotherapy to TKI: can we improve first-line treatment for EGFR-mutated NSCLC patients?

Abstract

colleagues (1) have recently reported the results of a phase II randomized trial comparing pemetrexed plus gefitinib vs. gefitinib in treatment-naive, East Asian patients, with advanced non-squamous non-small cell lung cancer (NSCLC) and activating epidermal growth factor receptor (EGFR) mutations. The study met its primary end-point in the intent-to-treat population, showing a significantly longer median progression free survival (PFS) in favors of the combination arm (15.8 months) compared to single agent arm (10.9 months) [hazard ratio (HR): 0.68; 95% CI, 0.48 to 0.96; one-sided P=0.014; two-sided P=0.029]. The significant improvement in PFS was independent from the specific type of mutation (EGFR exon 19 deletion vs. EGFR exon 21 L858R point mutation). The addition of pemetrexed to gefitinib resulted also in a significantly longer time to progressive disease (16.2 vs. 10.9 months; HR: 0.66; 95% CI, 0.47 to 0.93) and duration of response (15.4 vs. 11.3 months; HR: 0.74; 95% CI, 0.50 to 1.08), while no differences in response rate (RR: 80% vs. 74%) were observed between the two treatment arms. As attended, the percentage of patients who reported grade 3-4 drug-related adverse-events (AEs) was significantly higher (42% vs. 19%) in the combination arm, as well as the proportion of patients who discontinued treatment because of AEs nearly doubled with pemetrexed plus gefitinib compared to single agent arm.Several randomized phase III studies (2-10) previously showed that EGFR-tyrosine kinase inhibitors (TKIs) significantly improve both RR, PFS and quality of life (QoL) compared to platinum-based doublets chemotherapy as first-line treatment of EGFR-mutated NSCLC patients. Subsequently a pooled analysis of both LuxLung3 and LuxLung6 trials has also shown an overall survival (OS) benefit in favor of the EGFR-TKI Afatinib, even if it was limited to the subgroup of patients with EGFR exon 19 deletion (9). Overall, the results of all such studies convincingly and consistently demonstrated that for the subgroup of patients whose tumors harbor an EGFR activating mutation, the optimal strategy is starting with an EGFR-TKI, including gefitinib, erlotinib, or afatinib (11,12).The trial conducted by Ying Cheng and colleagues (1) suggests that the addition of chemotherapy to the EGFR-TKI may further improve the outcomes of EGFR-mutated, non-squamous NSCLC patients.Pre-clinical studies have shown a potential synergism between the EGFR-TKI, erlotinib, and the multi-targeted antifolate pemetrexed in NSCLC cell-lines (13,14). The modulation of both EGFR and Akt phosphorylation, together with a significant decrease of thymidylate synthase (TS) expression and activity in all NSCLC cells, represent the molecular mechanisms underlying such synergistic interaction. Later, early phase I-II studies demonstrated both a promising activity and a tolerable safety profile of EGFREditorial