First-line concomitant EGFR-TKI + chemotherapy versus EGFR-TKI alone for advanced <i>EGFR</i>-mutated NSCLC: a meta-analysis of randomized phase III trials

A tyrosine-kinase inhibitor (TKI) is indicated as a first-line treatment for patients with non-small-cell lung cancer (NSCLC) harboring an epidermal growth-factor – receptor (<i>EGFR</i>) mutation. Chemotherapy (ChT) given in combination with an EGFR-TKI in this setting is of interest. We conducted a meta-analysis of phase III randomized trials comparing EGFR-TKI + ChT vs. EGFR-TKI alone as first-line therapy for advanced NSCLC harboring an activating <i>EGFR</i> mutation. Three studies evaluated gefitinib + ChT (NEJ009, GAP-Brain, and Noronha et al.) and another evaluated osimertinib + ChT (FLAURA-2). Those four eligible studies included 1413 patients with non-squamous NSCLCs, 826 (58%) with an exon-19 deletion (ex19del) and 541 (38%) with <i>EGFR</i>^<i>L858R</i>. The EGFR-TKI + ChT combination was significantly associated with prolonged PFS (hazard ratio [HR]: 0.52 [95% confidence interval (CI): 0.45–0.59]; <i>p</i> &lt; 0.0001) and OS (HR: 0.69 [0.52–0.93]; <i>p</i> = 0.01). PFS was particularly improved for patients with brain metastases (HR: 0.41[0.33–0.51]; <i>p</i> &lt; 0.00001). For patients with untreated, advanced, <i>EGFR</i>-mutated NSCLCs, the EGFR-TKI + ChT combination, compared to EGFR-TKI alone, was associated with significantly prolonged PFS and OS. However, further studies are needed to identify which patients will benefit the most from the combination. PROSPERO CRD42024508055