Randomized Phase III Study of EGFR Tyrosine Kinase Inhibitor and Intercalated Platinum-doublet Chemotherapy for Non-small Cell Lung Cancer Harboring EGFR Mutation

Abstract Purpose: This study was performed to confirm the superiority in overall survival (OS) of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) (gefitinib or osimertinib) monotherapy versus EGFR-TKI with intercalation of cisplatin plus pemetrexed as the first-line treatment for patients with advanced non-squamous non-small cell lung cancer (NSqNSCLC) harboring EGFR mutation. Patients and Methods: This was an open-label, multicenter, randomized phase III study. Patients with chemotherapy-naïve advanced or recurrent NSqNSCLC harboring EGFR mutation (exon 19 deletion or exon 21 L858R point mutation) were randomly assigned (1:1) to EGFR-TKI monotherapy or EGFR-TKI plus intercalated chemotherapy group. The primary endpoint was OS, and the secondary endpoints included progression-free survival (PFS). Results: From December 2015 to October 2020, 501 patients were randomized. The EGFR-TKI was changed from gefitinib to osimertinib in October 2018 (gefitinib cohort: n=308, osimertinib cohort: n=193). There was no survival advantage in the EGFR-TKI plus intercalated chemotherapy group; the median survival time of both groups was 48.0 months (hazard ratio, 0.985; 91.4% confidence interval, 0.796–1.219; one-sided P=0.4496). The median PFS time was 12.0 months in the EGFR-TKI monotherapy group and 18.0 months in the EGFR-TKI plus intercalated chemotherapy group (hazard ratio, 0.762; 95% confidence interval, 0.628–0.925; one-sided P=0.003). The OS and PFS trends in both gefitinib and osimertinib cohorts were identical to those in the entire population. Conclusions: The intercalation of cisplatin plus pemetrexed after the response to EGFR-TKI improved PFS but not OS compared with EGFR-TKI monotherapy as the first-line treatment for advanced NSqNSCLC harboring EGFR mutation.