Background: The standard first-line treatment for pts with EGFR-NSqNSCLC is EGFR-TKI monotherapy, but acquired resistance to EGFR-TKI restricts duration of response and survival. We hypothesized that the insertion of platinum-doublet chemotherapy after the initial response to EGFR-TKI might prevent the emergence of acquired resistance to EGFR-TKI and prolong patient survival. Methods: This was an open-label, multicenter, randomized phase III study comparing two arms as below in pts with EGFR-NSqNSCLC. The key eligibility criteria were pts with advanced or recurrent NSqNSCLC harboring EGFR mutations (exon 19 deletion or exon21 L858R), age 20 to 74 years, and PS 0 or 1. In the standard arm (SA), gefitinib (GEF) or osimertinib (OSI) was administrated until disease progression. In the experimental arm (EA), GEF or OSI was administered on days 1-56. Then, after a two-week drug-free period, three cycles of CDDP and PEM were administered on days 71, 92, and 113. Thereafter, GEF or OSI was reinitiated on day 134 and continued until disease progression. The primary endpoint was overall survival (OS). The planned sample size (required number of events) of 500 patients (257 deaths) provided 75% power (one-sided alpha level of 5%) to detect an OS hazard ratio (HR) of 0.749. Results: From December 2015 to October 2020, 501 pts (GEF cohort: 308 pts, OSI cohort: 193 pts) were randomized. EGFR-TKI was changed from GEF to OSI in October 2018 considering the results of FLAURA study. The median age was 65. Advanced stage and recurrent disease were 86% and 14%, exon 19 deletion and exon 21 L858R were 56% and 44%, PS 0 and 1 were 47% and 53%, respectively. Median survival time (MST) was 48.0 months (95% confidence interval [CI] 40.8 to 56.4) in SA and 48.0 months (95% CI 43.2 to 54.0) in the EA (HR 0.985; 95% CI 0.772 to 1.257; one-sided p=0.4496). In GEF cohort, MST was 43.2 months (95% CI 37.2 to 51.6) in SA and 45.6 months (95% CI 40.8 to 51.6) in EA (HR 1.016; 95% CI 0.774 to 1.332). In OSI cohort, MST was not reached in both SA and EA (HR 0.835; 95% CI 0.484 to 1.442). Median progression-free survival (mPFS) was 12.0 months (95% CI 10.8 to 14.4) in SA and 18.0 months (95% CI 15.6 to 20.4) in EA (HR 0.762; 95% CI 0.628 to 0.925; one-sided p=0.0003). In GEF cohort, mPFS was 9.6 months (95% CI 9.6 to 12.0) in SA and 14.4 months (95% CI 12.0 to 18.0) in EA (HR 0.687; 95% CI 0.544 to 0.867). In OSI cohort, mPFS was 20.4 months (95% CI 20.4 to 25.2) in SA and 25.2 months (95% CI 18.0 to 34.8) in EA (HR 0.812; 95% CI 0.572 to 1.155). Conclusions: In patients with advanced EGFR-NSqNSCLC, the insertion of platinum-doublet chemotherapy after the initial response to EGFR-TKI could not prolong OS compared with EGFR-TKI, though that could prolong PFS. Clinical trial information: UMIN000020242.