Five-year outcomes of osimertinib-based treatment in a phase III study comparing EGFR tyrosine kinase inhibitor (EGFR-TKI) monotherapy and EGFR-TKI with inserted cisplatin plus pemetrexed as a first-line treatment for advanced non-squamous non–small-cell lung cancer harboring EGFR mutation (JCOG1404/WJOG8214L).

8649 Background: JCOG1404/WJOG8214L was an open label, multicenter, randomized phase III study comparing EGFR-TKI monotherapy (gefitinib Gef or osimertinib Osi) and EGFR-TKI with inserted cisplatin plus pemetrexed as a first-line treatment for advanced non-squamous non–small-cell lung cancer harboring EGFR mutation ( EGFR -NSqNSCLC). In the primary analysis, the insertion of platinum-doublet chemotherapy after the initial response to EGFR-TKI could improve progression-free survival (PFS), but not overall survival (OS) compared with EGFR-TKI monotherapy (Clin Cancer Res 2025;31:2317-26). This study was commenced using Gef in December 2015 and was switched to Osi in October 2018. 501 patients (pts) (308 in the Gef cohort, 193 in the Osi cohort) were enrolled to October 2020, but it resulted in later accrual and shorter follow-up for the Osi cohort at the time of the primary analysis (data cutoff November 2022; median follow-up of all randomized patients 36.0 months). Therefore, we conducted the five-year (5y) follow-up analysis of the Osi cohort. Methods: The key eligibility criteria were pts with advanced or recurrent EGFR -NSqNSCLC (exon 19 deletion or exon21 L858R), age 20 to 74 years, and PS 0 or 1. In the standard arm (SA), Gef or 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 cisplatin and pemetrexed were administered on days 71, 92, and 113. Thereafter, Gef or Osi was reinitiated on day 134 and continued until disease progression. Results: From October 2018 to October 2020, 193 pts were enrolled in the Osi cohort (97 pts in SA and 96 pts in EA). Median follow-up was 64.8 months. Advanced stage and recurrent disease were 79% and 21%, female and male were 63% and 37%, exon 19 deletion and exon 21 L858R were 54% and 46%, PS 0 and 1 were 50% and 50%, ≥ 65 year and < 65 year were 57% and 43%, central nerve metastasis (+) and (-) were 27% and 73%, respectively. Median OS were 54.0 months (95% confidence interval CI 44.4 to 66.0) in SA and 50.4 months (95% CI 43.2 to 69.6) in the EA (HR, 0.984; 95% CI, 0.684-1.415; p = 0.9279). 5y OS were 43.9% and 40.4%, respectively. Median PFS were 20.4 months (95% CI 14.4 to 28.8) in SA and 25.2 months (95% CI 18.0 to 33.6) in EA (HR, 0.902; 95% CI, 0.663-1.227; p = 0.5147). 5y PFS were 14.3% and 16.3%, respectively. Conclusions: The insertion of platinum-doublet chemotherapy after the initial response to Osi could not improve PFS and OS of pts with advanced EGFR -NSqNSCLC. On the other hand, JCOG1404/WJOG8214L demonstrated that Osi-based first-line treatment achieved 5y PFS in approximately 15% of this population, providing a benchmark for emerging Osi-based strategies. Clinical trial information: UMIN000020242.