A randomized phase II trial of 8 months of afatinib switching to osimertinib (A) versus osimertinib alone (B) as first-line treatment in advanced NSCLC patients with common EGFR mutation: YAMATO study (TORG1939/WJOG12919L).

8574 Background: NSCLC with common EGFR mutation (L858R or exon 19 deletion (Del19)) is known to originally comprise small portion of uncommon and compound EGFR variant cells including T790M-mutant ones albeit treatment-naïve. To overcome concomitant heterogeneous EGFR mutations, we planned a randomized phase II trial to assess the strategy of switching to osimertinib following 8 months of afatinib compared with osimertinib alone. Methods: YAMATO study is an open-label, multi-center, randomized phase II study. Patients with newly diagnosed stage III/IV/recurrent NSCLC harboring EGFR activating mutations (L858R or Del19) were randomized in a 1:1 ratio to receive up-front 8 months of afatinib (30 mg or 40 mg QD) followed by osimertinib (80 mg QD) (arm A) or osimertinib (80mg QD) alone (arm B) until disease progression or intolerable toxicity. The primary endpoint is 2-year progression free survival (PFS) rate with threshold rate of 22% and expected rate of 40% (one-tailed alpha of 0.1, beta of 0.2). Secondary endpoints are objective response rate (ORR), PFS, time to treatment failure, overall survival and adverse events. Results: Between May 2020 and Apr 2021, 113 patients were enrolled from 27 institutions (A/B 56/57). Patient characteristics were as follows: median ages, 73.5/71 years (range 41-85/41-92 years); proportion of males, 42.9/35.1%; EGFR mutation types, L858R/Del19 59/41% in A, 58/42% in B. The difference of two-year PFS rate was not observed statistically significant between groups (37.3% 80% CI, 29.0 to 45.5 in arm A vs 47.4% 80% CI, 38.5 to 55.7 in arm B; p=0.44; HR:1.28 80% CI, 0.95-1.73). The ORR was 82% in arm A and 87% in arm B. With the median follow-up of 27.5 months, median PFS was 16.8 months in arm A, and 22.2 months in arm B (HR: 1.280, p = 0.29). Severe pneumonitis occurred in 7% in arm A, most of which developed after switching to osimertinib, and 1.8% in arm B. Conclusions: YAMATO study failed to demonstrate the superiority of EGFR-TKI switching therapy of 8 months afatinib to osimertinib over osimertinib alone in terms of 2-year PFS rate in untreated advanced NSCLC patients with common EGFR mutations. Clinical trial information: 031200021 .