A randomized phase II study to assess trastuzumab beyond progression in HER2-positive advanced gastric cancer: WJOG7112G

Abstract

Background: While continuous use of Trastuzumab (Tmab) beyond progression (TBP) prolonged progression-free survival for HER2(+) metastatic breast cancer, it has not been studied, so not been established for HER2(+) gastric or gastro-esophageal junction (G/GEJ) cancer. Method(s): Patients (pts) with HER2(+) advanced G/GEJ cancer progressing during first-line chemotherapy with Tmab + fluoropyrimidine + platinum were randomized to receive either weekly paclitaxel (P) (80mg/m2, day1, 8, 15, q4w) or weekly paclitaxel plus Tmab (PT) (P + initially Tmab 8mg/kg followed by 6mg/kg, q3w). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), response rate (RR), safety, and translational biomarker research. A total of 69 events was required to achieve 80% power with one-sided 10% significance level, expecting median PFS of P and PT arms of 3 and 5 months, respectively. Result(s): From December 2012 to October 2016, 89 pts were allocated to P (n=45) or PT (n=44) arm. Median PFS was 3.2 and 3.7 months in the P and PT arms (HR=0.91, 95% CI 0.67-1.22, p=0.33). Median OS was 10.0 and 10.2 months in the P and PT arms (HR=1.23, 95% CI 0.75-1.99, p=0.20), and the RR were 31.6 and 33.3% (p=1.00), respectively. In the pts (P/PT arms n=15/16) whose interval from the last Tmab administration to randomization was >= 30 days, PT arm showed longer PFS (HR=0.45, 95% CI 0.21-0.96), but not in the pts (P/PT arms n=30/28) < 30 days (HR=1.40, 95%CI 0.82-2.37). Safety was comparable between two arms. HER2 amplification was detected by cell-free DNA in the serum (cfHER2amp) of 41 (60%) pts (P/ PT arms n=21/20). There was no benefit of TBP in PFS regardless of cfHER2amp (+) and (-) (HR=0.93, 95% CI 0.49-1.76, and HR=0.81, 95% CI 0.36-1.85, respectively). Conclusion(s): Trastuzumab beyond progression strategy failed to improve PFS in pts with HER(+) advanced G/GEJ cancer.