A phase 1b study of S-1 combined with trastuzumab emtansine (T-DM1) for HER2 positive metastatic breast cancer

Abstract

Introduction: T-DM1 and oral 5-FU are both approved drug for advanced or metastatic breast cancer, but the combination of these two drugs, especially T-DM1 and S-1 for Japanese breast cancer patients have not been evaluated. Preclinical data showed potential effect of the combination therapy of T-DM1 and oral 5-FU. Among developed countries, frequently used oral 5-FU for advanced/recurrence breast cancer is capecitabine, and there is a phase 1/2 TRAX-HER2 (NCT01702558) study which showed safety data in the phase 1 portion. In this study, combination of T-DM1 and S- 1 was evaluated for finding the feasible dose of S-1 for trastuzumab pretreated HER2 positive advanced or metastatic breast cancer. Methods: A 3+3 dose escalation design was used to determine the maximum tolerated dose (MTD) of twice-daily oral S-1, two weeks on one week off, in T-DM1 and S-1 combination therapy. As in the TRAX-HER2 study, dose of T-DM1 was fixed as 3.6mg/ kg q3w. Not having a clinical data of combination use of T-DM1 and S-1, starting dose was reduced to 80% of standard use as a single agent, 65mg/m2/day twice-daily. The primary endpoint is dose limiting toxicity (DLT) occurrence in each dose level of the first cycle. The secondary endpoints are response rate and safety of multiple cycles. Results: Twelve patients out of 15 enrolled were evaluable for DLT; six at level 0 and six at level 1. One DLT (grade≥3 non-hematological AE) occurred at dose level0, leading to the expansion of this cohort to 6 patients, with an additional further DLT (7 days or more discontinuation of medication), while no DLT occurred at dose level1. Two patients had grade 3 thrombocytopenia in level 0, one had grade 3 elevated transaminase and one had grade 3 nausea. Conclusion: The MTD for S-1 given in the combination of T-DM1 is 80 mg/m2/day twice-daily, 14/21 days. S-1 can be safely combine with a clinical relevant dose of TDM1 in patients with HER2 positive advanced or metastatic breast cancer.