Efficacy and Safety of Trastuzumab Emtansine Plus Capecitabine vs Trastuzumab Emtansine Alone in Patients With Previously Treated ERBB2 (HER2)-Positive Metastatic Breast Cancer A Phase 1 and Randomized Phase 2 Trial

Question What is the effect of adding capecitabine to trastuzumab emtansine (T-DM1) treatment in patients with previously treated ERBB2 (HER2)-positive metastatic breast cancer? Findings In this phase 1/2 randomized clinical trial of 161 patients with previously treated ERBB2-positive metastatic breast cancer, the overall response rate was 44% and 36% in the combination and single-agent T-DM1 arms, respectively; median overall survival was not estimable and 24.7 months. Adverse events occurred in 95% (grade 3-4: 44%) and 89% (grade 3-4: 41%) of patients in each arm, respectively. Meaning Adding capecitabine to T-DM1 increases toxic effects and does not improve clinical outcomes vs T-DM1 alone for previously treated ERBB2-positive metastatic breast cancer. Importance ERBB2 (HER2)-targeted therapy provides benefits in metastatic breast cancer (mBC) and gastric cancer, but additional treatments are needed to maximize efficacy and quality of life. Objective To determine maximum tolerated doses (MTDs) of trastuzumab emtansine (T-DM1) plus capecitabine in patients with previously treated ERBB2-positive mBC and locally advanced/metastatic gastric cancer (LA/mGC) (phase 1) and the efficacy and safety of this combination vs T-DM1 alone in patients with mBC (phase 2). Design, Setting, and Participants The MTD in phase 1 was assessed using a 3 + 3 design with capecitabine dose modification. Phase 2 was an open-label, randomized, international multicenter study of patients with mBC treated with T-DM1 plus capecitabine or T-DM1 alone. Eligible patients had previously treated ERBB2-positive mBC or LA/mGC with no prior chemotherapy treatment for advanced disease. Interventions Patients in the phase 1 mBC cohort received capecitabine (750 mg/m(2), 700 mg/m(2), or 650 mg/m(2)twice daily, days 1-14 of a 3-week cycle) plus T-DM1 3.6 mg/kg every 3 weeks. Patients with LA/mGC received capecitabine at the mBC phase 1 MTD, de-escalating as needed, plus T-DM1 2.4 mg/kg weekly. In phase 2, patients with mBC were randomized (1:1) to receive capecitabine (at the phase 1 MTD) plus T-DM1 or T-DM1 alone. Main Outcomes and Measures The phase 1 primary objective was to identify the MTD of capecitabine plus T-DM1. The phase 2 primary outcome was investigator-assessed overall response rate (ORR). Results In phase 1, the median (range) age was 54.0 (37-71) and 57.5 (53-70) years for patients with mBC and patients with LA/mGC, respectively. The capecitabine MTD was identified as 700 mg/m(2)in 11 patients with mBC and 6 patients with LA/mGC evaluable for dose-limiting toxic effects. In phase 2, between October 2014 and April 2016, patients with mBC (median [range] age, 52.0 [28-80] years) were randomized to receive combination therapy (n = 81) or T-DM1 (n = 80). The ORR was 44% (36 of 81 patients) and 36% (29 of 80 patients) in the combination and T-DM1 groups, respectively (difference, 8.2%; 90% CI, -4.5 to 20.9; P = .34; clinical cutoff, May 31, 2017). Adverse events (AEs) were reported in 78 of 82 patients (95%) in the combination group, with 36 (44%) experiencing grade 3-4 AEs, and 69 of 78 patients (88%) in the T-DM1 group, with 32 (41%) experiencing grade 3-4 AEs. No grade 5 AEs were reported. Conclusions and Relevance Adding capecitabine to T-DM1 did not statistically increase ORR associated with T-DM1 in patients with previously treated ERBB2-positive mBC. The combination group reported more AEs, but with no unexpected toxic effects. This phase 1 and phase 2 randomized clinical trial seeks to determine the maximum tolerated doses of trastuzumab emtansine plus capecitabine in patients with previously treated ERBB2 (HER2)-positive metastatic breast cancer and locally advanced/metastatic gastric cancer (phase 1) and the efficacy and safety of this combination vs trastuzumab emtansine alone in patients with metastatic breast cancer (phase 2).