Updated results of a randomized phase III study of trastuzumab, paclitaxel and carboplatin versus trastuzumab and paclitaxel in patients with HER2-overexpressing metastatic breast cancer (MBC): efficacy and safety

BACKGROUND: In the pivotal phase III combination trial (H0648g), adding trastuzumab (H; Herceptin®) to paclitaxel (P) was shown to improve clinical outcomes in women with HER2-overexpressing MBC compared with P alone. These data led to the regulatory approval of the combination of H + P. Preclinical data show that HP and carboplatin (C) are synergistic. In this trial we investigated the safety and efficacy of adding C to HP in patients with HER2-overexpressing MBC. PATIENTS AND METHODS: 188 patients with HER2-overexpressing (IHC 2+ or 3+) MBC were eligible for the study. 93 patients received HPC (H 4mg/kg loading dose, then 2mg/kg/week; P 175mg/m² q3w; C AUC 6 q3w) and 95 patients received HP. Chemotherapy was given for at least 6 cycles and H until progression. RESULTS: HP and HPC regimens were both well tolerated. As expected, grade 3/4 neutropenia and thrombocytopenia were more common on addition of C to HP. Other reported adverse events, including febrile neutropenia, neuropathy and fatigue, occurred with similar frequency in both trial arms. Two cases of congestive heart failure (CHF) were reported in the HP arm. Serial evaluations of LVEF showed no significant decreases from baseline in either arm. The triple combination was associated with improved efficacy compared with HP; ORR improved from 36% to 52% (p=0.04) and median TTP from 7.0 months to 10.7 months (p=0.02). In patients with IHC 3+ disease the improvements were even greater; ORR increased from 37% to 57% (p=0.03) and median TTP from 7.1 months to 14.0 months (p=0.007). Although not statistically significant, overall survival (OS) was prolonged with HPC compared with HP (36.0 months vs 32.0 months; p=0.49). Again the difference was greater in patients with IHC 3+ disease; 42.0 months with HPC compared with 29.0 months with HP (p=0.29). CONCLUSION: Treatment was well tolerated, with similar safety profiles for both HPC and HP. In all patients, there was a low incidence of CHF (1%). The triple combination of HPC was associated with significantly higher OR and TTP and with a trend of improved OS compared with HP in patients with HER2-overexpressing MBC.