Combining trastuzumab emtansine with docetaxel both with and without pertuzumab yielded promising efficacy in a phase Ib/IIa study of patients with HER2-positive locally advanced or metastatic breast cancer.
Combining trastuzumab emtansine with docetaxel both with and without pertuzumab yielded promising efficacy in a phase Ib/IIa study of patients with HER2-positive locally advanced (LABC) or metastatic breast cancer (MBC). Many patients, however, required dose reductions due to toxicity.
Trastuzumab emtansine (T-DM1) is a drug-antibody conjugate, and has been shown to offer significant survival benefits in phase III trials of HER2-positive metastatic breast cancer. “In preclinical studies, T-DM1 exhibited enhanced antitumor activity when combined with docetaxel or pertuzumab,” wrote study authors led by Miguel Martin, MD, PhD, of Hospital General Universitario Gregorio MaraÃ±Ã³n in Madrid.
The new trial was the first time T-DM1 was tested along with docetaxel and pertuzumab. In the first part of the study, 21 MBC patients received T-DM1 along with docetaxel to determine a maximum tolerated dose for T-DM1 (3.6 mg/kg). Using the doses established, 21 LABC patients were then enrolled for a second part of the phase Ib study, followed by 52 LABC patients for the phase IIa part of the trial; four additional MBC patients were also included in the phase IIa study. Of the total of 73 LABC patients, 40 received T-DM1 plus docetaxel and 33 received those two drugs along with pertuzumab. The results of the study were published online ahead of print in Annals of Oncology.
In the 25 MBC patients, the objective response rate was 80%, with one complete and 19 partial responses. The median PFS in these patients was 13.8 months.
In LABC patients, the pathologic complete response rate was 60.3%; this was similar in those who received the doublet regimen (60%) and the triplet regimen with pertuzumab (60.6%). Patients with estrogen receptor (ER)-negative/progesterone receptor (PR)-negative tumors had a numerically higher pathologic complete response rate than those with ER-positive and/or PR-positive tumors (74.2% vs 48.7%).
Almost half of both MBC (48%) and LABC patients (47%) experienced adverse events (AEs) that required a dose modification. In MBC patients, neutropenia (76%) was the most common AE, followed by asthenia (72%) and thrombocytopenia (64%). The most common grade 3 or higher AEs were neutropenia (72%) and leucopenia (44%).
In the LABC patients, the most common AEs included asthenia (62%), epistaxis (55%), and mucosal inflammation (49%). Most patients (64%) had a grade 3 or higher AE, the most common of which were neutropenia (29%), increased ALT (15%), and thrombocytopenia (12%). The authors noted that the safety profiles of the doublet and triplet regimens were generally similar, though there were some differences with regard to specific AEs.
“This study suggests that T-DM1 can be combined with docetaxel [with or without] pertuzumab,” the authors concluded. “While higher severe/serious AE rates were observed for these combination regimens relative to what has been seen in prior studies with single-agent T-DM1, some of the increase is likely a result of overlapping toxicities.” They noted that combining T-DM1 with these other agents could be efficacious in tumors that do not response to T-DM1 alone, though this could come with increased toxicity.