First-Line T-DM1 Improves PFS for HER2-Positive Breast Cancer

Ado-trastuzumab emtansine (Kadcyla) significantly improved progression-free survival (PFS) as first-line treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer, when compared with the standard treatment of trastuzumab (Herceptin) plus docetaxel in a randomized phase II multicenter study. Findings of the open-label study were reported in the Journal of Clinical Oncology. Treatment with ado-trastuzumab emtansine, formerly known as T-DM1, also resulted in a more favorable safety profile that “appears to translate into superior overall quality of life,” according to the team of investigators led by Edith A. Perez, MD, of the Mayo Clinic, Jacksonville, Florida.

Ado-trastuzumab emtansine is an antibody-drug conjugate (ADC) composed of cytotoxic microtubule polymerization inhibitor DM1 conjugated to the humanized, monoclonal antibody trastuzumab via a stable thioether linker. Because the monoclonal antibody targets HER2, and HER2 is only overexpressed in cancer cells, the conjugate delivers the toxin specifically to tumor cells. The drug was recently approved by the US Food and Drug Administration for use in patients with HER2-positive metastatic breast cancer, who previously received trastuzumab and a taxane, separately or in combination.

“To the best of our knowledge, this is the first randomized study to evaluate an ADC [as first-line therapy] for HER2-positive metastatic breast cancer, and these results demonstrate the therapeutic potential of the ADC platform to improve benefit and decrease risk in this population,” said Perez.

Patients (n = 137) with HER2-positive metastatic breast cancer or recurrent locally advanced breast cancer were randomly assigned to receive trastuzumab plus docetaxel (n = 70) or ado-trastuzumab emtansine (n = 67) as first-line treatment until disease progression or unacceptable toxicity. Ado-trastuzumab emtansine 3.6 mg/kg was administered intravenously (IV) once every 3 weeks; a loading dose of trastuzumab 8 mg/kg IV was followed by 6 mg/kg once every 3 weeks and IV docetaxel 75 mg/m² or 100 mg/m² (per investigator discretion) once every 3 weeks.

Primary endpoints were investigator-assessed PFS and safety. Key secondary endpoints included overall survival, objective response rate, duration of objective response, clinical benefit rate, and quality of life.

Patients in the ado-trastuzumab emtansine arm who discontinued treatment because of unacceptable drug-related toxicities were eligible to receive single-agent trastuzumab. For patients in the trastuzumab plus docetaxel arm, if either agent was discontinued before progressive disease, the remaining agent could be continued once every 3 weeks. If discontinuation was due to progressive disease, patients were eligible to cross over to the ado-trastuzumab emtansine regimen.

Median PFS was 9.2 months with trastuzumab plus docetaxel and 14.2 months with ado-trastuzumab emtansine (hazard ratio = 0.59; 95% CI, 0.36–0.97). Median follow-up was approximately 14 months in both arms. Objective response rate was 58% (95% CI, 45.5%–69.2%) with trastuzumab plus docetaxel and 64.2% (95% CI, 51.8%–74.8%) with ado-trastuzumab emtansine. A preliminary overall survival analysis was performed, with a median follow-up of approximately 23 months in both arms.

Ado-trastuzumab emtansine had a more favorable safety profile, with fewer grade ≥ 3 adverse events (46.4% vs 90.9%), fewer adverse events leading to treatment discontinuations (7.2% vs 40.9%), and fewer serious adverse events (20.3% vs 25.8%).

“The improvement in PFS observed with ado-trastuzumab emtansine in this study was associated with a more durable response, which could result from greater potency related to its unique mechanisms of action, longer treatment duration enabled by its favorable safety and tolerability, or both,” said Perez, who noted that grade 4 adverse events were reported for 57.6% of patients who received trastuzumab plus docetaxel vs 5.8% who received ado-trastuzumab emtansine.

The investigators acknowledged a number of limitations of the study, including its open-label design, with a primary endpoint of investigator-assessed PFS, a lower-than expected proportion of patients treated with prior therapy in the adjuvant setting, and the immaturity of the overall survival data, with few deaths reported at the final analysis. Given these and other limitations, they concluded, these data should be considered “hypothesis-generating” and require validation by results of MARIANNE, the ongoing phase III randomized study of ado-trastuzumab emtansine with or without pertuzumab (Perjeta) vs standard therapy (trastuzumab plus taxane) for first-line treatment of HER2-positive metastatic breast cancer.

Support for the present study was provided by Genentech.