T-DM1 Extends PFS in Heavily Pretreated Advanced Breast Cancer

Hans Wildiers, MD, PhD

T-DM1 (ado-trastuzumab emtansine; Kadcyla) extended progression-free survival (PFS) compared with “physician’s choice of treatment” in women with metastatic HER2-positive breast cancer, according to primary results from the TH3RESA trial reported at the 2013 European Cancer Congress. All the women in the trial had progressed on two or more previous HER2-directed treatments, including trastuzumab (Herceptin) and lapatinib (Tykerb). An interim analysis of overall survival (OS) suggests that T-DM1 may have a survival benefit in this setting, but longer follow-up is needed.

Previously, the EMILIA trial showed improved median PFS and OS with T-DM1 versus capecitabine (Xeloda) and lapatinib in women with HER2-positive metastatic breast cancer previously treated with a taxane and trastuzumab. TH3RESA is the first phase III trial to evaluate T-DM1 in patients previously treated with at least two HER2-specific therapies, explained the first author of the late-breaking presentation, Hans Wildiers, MD, PhD, University Hospital Leuven, Gasthuisberg, Belgium.

“T-DM1 demonstrated improved safety and efficacy compared with the physician’s choice of [therapy]. T-DM1 achieved a significant improvement in PFS, and the effect was clear and consistent across subgroups. These data affirm the results of EMILIA, demonstrating a consistent PFS benefit of T-DM1 in patients with previously treated HER2-positive advanced breast cancer. T-DM1 should become the new standard of care [in this setting],” Wildiers said.

T-DM1 is an antibody-drug conjugate linking trastuzumab to the potent cytotoxic agent DM1. Once the drug binds to the HER2 receptor, the cytotoxic chemotherapy is released directly into the cancer cells. T-DM1 is currently FDA-approved for metastatic breast cancer previously treated with a taxane and trastuzumab.

TH3RESA randomized approximately 600 patients with advanced HER2-positive breast cancer previously treated with at least two HER2-directed therapies in a 2:1 ratio to T-DM1 or physician’s choice of treatment. The breakdown of treatments for physician’s choice was HER2-targeted regimens for 83.2% and single-agent chemotherapy for 16.8%. Patients were treated until disease progression, and those progressing in the control arm could cross over to receive T-DM1.

Wildiers presented the final investigator-assessed PFS analysis. Patients treated with T-DM1 had a median PFS of 6.2 months versus 3.3 months in the control arm (hazard ratio = 0.528; 95% CI, 0.422-0.661; P <.0001).

In a preplanned subgroup analysis of PFS, a consistent benefit was observed for T-DM1 versus controls across all subgroups, including age, world region, race, performance status, tumor characteristics, and presence or absence of visceral disease, with nearly a doubling of PFS in the T-DM1-treated group.

The first interim analysis of OS with 105 available events suggested that T-DM1 may turn out to have a survival advantage, although this will not be clear until 2015, when final OS will be reported. Median OS was 14.9 months in the control arm but has not yet been reached in the T-DM1 arm. Wildiers pointed out that the stopping boundary for survival had not been crossed at the time of this analysis.

Adverse events of grade 3 or higher were more frequent in the control arm: 43.5% versus 32.3% in the T-DM1 arm. Adverse events leading to discontinuation of therapy occurred in 10.9% of controls versus 6.7% of the T-DM1 group. The rate of cardiac events was low in both arms: left ventricular ejection fraction (LVEF) <50 was reported in 1.1% and 1.5%, respectively.

Grade 3 or higher adverse events more frequently reported in the control arm included diarrhea (4.3% vs 0.7% in the T-DM1 arm), neutropenia (15.8% vs 2.5%), and febrile neutropenia (3.8% vs 0.2%), while grade 3 or higher thrombocytopenia was more frequent in the T-DM1 arm: 4.7% versus 1.6% in controls.

“In clinical practice, with the present data, it is clear that after first-line trastuzumab and a taxane, T-DM1 is better with more consistent safety than currently used drugs. This drug should be used as second-line therapy. Results from a phase III trial where T-DM1 is used [in the] first-line in this setting are expected next year,” Wildiers said.

The next research question is whether there is a benefit of treating patients with T-DM1 beyond disease progression, he added.

Wildiers H, Kim SB, Gonzalez-Martin A, et al. T-DM1 for HER2-positive metastatic breast cancer (MBC): primary results from TH3RESA, a phase 3 study of T-DM1 vs treatment of physician’s choice. Presented at: European Cancer Congress 2013; September 27-October 1, 2013; Amsterdam, The Netherlands. Abstract LBA15.

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