Results of the phase III TH3RESA trial show that the antibody-conjugate ado-trastuzumab emtansine (Kadcyla), formerly known as T-DM1, extends progression-free survival in women with advanced HER2-positive breast cancer that progressed on two or more previous HER2-directed therapies including trastuzumab (Herceptin) and lapatinib (Tykerb). The findings were presented at the European Cancer Congress 2013 in Amsterdam.¹

Building on EMILIA Trial

These results build on those of the EMILIA trial, which showed that ado-trastuzumab emtansine extended progression-free survival compared with capecitabine/lapatinib in HER2-positive advanced breast cancer in women previously treated with trastuzumab and a taxane. Patients in TH3RESA were more heavily pretreated than those in EMILIA.

“In TH3RESA, [ado-trastuzumab emtansine] demonstrated improved safety and efficacy compared with the physician’s choice of chemotherapy. [Ado-trastuzumab emtansine] achieved a significant improvement in progression-free survival, and the effect was clear and consistent across subgroups. These data affirm the results of EMILIA, demonstrating a consistent progression-free survival benefit of [ado-trastuzumab emtansine] in patients with previously treated HER2-positive advanced breast cancer,” said the lead author of the late-breaking presentation, Hans Wildiers, MD, PhD, of University Hospitals Leuven in Leuven, Belgium. He added that ado-trastuzumab emtansine should become the new standard of care for second-line treatment.

“Once HER2-positive breast cancer recurs and metastasizes, there are few treatment options that show any clear benefit for women who have probably undergone several previous treatments for the disease. These results confirm and extend the usefulness of [ado-trastuzumab emtansine] for the treatment of women with advanced HER2-positive disease. This is good news for these women,” said Cornelis van de Velde, MD, current President of the European Cancer Organization (ECCO) and moderator of a press conference where these findings were discussed.

Ado-trastuzumab emtansine is an antibody-drug conjugate currently FDA-approved for metastatic breast cancer previously treated with a taxane and trastuzumab.

TH3RESA Trial

The study included 602 patients with advanced breast cancer previously treated with at least two previous HER2-directed therapies. Patients were randomly assigned in a 2:1 ratio to ado-trastuzumab emtansine or physician’s choice of chemotherapy (83% received trastuzumab-based regimens and 17% received chemotherapy). Treatment was continued until disease progression, when patients could remain on or cross over to ado-trastuzumab emtansine.

Final progression-free survival results were as follows: median progression-free survival of 6.2 months for the ado-trastuzumab emtansine–treated group vs 3.3 months in the control arm, a highly significant difference in favor of ado-trastuzumab emtansine, nearly doubling progression-free survival compared with controls (P < .0001). Dr. Wildiers said this difference was both statistically and clinically significant.

A subgroup analysis showed a consistent near-doubling of progression-free survival with ado-trastuzumab emtansine regardless of age, geographic area, race, performance status, tumor characteristics, and visceral disease.

The first interim analysis of overall survival showed median survival of 14.9 months in the control arm; median overall survival was not yet reached in the ado-trastuzumab emtansine arm at the time of analysis. Although this suggests that there may be a survival advantage for ado-trastuzumab emtansine, long-term confirmation is needed. Final survival results are expected in 2015.

Reassuring Safety Profile

The safety of ado-trastuzumab emtansine was reassuring and similar to what was reported in the EMILIA trial. Adverse events of grade 3 or higher were more frequent in the control arm: 43.5% vs 32.3% in the ado-trastuzumab emtansine arm. Adverse events of any grade were reported by 94% of those who received ado-trastuzumab emtansine vs 89% in the control arm.

Adverse events leading to discontinuation of therapy occurred in 6.7% of the ado-trastuzumab emtansine group vs 10.9% of controls. The rate of cardiac events was low in both arms: left-ventricular ejection fraction < 50 was reported in 1.5% and 1.1%, respectively. Lower rates of diarrhea, neutropenia, and febrile neutropenia were reported in the ado-trastuzumab emtansine arm, but a slight increase was observed in severe thrombocytopenia (4.4% vs 1.8%, respectively) and hemorrhage (2.2% vs 0.5%).

According to Dr. Wildiers, an ongoing phase III trial is evaluating use of ado-trastuzumab emtansine as first-line therapy in advanced HER2-positive breast cancer, and results are expected next year. The benefit of treatment with ado-trastuzumab emtansine after disease progression will also be studied. ■

Disclosure: Dr. Wildiers has received lecture fees from Roche. Dr. van de Velde reported no potential conflicts of interest.

Reference

1. Wildiers H, Kim SB, Gonzalez-Martin A, et al: T-DM1 for HER2-positive metastatic breast cancer. 2013 European Cancer Congress. Abstract 15. Presented September 28, 2013.