T-DM1 Achieves Longer Progression-Free Survival vs. Standard Therapy in HER2+ Metastatic Breast Cancer

STOCKHOLM, SWEDEN —Treatment with a novel conjugate antibody/chemotherapy drug called T-DM1 extended progression-free survival (PFS) in HER2-positive metastatic breast cancer compared with standard docetaxel/trastuzumab therapy in the first randomized trial of T-DM1, and T-DM1 was far less toxic than standard treatment.

“Our study showed that women with metastatic breast cancer who received T-DM1 had a 41% improvement in the time they lived without their breast cancer worsening compared with those who received standard docetaxel chemotherapy plus trastuzumab. These provocative phase II data illustrate that front-line treatment with T-DM1 provides a longer time to live without cancer progression with fewer side effects than standard chemotherapy plus trastuzumab,” said Sara Hurvitz, MD, Director of the Breast Oncology Program at the University of California Los Angeles (UCLA).

About 20% of all breast cancers are HER2-positive, which is more aggressive and difficult to treat than other types of breast cancer. Trastuzumab plus docetaxel is considered standard treatment for metastatic HER2-positive breast cancer, but this therapy has some severe side effects, including neutropenia and alopecia.

T-DM1 is designed to deliver targeted therapy with trastuzumab along with chemotherapy but has an improved tolerability profile compared with standard chemotherapy. T-DM1 links trastuzumab to extremely cytotoxic chemotherapy called emtansine (DM1) through a stable linker. To give some idea of the cytotoxicity of emtasine, this chemotherapy is 100 times more potent than vinorelbine.

“The magic in T-DM1 is the linker,” Hurvitz said. “With the antibody/chemotherapy conjugate, trastuzumab attaches to HER2-positive cells; this triggers release of the lethal chemotherapy component.”

“I tell my patients that trastuzumab is the bullet, but DM1 is the gun,” Hurvitz explained at an official press conference during the 2011 European Multidisciplinary Cancer Congress (ESMO/ECCO/ESTRO).

The randomized, open-label phase II study enrolled 137 patients with no prior chemotherapy or HER2-targeted therapy for locally advanced or metastatic HER2-positive breast cancer. Patients were randomly assigned to treatment with either T-DM1 or standard therapy with trastuzumab plus docetaxel.

Median progression-free survival (PFS) was 5 months longer with T-DM1: 14.2 months in the T-DM1 arm versus 9.2 months in the standard treatment arm (P=.0353). “This represents a 40% relative reduction in the risk of disease progression,” Hurvitz told listeners.

Interestingly, no significant differences in objective response rate (58% for controls versus 64% for T-DM1) or in clinical benefit (complete response plus partial response plus stable disease, 81% for controls versus 75% for T-DM1) were observed between the two arms. However, a major difference was seen favoring T-DM1 for the duration of maintaining response: median of 9.5 months for controls and median duration of response not yet reached in the T-DM1 arm.

Patients were treated with T-DM1 for a median of 10 months versus 5.5 months with standard chemotherapy. Hurvitz said one of the reasons for this difference in the ability to stay on therapy could be attributed to more severe toxicity in the standard chemotherapy arm.

Grade 3 or higher adverse events were reported in 89% of those treated with standard chemotherapy versus 32% in the T-DM1 arm. Grade 3 or 4 neutropenia was observed in 61% of the standard chemotherapy arm versus 5.8% with T-DM1. Alopecia, a troubling side effect for women, occurred in 67% of the standard chemotherapy arm versus 4.3 in the T-DM1 arm.

Three different phase III studies of T-DM1 in HER2-positive metastatic breast cancer are now under way, Hurvitz said. The EMILIA study will compare T-DM1 versus lapatinib plus capecitabine in 980 patients; the MARIANNE study will compare docetaxel/trastuzumab versus T-DM1 versus T-DM1 plus pertuzumab; and the TH3RESA study is comparing T-DM1 versus best supportive care in the salvage setting.

At the press conference, Jean-Charles Soria, MD, Scientific Cochair for ESMO, Professor at the Institut Gustave-Roissy, Villejuif, France, said that Genentech has at least 12 antibody/conjugate molecules in development. “This is an exciting concept,” he noted.

ESMO member Angelo DiLeo, MD, Istituto Toscano Tumori, Italy, said: “These promising data do not yet allow us to consider T-DM1 as a new standard of care for first-line treatment of HER2-positive metastatic breast cancer. We eagerly await results of ongoing phase III trials.”

Martine Piccart, MD, Jules Bordet Institut, Brussels, Belgium, who was formal discussant of this trial, commented as follows: “I believe this is a magic drug, a clever drug, and the drug we’ve been waiting for… But we still need validation of these findings in a large randomized trial, and we need to identify markers for response. If the phase III trials are positive, T-DM1 will be available to patients in the not-too-distant future.