T-DM1 APPROVED BY FDA

The US Food and Drug Administration (FDA) today approved ado-trastuzumab emtansine (Kadcyla, Genentech), also known as T-DM1, for the treatment of patients with HER2-positive metastatic breast cancer.

T-DM1 is indicated for patients who were previously treated with the anti-HER2 therapy trastuzumab (Herceptin, Genentech) and a taxane chemotherapy.

This product offers a new twist on an older product; it is an antibody–drug conjugate in which the HER2-targeted antibody trastuzumab is chemically linked to the cytotoxin mertansine (DM1). The antibody homes in on HER2 breast cancer cells, delivering the chemotherapy directly to the tumor, which reduces the risk for toxicity.

T-DM1 "delivers the drug to the cancer site to shrink the tumor, slow disease progression, and prolong survival," said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products at the FDA Center for Drug Evaluation and Research, in a press statement. "It is the fourth approved drug that targets the HER2 protein."

In the pivotal phase 3 EMILIA study, patients receiving T-DM1 survived nearly 6 months longer than patients receiving the standard therapy of lapatinib (Tykerb) plus capecitabine (Xeloda) (median overall survival, 30.9 vs 25.1 months). Also, there were fewer grade 3 or higher (severe) adverse events with TDM-1 than with standard therapy (43.1% vs. 59.2%), according to the company.

The approval represents a "momentous" day in breast cancer, said Kathy Miller, MD, from Indiana University in Indianapolis, in her Miller on Oncology Medscape blog.

"Our HER2-positive patients with metastatic disease have another very powerful therapy that offers the real hope for prolonged disease control with less toxicity," she said.

"This is the classic light-beer scenario; it's less filling and tastes great," she summarized, adding that T-DM1 was more effective in EMILIA than standard therapy on every outcome: overall response rate, disease-free survival, progression-free survival, and overall survival.

However, another expert sees T-DM1 in a less dramatic light.

Steve Vogl, MD, a private practitioner and former academic who practices in the Bronx, New York, called T-DM1 a "nice" drug when he discussed the product in an online essay last year.

T-DM1 causes "no alopecia, little neutropenia, and only moderate thrombocytopenia. It requires only a short infusion every 3 weeks, lacks cumulative toxicity, and has a response rate as first-line chemotherapy that is about the same as that of docetaxel and trastuzumab, with apparently longer remissions," he wrote.

However, Dr. Vogl called the EMILIA control regimen (lapatinib and capecitabine) "distinctly suboptimal" and not a standard of care, even though it is an FDA-approved treatment option in this setting.

"TDM-1 does not meet [the] goals of a major advance," wrote Dr. Vogl, who explained that such an advance must cure some patients, increase the rate of clinical complete remission, or produce a high rate of very long partial response.

TDM-1 does not provide a "major change in prognosis" for women with metastatic disease who have progressed on trastuzumab treatment, he wrote, adding that it is likely to be "very expensive."

Study Data and Boxed Warning

The international open-label EMILIA study involved 991 patients with HER2-positive locally advanced breast cancer or metastatic breast cancer who had previously been treated with trastuzumab and a taxane chemotherapy. The study met the coprimary efficacy end points of overall survival and progression-free survival (assessed by an independent review committee).

Median progression-free survival was longer with TDM-1 than with lapatinib plus capecitabine (9.6 vs 6.4 months). In addition, patients treated with TDM-1 lived significantly longer without their disease getting worse (hazard ratio [HR], 0.65; reduction in risk of disease worsening or death, 35%; P < .0001).

The risk of dying was 32% lower with TDM-1 than with lapatinib and capecitabine (HR, 0.68; P = .0006).

For patients receiving TDM-1, the most common adverse events (occurring in more than 2% of participants) of grade 3 or higher were low platelet count (14.5%), increased levels of enzymes released by the liver and other organs (8%), low red blood cell count (4.1%), low levels of potassium in the blood (2.7%), nerve problems (2.2%), and tiredness (2.5%).

T-DM1 was reviewed under the FDA's priority review program, which provides for an expedited 6-month review of drugs that might provide safe and effective therapy when no satisfactory alternative exists, or that offer significant improvement over comparable products on the market.

T-DM1 is being approved with a boxed warning that alerts patients and healthcare professionals that the drug can cause liver toxicity, heart toxicity, and death. The drug can also cause severe life-threatening birth defects, so pregnancy status should be verified prior to starting T-DM1 treatment.

Dr. Vogl has disclosed no relevant financial relationships. Dr. Miller reports financial ties with Genentech, Bristol-Myers Squibb, AstraZeneca, Roche, and Clovis Oncology.