Results of a Phase II study of trastuzumab (Herceptin®, Genentech) in combination with DM1 (T-DM1), an investigational HER2 antibody-drug conjugate being developed by Genentech, in collaboration with Roche and Immunogen, Inc., shows encouraging results in women with highly advanced HER2-positive breast cancer.

Positive Phase I and Phase II findings were first reported at the 2007 [1] and 2008 [2], respectively, annual meetings of the American Society of Clinical Oncology (ASCO) with T-DM1 in patients with HER2-positive (HER2+) metastatic breast cancer (MBC) that progressed on treatment with trastuzumab. In the Phase II study, 60% of patients also had been treated with lapatinib (Tykerb®, GlaxoSmithKline).

As assessed by independent review, the T-DM1 combination shrank the tumors (also known as objective response) in 33% of women with advanced (metastatic) HER2-positive breast cancer that had worsened following previous treatment. Women in the study had already received an average of seven drugs for metastatic disease, including chemotherapy, trastuzumab and lapatinib, prior to receiving T-DM1. No new or unexpected safety signals were observed. The results were presented today at the 32nd Annual CTRC-AACR San Antonio Breast Cancer Symposium (SABCS) from 9 to 13 December 2009 (Abstract #710). [3]

Antibody-drug conjugates or ADCs [4] are a unique combination of a precise and targeted monoclonal antibody, a stable linker, and a potent cytotoxic. They have broad utility in basic, preclinical, and clinical applications. [5] T-DM1 combines two approaches in one medicine: the anti-cancer activity of the trastuzumab antibody, which blocks signals that make the cancer more aggressive and signals the body’s immune system to destroy the cancerous cells, and the targeted delivery of the potent cytotoxic DM1.

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“Breast cancer is the most common cancer among women worldwide with more than one million new cases diagnosed every year and nearly 400,000 deaths, so it is vital that we continue to provide more treatment options” said William M. Burns, CEO of Roche Pharma.

According to the American Cancer Society [6], breast cancer is the second leading cause of cancer death in the United States. Women diagnosed with advanced (metastatic) disease have a poor prognosis and only 27% survive five years.

Approximately 15 to 30% of breast cancers are HER2-positive. [7] When HER2-positive breast cancer is advanced, the disease has spread to other parts of the body, most commonly to the lungs, bones, liver and brain. At this stage of the disease, the current goals of existing treatments include symptom relief, tumor shrinkage, improved quality of life and increasing the amount of time women with advanced breast cancer live without the cancer worsening. There are no treatment guidelines or FDA-approved treatment options for women with advanced HER2-positive breast cancer if the disease progresses following treatment with trastuzumab and lapatinib.

“The much anticipated data on the investigational drug T-DM1 will be welcomed by physicians treating women with early and very advanced stages of breast cancer as it will offer them more choices for fighting this devastating disease,” Burns noted.

“Despite major advances in HER2-positive breast cancer, the disease may still progress after multiple treatments, to the point where there are no approved HER2-targeted medicines,” said Hal Barron, M.D., executive vice president, Global Development and chief medical officer, Genentech. “Results from this study are promising for women who need new treatment options, and we will discuss next steps of the T-DM1 development program with the FDA.”

“These results are significant because they demonstrate that T-DM1 was effective at shrinking tumors in women whose cancer had progressed following prior treatment with standard therapies for HER2-positive breast cancer,” said Ian Krop, M.D., Ph.D., a medical oncologist at Dana-Farber Cancer Institute, and lead investigator on the study. In this single-arm study, 45% of women experienced a clinical benefit (defined as a complete or partial tumor response, or stable disease, maintained for at least six months), as assessed by independent review. Adverse events were similar to those observed in previous clinical trials of T-DM1. The most common severe adverse events included thrombocytopenia (a low level of platelets in the blood, 5.5%) and back pain (3.6%), and the most common adverse events were fatigue (59.1%) and nausea (37.3%). No severe (Grade 3 or higher) cardiac-specific side effects were observed. One patient with pre-existing, non-alcoholic fatty liver disease died with hepatic failure.

Ongoing clinical trials
The new treatment options is currently in trial in a Phase II study, known as TDM4374g, a single-arm, multi-center trial designed to assess T-DM1 as a single agent in 110 women with HER2-positive advanced breast cancer whose disease had progressed after receiving at least two prior HER2-targeted treatments (trastuzumab and lapatinib) in the metastatic setting, as well as an anthracycline, a taxane, and capecitabine. [8]

The primary endpoint of this study is objective response rate (a complete or partial tumor shrinkage of at least 30%, determined by two tumor assessments at least 28 days apart), as measured by an independent review facility. Secondary endpoints include safety, clinical benefit rate, duration of response and progression-free survival (PFS).
Duration of response and PFS data are not yet mature and will be presented at a future meeting.

The results of the data presented during the SABCS follow on from results from another phase II study (TDM4258) presented at ASCO 2009 which also showed encouraging results in women with advanced HER2-positive breast cancer [9, 10].

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