FDA denies accelerated approval of Genentech's trastuzumab-DM1 (T-DM1) BLA for metastatic breast cancer

Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced the U.S. Food and Drug Administration (FDA) issued a Refuse to File letter for accelerated approval for the company's trastuzumab-DM1 (T-DM1) Biologics License Application (BLA). As planned, Genentech will continue with its ongoing Phase III registrational T-DM1 trial, EMILIA. Genentech will continue to work with the FDA and expects to submit a new T-DM1 BLA in mid-2012.

“We firmly believe in the potential of T-DM1 as a novel HER2-targeted option and remain fully committed to its ongoing development”

The BLA submitted in July 2010 requested accelerated approval for T-DM1 based on the results of a single-arm Phase II study, which showed T-DM1 shrank tumors in one-third of women with advanced HER2-positive breast cancer, who had received on average seven prior medicines, including two HER2-targeted medicines.

Consideration by the FDA for accelerated approval requires recognition of a defined patient population of unmet need (a life-threatening disease with limited treatment choices), for whom a medicine's early safety and efficacy data are reasonably likely to predict clinical benefit. Following the pre-submission meeting with the FDA in March 2010, Genentech concluded it was appropriate to submit a BLA for accelerated approval. In its review of the BLA, the FDA stated the T-DM1 trials did not meet the standard for accelerated approval because all available treatment choices approved for metastatic breast cancer, regardless of HER2 status, had not been exhausted in the study population.

"We firmly believe in the potential of T-DM1 as a novel HER2-targeted option and remain fully committed to its ongoing development," said Hal Barron, M.D., executive vice president, Product Development and chief medical officer.

Genentech will submit data from the amended Phase III randomized EMILIA study to the FDA to support a new T-DM1 BLA in mid-2012. The EMILIA study compares T-DM1 to lapatinib in combination with capecitabine in people with advanced HER2-positive breast cancer whose disease has worsened after receiving initial treatment.

About T-DM1

T-DM1 is an antibody-drug conjugate (ADC), also known as an armed antibody, being studied for advanced HER2-positive breast cancer. T-DM1 attaches trastuzumab and the chemotherapy DM1 together using a stable linker, which is designed to keep T-DM1 in one piece until it reaches specific cancer cells. The antibody (trastuzumab) binds to the HER2-positive cancer cells, and is thought to block out-of-control signals that make the cancer grow while also calling on the body's immune system to attack the cells. Then, once T-DM1 is absorbed into those cancer cells, it is designed to destroy them by releasing the DM1. Genentech licenses technology for T-DM1 under an agreement with ImmunoGen, Inc.

About Studies of T-DM1 and other HER2-Targeted Medicines

The FDA submission was based on a Phase II study known as TDM4374g, a single-arm, multi-center trial designed to assess single-agent T-DM1 in 110 women with advanced HER2-positive breast cancer whose disease had worsened after receiving at least two prior HER2-targeted treatments (Herceptin^® [trastuzumab] and lapatinib) in the metastatic setting, as well as an anthracycline, a taxane and capecitabine. The primary endpoint of the study was objective response rate (a complete or partial tumor shrinkage of at least 30 percent, determined by two tumor assessments at least 28 days apart), as measured by an independent review facility.

Results from the study were presented at the 2009 San Antonio Breast Cancer Symposium and demonstrated that T-DM1 shrank tumors in 33 percent of women with advanced HER2-positive breast cancer that had worsened following treatment with an average of seven prior medicines for metastatic disease. In the study, most side effects were mild (Grade 1-2) and similar to those observed in previous clinical trials of T-DM1. The most common adverse events of any grade were fatigue (62 percent) and nausea (37 percent). The most common severe adverse events (Grade 3 or higher) were a low level of platelets in the blood (7 percent), fatigue (5 percent) and cellulitis (4 percent). No severe cardiac-specific side effects were observed. One patient with pre-existing, non-alcoholic fatty liver disease died with liver failure. The safety results were consistent with data from earlier studies, including a proof-of-concept Phase II study (TDM4258g), which also was included in the submission to the FDA.

Several other Phase II and III trials of T-DM1 and other HER2-targeted medicines are ongoing, including:

• Preliminary results from a randomized Phase II study (TDM4450g) comparing T-DM1 to Herceptin in combination with docetaxel chemotherapy in people who have not been previously treated for advanced HER2-positive breast cancer have been accepted for presentation at the European Society of Medical Oncology (ESMO) congress in Milan (Italy) in October 2010.
• An ongoing Phase III study, MARIANNE, is comparing both T-DM1 alone, and T-DM1 in combination with pertuzumab, to Herceptin in combination with a taxane chemotherapy in people with advanced HER2-positive breast cancer who have not been previously treated for advanced disease.
• CLEOPATRA is a pivotal registrational trial with pertuzumab in combination with Herceptin and docetaxel in first-line, HER2-positive metastatic breast cancer. Submission timelines remain unchanged; Genentech expects a U.S. regulatory submission of pertuzumab based on the CLEOPATRA study at the end of 2011.

Pertuzumab, a humanized monoclonal antibody, represents the first in a new class of investigational medicines known as HER (human epidermal growth factor receptor) dimerization inhibitors (HDIs). Pertuzumab is designed to bind to the HER2 receptor — a protein found on the surface of epithelial cells — and inhibit the ability of HER2 to interact with other HER family members (HER1/EGFR, HER2, HER3 and HER4). HER dimerization (receptor pairing) is believed to play an important role in the growth and formation of several different cancer types. Pertuzumab binds to a different part of the HER2 receptor than other approved products, known as the dimerization domain.