Earlier today the U.S. Food and Drug Administration (FDA) issued a Refuse to File letter for accelerated approval for the Roche’s trastuzumab-DM1 (T-DM1) Biologics License Application (BLA). However, as planned, Roche will continue with its ongoing Phase III EMILIA registration study. Furthermore, Roche will continue to work with the FDA and expects a global regulatory submission of T-DM1 mid 2012.

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, a subsidiary of Roche, licenses technology for T-DM1 under an agreement with ImmunoGen, Inc.

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 agents.

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Defined patient population
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, Roche concluded it was appropriate to submit a BLA for accelerated approval. In their review of the BLA, 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., Head of Global Development and Chief Medical Officer for Roche. The company will submit the data from the amended Phase III randomized EMILIA study to support a global regulatory submission 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.

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 HER2 positive advanced breast cancer whose disease had worsened after receiving at least two prior HER2 targeted treatments (Herceptin 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.

Prior medication for metastatic disease
Results from the study were presented at the 2009 San Antonio Breast Cancer Symposium (SABCS) and demonstrated that T-DM1 shrank tumors in 33% 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%) and nausea (37%).

The most common severe adverse events (Grade 3 or higher) were a low level of platelets in the blood (7%), fatigue (5 percent) and cellulitis (4%). 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:

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