T-DM1 demonstrates overall survival benefit in metastatic breast cancer: Next target, FDA approval

In news that is bound to excite breast cancer patients and investors, Genentech/Roche/Immunogen issued press releases on August 26, 2012, confirming that their drug-of-the-moment T-DM1 (trastuzumab emtansine) offers a “significant” overall survival increase to patients with metastatic breast cancer compared to the combination of GSK’s Tykerb (lapatinib) and Roche/Genentech’s Xeloda (capecitabine).

This is the latest data from the 991-person, randomized, open-label Phase III EMILIA study, which compared the efficacy of T-DM1 to the Tykerb/Xeloda combination in patients with HER2-positive locally advanced or metastatic breast cancer previously treated with Herceptin and chemotherapy. While a trend suggesting an overall survival (OS) increase as well as clear improvement in progression-free survival (PFS) was presented at the 2012 annual meeting of the American Society of Clinical Oncology, this definitive OS benefit will greatly facilitate T-DM1’s regulatory approval. PFS and OS were the co-primary endpoints of the EMILIA trial, both of which now have been met. The companies have not revealed the extent of the OS increase, only that it was “significant”, meaning that the improvement exceeded a pre-specified boundary. Following the results of this analysis, EMILIA patients taking Tykerb/Xeloda will be offered the option to switch to T-DM1, and the companies are planning to initiate an Expanded Access Program in the US so that certain patients in dire need can have access to the drug.

T-DM1 is a next generation antibody-drug conjugate (ADC) that has garnered ample media attention over the last year. The basic concept of an ADC is to use an antibody that binds to a cancer-specific marker to deliver a cytotoxic agent directly to cancer cells. By targeting the toxic compounds specifically to the cancerous cells, lower doses can be used, and the overall safety profile of a cytotoxic drug will theoretically improve compared to non-targeted therapy. T-DM1 adds another benefit, as the cytotoxic compound, Immunogen’s DM-1, is linked with the company’s Targeted Antibody Payload technology (TAP) to Roche/Genentech’s blockbuster therapeutic antibody Herceptin (trastuzumab). Herceptin not only targets DM1 to HER2-positive breast cancer cells, but acts as a targeted anti-cancer agent in its own right by blocking HER2 signaling and mediating the immune system’s clearance of HER2-positive cells. Therefore T-DM1 should be more effective and better tolerated than first generation ADCs, and this positive OS data is proof of concept, representing a major advance in targeted drug development.

Genentech announced that it has filed a Biologics License Application (BLA) to the FDA in the US, and Roche is planning to submit a Marketing Authorization Application to the European Medicines Agency in the near future. The companies’ first attempt at gaining regulatory approval fell flat in 2010, when the FDA refused to file Roche’s application for accelerated approval of T-DM1. The initial application was based on results from a single-arm Phase II study showing that the drug shrank tumors in women with advanced HER2-positive breast cancer. With T-DM1 now demonstrating both OS and PFS benefits, as well as a more tolerable safety profile compared to Tykerb/Xeloda, the drug is expected to breeze through the approval process. US approval could come as early as Q2 2013, although EMA approval is unlikely before Q4 2013.

The companies will initially seek approval of T-DM1 as a treatment for patients with metastatic breast cancer who have previously been treated with multiple lines of therapy, but that is only the beginning of the companies’ plan for the drug. The Phase III MARIANNE trial has completed enrollment, and is intended to provide data to support the regulatory filing of T-DM1 as a first-line treatment for HER2-positive metastatic breast cancer. Additionally, the companies are exploring the benefits of T-DM1 in combination with Roche/Genentech’s Perjeta (pertuzumab) in patients with HER2-positive locally advanced or metastatic breast cancer. Roche and Genentech hope that eventually T-DM1 will infiltrate the early stage HER2-positive breast cancer treatment algorithm, as the majority of patients are diagnosed with localized disease. In June, Roche announced plans to initiate three more T-DM1 trials in patients with early disease, evaluating the drug for neoadjuvant use, adjuvant use, and to treat recurrent disease following surgery within this patient segment.

If all goes as planned, T-DM1 should be able to replace Herceptin in the majority of breast cancer patient segments in which Herceptin is currently used. Given the potential breadth of use, the high prevalence of breast cancer and the fact that T-DM1 (similarly to Perjeta) will be priced at a premium to Herceptin, T-DM1 undoubtedly has blockbuster potential. This is good news for Roche/Genentech, as their top-selling product Herceptin, with sales grossing over $3 billion in 2012 H1, will be facing generic competition following patent expiry in 2015. Immunogen also stands to reap rewards from T-DM1’s success, as the company will collect mid-single-digit royalties on the sales. This will help fund the clinical development of IMGN901, Immunogen’s lead wholly-owned compound, for the first-line treatment of small-cell lung cancer and for relapsed multiple myeloma.

*T-DM1 Demonstrates Overall Survival Benefit in Metastatic Breast Cancer: Next Target, FDA Approval