Roche/Genentech’s blockbuster antibody Trastuzumab (Herceptin) received FDA approval in 1998 to treat patients with HER2-positive metastatic breast cancer. Subsequently, additional approvals were obtained for HER2-positive early breast cancer and HER2-positive metastatic gastric cancer. The patent on Herceptin is expiring in Europe in 2015 and several companies are jumping on the bandwagon to develop biosimilars. In addition, dozens of companies are developing anticancer agents that target HER2 overexpressing tumors. At SMS-oncology we recently assessed the competitive landscape and identified a stunning 46 HER2 targeting compounds that are currently in development. The majority of compounds are monoclonal antibodies, kinase inhibitors and therapeutic vaccines.
Of course Roche/Genentech is developing follow-on products to protect their market share. One of those products is the humanized monoclonal antibody Pertuzumab (Perjeta), which is designed to bind HER2 and inhibit receptor dimerization between HER2 and other HER receptors (EGFR/HER1, HER3 and HER4). Preventing dimerization may inhibit cancer cell growth or lead to cancer cell death. In addition, Perjeta binding to HER2 cancer cells may activate the immune system to destroy HER2-positive cells. Interestingly, Perjeta binds HER2 at a different epitope than Herceptin and therefore it was speculated that these antibodies could work complementarily. This was proven in the international, Phase III, randomized, double-blind, placebo-controlled pivotal study named CLEOPATRA. In this study the efficacy and safety of Perjeta + Herceptin + Docetaxel (Taxotere) was compared to Placebo + Herceptin + Taxotere in previously untreated HER2-positive metastatic breast cancer patients. The Perjeta arm demonstrated a 6.1 month improvement in progression free survival (PFS) as well as an encouraging overall survival trend in the interim analysis. Based on a favourable risk-benefit profile, the FDA under priority review approved Perjeta when added to Herceptin and Taxotere as front-line therapy for HER2-postive metastatic breast cancer on June 8th 2012. A few days later Dako received approval for its HercepTest and HER2 FISH pharmDx as companion diagnostics for Perjeta. Studies with Perjeta in early breast cancer and metastatic gastric cancer are ongoing.
In addition, Roche/Genentech in collaboration with Immunogen is focusing on T-DM1, an antibody-drug conjugate consisting of Herceptin linked to the cytotoxin mertansine (DM1). T-DM1 is currently being evaluated in three Phase III trials. At the recent ASCO meeting, primary results from the lead trial EMILIA were shown. In this study T-DM1 was compared with the combination capecitabine (Xeloda) and Lapatinib (Tykerb) in Herceptin-refractory HER2-positive metastatic breast cancer. A significant improvement in PFS was seen for the T-DM1 arm (9.6 months vs 6.4 months). Roche/Genentech plans to apply for marketing approval of T-DM1 in the US and Europe in 2012.
Roche/Genentech is the heavy hitter in the HER2 field and has with Perjeta and T-DM1 two promising compounds in its hands. It will be interesting to see how the HER2 field will develop in the near future and what other compounds will receive approval in this field.