The highly anticipated US Food and Drug Administration's approval on June 8 of Perjeta (pertuzumab) for metastatic HER2/neu-overexpressing breast cancer provides additional benefit to a patient population who, before the advent of the first HER2-directed therapy in 1998, generally had a poor prognosis. The agency approved Genentech's monoclonal antibody to be used in combination with Herceptin (trastuzumab) and Taxotere (docetaxel). Perjeta is a HER-dimerization inhibitor that hits a different epitope on the HER2 receptor than that targeted by Herceptin, and the combination of the two has an additive effect. In the phase 3 Cleopatra trial that led to the approval, women who received the Perjeta-Herceptin-Taxotere combination achieved a 6.1-month improvement in progression-free survival (PFS) over those in the control group receiving Herceptin and Taxotere plus placebo. (In absolute terms, those in the treatment arm attained a median PFS of 18.5 months versus 12.4 months for those in the placebo group.) Overall survival data are expected in 2013, but the PFS data were sufficiently strong to convince the FDA of the drug's efficacy, despite agency concerns that manufacturing problems at the S. San Francisco–based Genentech could limit its initial availability. Perjeta is still undergoing regulatory review in Europe. A subsidiary of Basel-based Roche, Genentech, which developed the two drugs, also recently reported that T-DM1 (trastuzumab emtansine) led to better PFS than a combination of the HER2 signal inhibitor Tykerb (lapatinib) plus Xeloda (capecitabine) in a pivotal phase 3 trial in metastatic breast cancer patients who had relapsed on Herceptin. “You're now getting multiple ways of targeting one key oncogene,” says Susan Cleator, an oncologist at Imperial College NHS Healthcare Trust London. “Pertuzumab and the other drugs that are coming after it are opening up the possibility of treating HER2+ breast cancer with biologic therapy alone, without chemotherapy.” Such an approach could alleviate the long-term toxicity risks associated with chemotherapy, which include secondary malignancies and impairments of cardiac and ovarian function. Figuring out the optimal treatment regimens for different categories of HER2+ breast cancer patients may be hampered, however, by a lack of biomarkers and by the very success of the drugs themselves. “Because we're currently curing so many people, the event rate is lower than it's ever been,” says Justin Stebbing, professor of cancer medicine and oncology at Imperial College.