Nature Medicine | Spoonful of Medicine

Antibody–drug combo approved for fighting breast cancer

Drug regulators in the US have already approved a handful of treatments for women with HER2-positive breast cancer, an aggressive form of the disease in which a cell surface protein known as human epidermal growth factor receptor type 2, or HER2, is elevated. Although most patients with this type of cancer respond well to at least one of the existing anti-HER2 therapies, some individuals with HER2-positive breast tumors develop drug resistance and remain unresponsive to further treatment. For these women, a new drug combination approved earlier today offers hope.

The therapy—known as trastuzumab–DM1, or T–DM1, and marketed under the brand name Kadcyla by Genentech, a US subsidiary of the Swiss drug giant Roche—is a so-called ‘antibody–drug conjugate’ (ADC) that couples Genentech’s blockbuster antibody Herceptin (trastuzumab) to the cytotoxic agent DM1. In a pivotal 1000-person, phase 3 trial, participants treated with Kadcyla had a median overall survival of 31 months compared to 25 months in women given a tyrosine kinase inhibitor that interrupts HER2 and chemotherapy. Fewer women in the T-DM1 treatment arm also experienced severe side effects, although the newly-approved treatment was found to cause liver toxicity, heart toxicity and severe life-threatening birth defects in some patients.

“Kadcyla is the first ADC to result from Genentech’s 30 years of HER2 pathway research and decade of ADC research,” Dietmar Berger, head of clinical oncology at the company, told Nature Medicine. And it looks like all these years of research have paid off for Genentech: the South San Francisco, California–based firm announced this week that it will be hiring 600 more researchers to continue the work on more than 25 ADCs in the Genentech pipeline, including eight currently in human clinical development.

The idea of linking a toxin to an antibody to target cancer has been around for at least 30 years. However, several factors impeded the success of ADCs in the clinic. For example, in 2000 the US Food and Drug Administration approved the first ADC therapy for the treatment of patients with acute myeloid leukemia. The drug was called gemtuzumab ozogamicin, marketed under the name Mylotarg, and consisted of a humanized monoclonal antibody specific for the receptor protein CD33 conjugated to the cytotoxic drug calicheamicin. However, in June 2010 Myotarg’s manufacturer, New York–based Pfizer, voluntarily withdrew the product from the market after follow-up studies showed that Myotarg treatment did not yield improved survival rates and actually demonstrated worse toxicity than other standards of care. The problem, it turned out, was that the toxic drug did not have a very high specificity and would often dissociate from the antibody in the plasma.

The success of Kadcyla can be attributed to the next generation of technology that provides better linking as well as development of more specific and discriminate cytotoxin drugs, according to Daniel Junius, president and chief executive of Immunogen, a Waltham, Massachusetts–based company and one of Genentech’s partners behind the therapy. “This technology develops a highly potent agent that’s 100- to 1000-times more potent than traditional chemotherapeutics,” he says. As “a highly effective therapy without the toxicity that is so common to many cancer therapies today,” this approval should inspire a whole new generation of ADCs, Junius adds.

Image: Shutterstock

Correction (26 February): An earlier version of this story incorrectly stated that trial participants in the arm treated with Kadcyla had a median overall survival of 40 months compared to 20 months in the arm treated with tyrosine kinase inhibitor and chemotherapy when in fact Kadcyla treated group had a median survival of 31 months compared to 25 months in the other group. Nature Medicine regrets the error, which has been corrected.

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