The combination of the antibody–drug conjugate ado-trastuzumab emtansine, or T-DM1, plus pertuzumab given prior to surgery outperformed standard therapy in women with HER2-positive breast cancer enrolled in the I-SPY 2 trial. The results, reported at the American Association for Cancer Research Annual Meeting 2016, suggest that the drug combination would be successful in a phase III trial, potentially leading to an effective, less toxic treatment option for women at risk for metastatic disease.

The combination of the antibody–drug conjugate ado-trastuzumab emtansine, known as T-DM1 (Kadcyla; Genentech), plus pertuzumab (Perjeta; Roche) given prior to surgery outperformed standard therapy in women with HER2-positive breast cancer enrolled in the phase II I-SPY 2 trial. The data suggest that the combination may be successful in a phase III trial, potentially leading to a more effective, less toxic treatment option for women at risk for metastatic disease. Researchers reported their findings on April 18 at the American Association for Cancer Research Annual Meeting 2016, held in New Orleans, LA.

In the trial, 83 women with HER2-positive invasive breast cancers with any one of three biomarker signatures (HER2-positive; HER2-positive and HR-positive; and HER2-positive and HR-negative) and tumors measuring 2.5 cm or larger were randomly assigned to receive either T-DM1 plus pertuzumab (52 patients) or trastuzumab (Herceptin; Roche) and paclitaxel (31 patients) for 12 weeks. For the subsequent 4 weeks, all patients received combination chemotherapy with doxorubicin and cyclophosphamide, followed by surgery.

Substantially more women in the T-DM1 group (from 46% to 64% for each of the three biomarker signatures) compared with the control group (17% to 33%) reached the primary endpoint of estimated pathologic complete response (pCR)—meaning that no residual tumor was found in the tissue or lymph nodes removed during surgery, said lead investigator Angela DeMichele, MD, professor of medicine and epidemiology at the University of Pennsylvania in Philadelphia. Based on the pCR rate, considered a predictor of long-term benefit, DeMichele's team projected a 90% to 94% probability that T-DM1 plus pertuzumab would be successful in a future confirmatory 300-patient phase III trial.

T-DM1 is already approved for patients with metastatic HER2-positive disease who have been previously treated with trastuzumab and a taxane chemotherapy. These results demonstrate that using the T-DM1–pertuzumab combination before surgery may help patients experience a pCR—and help them avoid the side effects associated with paclitaxel and other chemotherapies.

“With T-DM1, less than 10% of patients in this trial lost their hair, suggesting that many women can get through the entire first half of treatment without having to deal with that particularly bothersome side effect,” said DeMichele. “In addition, the incidence of neuropathy and hypertension was much less frequent in women who took the T-DM1 combination compared with the control group.”

I-SPY 2 is a multicenter, adaptively randomized trial in which multiple experimental drugs are simultaneously tested against a standard comparator arm. Patients are matched to treatments based on the molecular signature of their tumors. Therapies “graduate” to phase III trials when they reach a predetermined threshold of efficacy, based on Bayesian statistical modeling, whereas drugs that do not show likelihood of improved pCR are dropped from the trial. Compared to traditional trials, the design allows researchers to assess therapies more quickly and with smaller groups of patients, said DeMichele.

“What we ultimately want to achieve is to get the greatest proportion of patients to a pCR,” she said. “We know now that we can use trials like I-SPY 2 to do that without using more-toxic chemotherapies.” –Janet Colwell