The adaptive design of the I-SPY 2 trial enables us to study the smallest number of patients needed to reach a result.… This speeds the process of getting results to physicians, pharmaceutical companies, regulators and, most important, patients.
—Angela DeMichele, MD, MSCE
The combination of ado-trastuzumab emtansine (Kadcyla) plus pertuzumab (Perjeta) is a worthy combination to pursue in phase III studies as neoadjuvant therapy for HER2-positive invasive breast cancer, according to findings in the I-SPY 2 trial presented at the 2016 Annual Meeting of the American Association for Cancer Research (AACR).1
The combination achieved a superior pathologic complete response rate compared to the control arm in the I-SPY 2 trial. Pathologic complete response at the time of surgery is considered an excellent surrogate marker for long-term relapse-free survival.
Effective, Less Toxic Strategy
Ado-trastuzumab emtansine is an antibody-drug conjugate that combines the anti-HER2 drug trastuzumab (Herceptin) with a potent chemotherapy that is released directly into the tumor—sparing patients most of the side effects of systemically delivered chemotherapy. Pertuzumab is a HER2-directed therapy that binds the HER2 receptor at a separate site, blocking HER2/HER3 heterodimerization.
“The combination of [ado-trastuzumab emtansine] and pertuzumab graduated from I-SPY 2 in all biomarker signatures tested,” said lead author Angela DeMichele, MD, MSCE, Professor of Medicine and Epidemiology at the Perelman School of Medicine, University of Pennsylvania. “The combination increased pathologic complete response rates by approximately 30% compared with controls. If these results are confirmed in a phase III trial, this could reduce the number of women developing recurrent, metastatic breast cancer without the short- and long-term toxicity of taxane chemotherapy,” she added.
“The study provides us with data that suggest that alternatives to toxic chemotherapy for HER2-positive patients will get us to the pathologic complete response endpoint. We can start to tailor therapy to patients and avoid toxic chemotherapy,” she said.
I-SPY 2 is part of a series of trials with an adaptive randomization design, which aims to identify drugs and/or drug combinations to take to phase III trials with a high likelihood of success. The trial randomly assigns patients to control and experimental arms and continually updates all outcomes. Some drugs and combinations turn out to be “futile” and are terminated according to preset criteria, whereas other arms move forward in the process. A Bayesian analysis is used to determine the likelihood of achieving pathologic complete response, probability of being superior to the control arm, and likelihood of success in a phase III trial.
I-SPY 2 enrolled 248 patients with HER2-positive invasive breast cancer and tumors larger than 2.5 cm. They were randomly assigned to receive paclitaxel plus trastuzumab (n = 32, control arm), ado-trastuzumab emtansine plus pertuzumab (n = 52, experimental arm), or other simultaneous experimental arms (n = 185) for 12 weeks of neoadjuvant therapy. Patients were then treated with 8 to 12 weeks of doxorubicin plus cyclophosphamide, followed by surgery.
Probability curves showed that the combination of ado-trastuzumab emtansine plus pertuzumab was superior to the control arm among all HER2-positive participants as well as the subgroups of those with hormone receptor–negative/HER2-positive breast cancer and those with hormone receptor–positive/HER2-positive breast cancer.
Among all patients, estimated pathologic complete response rates were 52% for the experimental arm and 22% for the control arm. Among the subgroup with hormone receptor–negative/HER2-positive disease, the estimated pathologic complete response rate was 64% vs 33%, respectively, and among hormone receptor–positive/HER2-positive patients, estimated pathologic complete response rates were 46% vs 17%.
The estimated probability of being superior to the control arm was 98% to 99% in the entire population and the two subgroups. The probability of success in a phase III trial was 90% to 93%.
Adverse events that are bothersome and debilitating to patients with cancer were more frequent in the control arm (ie, hypertension, neuropathy, alopecia). Elevated transaminase levels were more frequent in the ado-trastuzumab emtansine plus pertuzumab arm, but this was not clinically significant and was transient, Dr. DeMichele explained.
“The adaptive design of the I-SPY trials enables us to study the smallest number of patients needed to reach a result and report those results within 1 month of the last patient reaching surgery. This speeds the process of getting results to physicians, pharmaceutical companies, regulators, and most important, patients,” she said.
Future directions for the I-SPY trials in breast cancer include studying new combinations with the ado-trastuzumab emtansine backbone and non–anthracycline-containing combinations.
Dr. DeMichele pointed out that the I-SPY 2 study does not compare the experimental arms with each other. “We are testing multiple arms from multiple drug companies simultaneously, and this preserves the integrity of our trial. Drug companies need assurance that their drugs will not be compared to competitors,” she stated. ■
Disclosure: Dr. DeMichele reported no potential conflicts of interest.
1. DeMichele AM, Moulder S, Buxton M, et al: Efficacy of T-DM1 + pertuzumab over standard therapy for HER2+ breast cancer: Results from the neoadjuvant I-SPY 2 trial. 2016 AACR Annual Meeting. Abstract CT042. Presented April 18, 2016.
Formal discussant of the ado-trastuzumab emtansine plus pertuzumab trial, Mark Pegram, MD, Director of the Breast Cancer Program at Stanford Women’s Cancer Center and Co-Director of Stanford’s Molecular Therapeutics Program, Stanford, California, said that I-SPY 2 has several strengths....!-->!-->