I-SPY 2 Trial Graduates Neratinib for HER2-Positive Breast Cancer

Laura J. Esserman, MD, MBA

The adaptive I-SPY 2 trial has found that a neoadjuvant regimen of neratinib and standard chemotherapy is beneficial for high-risk patients with hormone receptor (HR)-negative, HER2-positive stage II/III breast cancer, according to research presented at the 2014 AACR Annual Meeting.

According to the trial, which used an algorithm to identify which patients would receive the most benefit from a variety of different treatments, neratinib had an estimated pathological complete response (pCR) of 55% for patients in the trial with HR-negative, HER2-positive breast cancer. Based on these findings, further evaluation in the phase III I-SPY 3 study is planned.

“We were pleased that the algorithm used for the predictions functioned so well and that it actually stopped assigning neratinib to patient subgroups which were not benefiting from the drug while at the same time increasing its assignment to patient subgroups which were benefiting from the drug,” John W. Park, MD, professor of medicine at the UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco, said in a press release.

The trial works by using adaptive randomization. When a patient with a particular subtype of breast cancer enters the trial, they are preferentially assigned to treatment regimens that are performing better in patients with the same subtype of breast cancer.

The Bayesian algorithm randomly assigned 115 patients to the arm of the trial that contained neratinib. The rates of pCR on the neratinib arm were compared with 78 patients who were concurrently randomized to the control arm containing standard chemotherapy. These comparisons were made for 10 biomarker signatures prospectively defined by categories of HR, HER2, and MammaPrint, which analyzes 70 genes from early-stage breast cancer tissue samples and determines if the cancer has a low or high risk of recurrence within 10 years after diagnosis.

The investigators of the study concluded that the probability that the neratinib-regimen would have a higher rate of pCR than the control therapy in HR-negative, HER2-positive breast cancer was 95%. The predictive probability of success in a future, randomized, 300-patient phase III trial is 79%. In addition, the study established that the probability of the neratinib combination showing statistical superiority to trastuzumab plus paclitaxel was 72.7%.

The algorithm also predicted that the neratinib combination is likely to be beneficial for all patients with HER2-positive breast cancer (pCR = 39%), with the probability of superiority over standard therapy and the probability of success in a phase III trial being 95% and 73%, respectively.

All MammaPrint High2 (MP+) tumors saw a pCR of 45% and may also benefit from the drug combination, according to results of the trial.

“Traditional phase III clinical trials are large because they include patients who do not benefit from the experimental therapy, and they persist in randomizing such patients in the trial to the very end,” Donald A. Berry, PhD, professor of biostatistics at The University of Texas MD Anderson Cancer Center and founder of Berry Consultants, said in a press release.

The phase III I-SPY 3 study is designed to confirm the results from the I-SPY 2 trial in a larger patient population. Taken together, the two trials hope to accelerate the development of effective new therapies for patients with breast cancer.

“Clinical trial designs have to change to keep pace with the amazing advances being made in biology. I-SPY 2 may not be the final answer, but so far it has been successful in expanding the boundaries of clinical trials, making them more patient-friendly while preserving their scientific integrity,” Laura J. Esserman, MD, MBA, professor of surgery and radiology and director of the Carol Frank Buck Breast Care Center at UCSF Helen Diller Family Comprehensive Cancer Center, said in a press release.

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