San Diego, CA—A multitargeted kinase inhibitor met criteria for a phase 3 clinical trial in breast cancer after statistical modeling of clinical data showed a high probability of success versus standard therapy for patients with HER2-positive/hormone receptor (HR)-negative (HER2+/HR–) disease.
Neoadjuvant treatment with paclitaxel plus neratinib (followed by doxorubicin plus cyclophosphamide) led to an estimated pathologic complete response (pCR) rate of 56% compared with 33% for paclitaxel paired with trastuzumab and followed by doxorubicin plus cyclophosphamide. Statistical modeling showed that the neratinib combination had a 95% probability of demonstrating superiority to paclitaxel plus trastuzumab, and a 79% likelihood of success in a phase 3 clinical trial of patients with HER2+/HR– breast cancer, as reported at the 2014 American Association for Cancer Research meeting.
“The adaptive trial identified a biomarker signature for neratinib, and neratinib has graduated in the HER2+/HR– signature,” said John W. Park, MD, Professor of Clinical Medicine, University of California, San Francisco Helen Diller Family Comprehensive Cancer Center. “Based on these results, neratinib is under consideration for phase 3 testing in the neoadjuvant population.”
The results came from the ongoing Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis (I-SPY) 2 trial, which uses a combination of adaptive randomization and Bayesian modeling to match a breast cancer therapy with the subgroup of patients most likely to benefit. The strategy is designed to provide results in a short period of time, and with as few patients as possible.
Neratinib is an irreversible pan-ErbB/HER2 inhibitor. According to Dr Park, I-SPY 2 has 6 experimental regimens under investigation.
The HER2+/HR– breast cancer subtype was 1 of 10 biomarker signatures evaluated in the trial. The signatures are derived from combinations of HER2 status, HR status, and results of the MammaPrint gene-expression assay. Patients with early breast cancer are randomized to the experimental or control arm. Response data are incorporated into the statistical model, which “learns” from the information and narrows the biomarker signature to patients most likely to respond to the experimental arm.
As tumor signatures unlikely to benefit from the experimental therapy are excluded, randomization continues in the remaining signatures, a process known as adaptive randomization. Because of confounding by the randomization process, estimated response rates are calculated for each signature, said Dr Park.
The phase 2 clinical trial has 3 principal end points: estimated pCR, probability that the experimental regimen is superior to the current standard, and predicted probability of success. To receive consideration for phase 3 evaluation, a treatment regimen must achieve a 95% probability of superiority and an 85% probability of success versus standard care in a trial of 300 patients whose breast cancer has the signature identified in the phase 2 trial.
Dr Park reported data from 115 patients treated with neratinib and 78 patients receiving standard care. On the basis of the results, the statistical model yielded an estimated pCR of 56% for the neratinib regimen and 33% for the standard regimen. The regimen met the 85% probability threshold for a phase 3 trial, but the recent addition of new data decreased the probability to 79%, said Dr Park.
The principal toxicity issue with neratinib was severe diarrhea (grade 3/4), which occurred in 39% of patients who received the drug compared with 4% of patients in the control arm. Early in the trial, investigators modified supportive care for diarrhea and initiated the prophylactic use of loperamide. The changes appeared to reduce problem diarrhea, said Dr Park. Cardiac toxicity was not a problem in the neratinib arm or in the control arm.
Discontinuation resulting from toxicity occurred more often with neratinib, whereas disease progression was a more common cause of discontinuation in the control arm.