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Researchers identify breast cancer subtype that may benefit from neratinib
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The combination of chemotherapy plus neratinib induced a higher rate of complete response in patients with HER-2–positive, HR-negative breast cancer than the standard regimen of chemotherapy plus trastuzumab, according to results of a phase 2 study presented at the American Association for Cancer Research Annual Meeting.
The I-SPY 2 trial included women with high-risk, stage II/III breast cancer.
“The trial begins with equal randomization probabilities to different breast cancer subtypes,” John W. Park, MD, lead study author and professor of medicine at the USCF Helen Diller Family Comprehensive Cancer Center, said during a press conference. “The primary endpoint —pathologic complete response rate — is estimated for each subtype and for each associated molecular signature.”
Through the trial’s adaptive randomization, patients who enroll after the initial randomization receive preferential assignment to therapeutic regimens that were demonstrating the greatest benefit in patients with their particular disease subtype.
Park and colleagues evaluated a predefined threshold for successful completion of the endpoint — which was 85% in the current analysis — with a Bayesian algorithm, which determined whether the agent “graduated” based on the likelihood of success in a similar patient population in a phase 3 trial.
“If, at any point in the trial, this endpoint has not been met, the trial continues to learn from the responses attained to date, and the randomization is revised to reflect the results that have been attained thus far,” Park said. “The trial continues to accrue patients, but in this weighted randomization fashion, iteratively, until graduation or futility is the result.”
In the current analysis, Park and colleagues sought to evaluate the efficacy of neratinib (PB272, Puma Biotechnology) according to breast cancer subtype. Patients were evaluable if they had stage II breast cancer with a tumor size of at least 2.5 cm, and if the MammaPrint (Agendia) assay determined they were at high risk for recurrence.
The Bayesian algorithm assigned 115 patients to a treatment regimen consisting of neratinib plus chemotherapy. The other 78 patients were assigned to a control arm. HER-2–positive patients in the control arm received paclitaxel plus trastuzumab (Herceptin, Genentech), whereas HER-2–negative patients in the control arm received paclitaxel alone.
“For the HER-2–negative patients, neratinib was able to be open for enrollment. This represented recognition that neratinib has preclinical activity against both HER-2–negative and HER-2–positive tumor cells, potentially by virtue of its pan-HER spectrum,” Park said. “Therefore, neratinib was eligible to graduate in all 10 pre-specified signatures.”
The algorithm then predicted which of 10 breast cancer signatures would be associated with benefit in a hypothetical phase 3 trial comprised of 300 patients.
Neratinib graduated among patients with HER-2–positive, HR-negative disease. A higher percentage of patients with that disease subtype achieved pathologic complete response with neratinib compared with trastuzumab (56% vs. 33%).
Researchers calculated a 95% probability that neratinib would be superior to trastuzumab among patients with HER-2–positive, HR–negative disease in a phase 3 trial, and a 79% likelihood that these patients would derive benefit from neratinib.
Incidence of grade 1 or grade 2 diarrhea was higher in the neratinib arm than the control arm (95% vs. 45%). Grade 3 diarrhea occurred in 39% of patients assigned neratinib.
“This trial speaks of a 95% probability to neratinib’s performance being superior to trastuzumab in the endpoint of pathologic complete response,” Park said. “Neratinib is not just HER-2 inhibitory, but potentially it is also EGFR inhibitory. It’s mechanism of action is certainly distinct from trastuzumab, and how it interacts with chemotherapy wouldn’t necessarily be exactly the same. It is certainly a notable finding.”
For more information:
Park JW. Abstract #CT227. Presented at: AACR Annual Meeting; April 5-9, 2014; San Diego.
Disclosure: The study was funded by the QuantumLeap Healthcare Collaborative.
Perspective
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Chau T. Dang, MD
I-SPY 2 is an innovative adaptive trial design by Laura J. Esserman, MD, MBA, and Donald A. Berry, PhD, using an algorithm with decisions based on 10 signatures. This unique design identifies patients who would receive the most benefit from specific therapies. The primary endpoint is pathologic complete response (pCR) in the breast and lymph nodes. Park and colleagues presented the data on patients with stage II/III, hormone receptor-negative, HER-2–positive breast cancer.
The Bayesian algorithm randomized 115 patients to the neratinib combination versus 78 to the chemotherapy arm in the neoadjuvant setting. The pCR of the neratinib combination was estimated to be 55%. The probability of the neratinib-containing arm being superior to control was 95% in terms of pCR. Its probability of success in a future randomized, phase 3 study of 300 patients was 79%, and thus neratinib was graduated.
This important study is one of a series of trials testing novel agents using the I-SPY2 design that efficiently graduates effective therapies to be further evaluated. This bypasses the old traditional phase 3 study design, in which thousands of patients are enrolled, many of whom will not benefit from the experimental therapy. In the era of precision medicine and with limited resources, this allows us to do more with less, and the authors of this study should be congratulated.
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