I-SPY 2 study mechanism efficiently evaluates agents in biomarker-defined patient subsets. In a modest number of patients, its adaptive randomisation strategy successfully identified a biomarker signature for further development of pan-HER inhibitor, neratinib. A neoadjuvant regimen of standard chemotherapy and neratinib was beneficial for hormone receptor (HR)-negative, HER2-positive patients with primary breast cancer, according to data presented at the AACR Annual Meeting 2014 (5-9 April, San Diego, USA).
I-SPY 2 is a multicenter, phase II neoadjuvant trial in patients with high-risk stage II/III breast cancer. The researchers use an adaptive randomisation within biomarker subtypes to evaluate novel agents added to standard chemotherapy.
The study primary endpoint is pathologic complete response (pCR). The goal is to identify regimens that meet a high Bayesian predictive probability of statistical significance in a neoadjuvant phase III trial among 300 patients, defined by HR, HER2 status, and MammaPrint.
Tumours of at least 2.5 cm by clinical examination and at least 2 cm as seen by imaging were eligible for screening. Patients with MammaPrint low risk/HR-positive/HER2-negative tumours were ineligible for randomisation.
The study algorithm randomly assigned 115 patients to neratinib arm. The rates of pCR in the neratinib arm were compared with those of 78 patients who were concurrently randomised to the control arm containing standard chemotherapy only.
The investigators found that the probability that the regimen with neratinib has a higher rate of pCR than control therapy in HR-negative, HER2-positive breast cancer is 95% and its predictive probability of success in a future, randomized, 300-patient phase III trial is 79%.
The algorithm also predicted this drug combination is likely to be beneficial for all HER2-positive breast cancer patients, with the probability of superiority over standard therapy and the probability of success in a phase III trial being 95% and 73%, respectively.
The investigators concluded that adaptive randomisation in the trial successfully identified a biomarker signature (HR-negative/HER2-positive) for neratinib’s further development. All HER2-positive and MammaPrint-positive tumours may also benefit from this regimen, a finding that is consistent with preclinical data.
Evaluation in I-SPY 3, a phase III registration trial, is planned.
I-SPY 2 is sponsored by QuantumLeap Healthcare Collaborative, a 501(3)C charitable foundation, dedicated to accelerating health care solutions. QuantumLeap shares a unique partnership with the Foundation for the USA National Institutes of Health Biomarkers Consortium, which sponsored the trial until 2013, and continues to manage the intellectual property that emerges from it.
The results were presented by Dr John Park, professor of medicine at the UCSH Helen Diller Family Comprehensive Cancer Center in San Francisco at 105th Annual Meeting of the American Association for Cancer Research (AACR). The theme for AACR Annual Meeting 2014, “Harnessing Breakthroughs – Targeting Cures,” reflects the fact that the translation of basic science into clinical advances for the benefit of cancer patients is occurring at an increasing pace and more seamlessly than ever before.
Park JW, Liu MC, Yee D,et al.Neratinib plus standard neoadjuvant therapy for high-risk breast cancer: Efficacy results from the I-SPY 2 TRIAL. Abstract CT227, AACR Annual Meeting 2014. Page visited last time on 7 April 2014.