Two Breast Cancer Drugs Graduate from Novel Trials

Summary and Comment |
July 26, 2016

Two Breast Cancer Drugs Graduate from Novel Trials

  1. William J. Gradishar, MD

Phase II I-SPY 2 trials based on an adaptive-randomization framework predict that neratinib and veliparib will prove successful in phase III studies.

  1. William J. Gradishar, MD

The I-SPY 2 TRIAL (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis 2) platform is based on an adaptive-randomization framework that changes as results emerge instead of using traditional statistical assumptions to dictate sample size and power. With this approach, trials may be completed faster than with conventional methods or abandoned earlier when the data suggest futility. Now, investigators have conducted two I-SPY 2, multicenter, adaptively randomized, open-label, phase II breast cancer studies to predict the success of adding targeted agents to chemotherapy.

Park and colleagues evaluated combining standard neoadjuvant chemotherapy (paclitaxel followed by doxorubicin and cyclophosphamide) with either the tyrosine kinase inhibitor neratinib or trastuzumab in 183 patients with stage II or III human epidermal growth factor receptor 2 (HER2)-positive, estrogen receptor (ER)-negative disease. The prespecified threshold of efficacy was a Bayesian predictive probability of ≥85% success in a simulated phase III trial of neoadjuvant therapy in 300 patients who had undergone 1:1 randomization, whereas futility was defined as a predicted probability of <10%.

The estimated rate of pathological complete response (pCR; the primary endpoint) determined by serial magnetic resonance imaging was 56% among the 115 patients receiving neratinib and 33% among the 78 receiving trastuzumab. Based on these results, neratinib was estimated to have a 79% probability of success in a phase III trial. These data have led to the planned design of a phase III trial comparing pertuzumab, trastuzumab, and a taxane versus neratinib, pertuzumab, trastuzumab, and a taxane versus neratinib, trastuzumab, and a taxane, all followed by doxorubicin and cyclophosphamide, in patients with HER2-positive, ER-negative disease and those with HER2-positive, ER-positive disease.

Rugo and colleagues evaluated combining standard neoadjuvant chemotherapy (paclitaxel followed by doxorubicin and cyclophosphamide) with veliparib and carboplatin in 116 patients with stage II or III triple negative breast cancer (TNBC). Success or failure was determined by a strategy similar to that outlined above for neratinib.

The estimated pCR rate was 51% among the 72 patients receiving veliparib and carboplatin and 26% among the 44 receiving chemotherapy alone. Adding veliparib and carboplatin to a standard preoperative chemotherapy regimen was estimated to have an 88% probability of success in a phase III trial. These data have led to the design of a phase III neoadjuvant trial in TNBC comparing standard chemotherapy with or without veliparib or with or without veliparib and carboplatin.

Comment

Traditional trials that proceed from phase I through phase III require years of time, extraordinary expense, and valuable resources (patients). Novel trial designs that may predict winners and losers among drug candidates earlier can potentially streamline drug development and bring promising drugs to market faster. The I-SPY program is one such strategy. However, caution must be exercised in interpreting pCR rates as surrogates for long-term outcomes, since many trials with high pCR rates have not demonstrated improved overall survival.

Editor Disclosures at Time of Publication

  • Disclosures for William J. Gradishar, MD at time of publication Consultant / Advisory board Eisai Editorial boards Clinical Breast Cancer; Oncology Leadership positions in professional societies National Comprehensive Cancer Network (Chair, Breast Cancer Panel)

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