Adaptive Randomization of Neratinib in Early Breast Cancer
John W Park1, Minetta C Liu1, Douglas Yee1
1From University of California, San Francisco (J.W.P., C.Y., L.J.V., N.M.H., M.B.B., A.J.C., M.M., J.L., S.E.D., G.L.H., L.J.E.), and QuantumLeap Healthcare Collaborative (M.P.), San Francisco, Buck Institute for Research and Aging, Novato (C.Y.), University of California, Davis, Davis (M.H.), University of California, San Diego, San Diego (A.M.W., R.S., T.H.), and University of Southern California, Los Angeles (D.T.) - all in California; Georgetown Lombardi Comprehensive Cancer Center, Washington, DC (M.C.L., C.I.); University of Minnesota, Minneapolis (D.Y., T.C.H.), and Mayo Clinic, Rochester (J.C.B.) - both in Minnesota; M.D. Anderson Cancer Center, Houston (W.F.S., L.P., S.L.M., D.A.B.), University of Texas Southwestern Medical Center, Dallas (D.M.E., B.B.H.), and Berry Consultants, Austin (A.S., D.A.B.) - all in Texas; Gemini Group, Ann Arbor, MI (J.P.); University of Pennsylvania, Philadelphia (A.D.); Oregon Health and Sciences University, Portland (S.Y.C., K.A.K.); Swedish Medical Center, Seattle (H.G.K.); University of Chicago (R.N.) and Loyola University (K.S.A.) - both in Chicago; Inova Fairfax Hospital, Falls Church, VA (K.K.E.); University of Denver, Denver (A.D.E.); Mayo Clinic, Scottsdale (D.W.N.), and University of Arizona, Tucson (J.E.L., R.K.V.) - both in Arizona; University of Kansas, Lawrence (Q.J.K.); and Emory University, Atlanta (W.C.W.).
Background:
The heterogeneity of breast cancer makes identifying effective therapies challenging. The I-SPY 2 trial, a multicenter, adaptive phase 2 trial of neoadjuvant therapy for high-risk clinical stage II or III breast cancer, evaluated multiple new agents added to standard chemotherapy to assess the effects on rates of pathological complete response (i.e., absence of residual cancer in the breast or lymph nodes at the time of surgery).
Methods:
We used adaptive randomization to compare standard neoadjuvant chemotherapy plus the tyrosine kinase inhibitor neratinib with control. Eligible women were categorized according to eight biomarker subtypes on the basis of human epidermal growth factor receptor 2 (HER2) status, hormone-receptor status, and risk according to a 70-gene profile. Neratinib was evaluated against control with regard to 10 biomarker signatures (prospectively defined combinations of subtypes). The primary end point was pathological complete response. Volume changes on serial magnetic resonance imaging were used to assess the likelihood of such a response in each patient. Adaptive assignment to experimental groups within each disease subtype was based on Bayesian probabilities of the superiority of the treatment over control. Enrollment in the experimental group was stopped when the 85% Bayesian predictive probability of success in a confirmatory phase 3 trial of neoadjuvant therapy reached a prespecified threshold for any biomarker signature ("graduation"). Enrollment was stopped for futility if the probability fell to below 10% for every biomarker signature.
Results:
Neratinib reached the prespecified efficacy threshold with regard to the HER2-positive, hormone-receptor-negative signature. Among patients with HER2-positive, hormone-receptor-negative cancer, the mean estimated rate of pathological complete response was 56% (95% Bayesian probability interval [PI], 37 to 73%) among 115 patients in the neratinib group, as compared with 33% among 78 controls (95% PI, 11 to 54%). The final predictive probability of success in phase 3 testing was 79%.
Conclusions:
Neratinib added to standard therapy was highly likely to result in higher rates of pathological complete response than standard chemotherapy with trastuzumab among patients with HER2-positive, hormone-receptor-negative breast cancer. (Funded by QuantumLeap Healthcare Collaborative and others; I-SPY 2 TRIAL ClinicalTrials.gov number, NCT01042379.).
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