Adaptive Randomization of Neratinib in Early Breast Cancer

Abstract

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.).

Figure 1

A. I-SPY 2 Adaptive Design. B. Study Design. Study schema for the neratinib experimental arm and control arm in I-SPY2. Following screening, HER2+ patients were randomized to receive either neratinib plus paclitaxel vs. trastuzumab plus paclitaxel. HER2− patients were randomized to receive either neratinib plus paclitaxel vs. paclitaxel alone. HER2+ and HER2− patients then received standard AC treatment to complete their neoadjuvant therapy. C. I-SPY 2 Consort Diagram for Neratinib and Its Controls. Did/did not received allotted intervention: Patients were categorized as receiving no experimental therapy or at least 1 dose of experimental therapy.

Figure 1

A. I-SPY 2 Adaptive Design. B. Study Design. Study schema for the neratinib experimental arm and control arm in I-SPY2. Following screening, HER2+ patients were randomized to receive either neratinib plus paclitaxel vs. trastuzumab plus paclitaxel. HER2− patients were randomized to receive either neratinib plus paclitaxel vs. paclitaxel alone. HER2+ and HER2− patients then received standard AC treatment to complete their neoadjuvant therapy. C. I-SPY 2 Consort Diagram for Neratinib and Its Controls. Did/did not received allotted intervention: Patients were categorized as receiving no experimental therapy or at least 1 dose of experimental therapy.

Figure 1

A. I-SPY 2 Adaptive Design. B. Study Design. Study schema for the neratinib experimental arm and control arm in I-SPY2. Following screening, HER2+ patients were randomized to receive either neratinib plus paclitaxel vs. trastuzumab plus paclitaxel. HER2− patients were randomized to receive either neratinib plus paclitaxel vs. paclitaxel alone. HER2+ and HER2− patients then received standard AC treatment to complete their neoadjuvant therapy. C. I-SPY 2 Consort Diagram for Neratinib and Its Controls. Did/did not received allotted intervention: Patients were categorized as receiving no experimental therapy or at least 1 dose of experimental therapy.

Figure 2. Probability distributions for select signatures

Histograms showing posterior (final) probability distributions for neratinib and control pCR rates for 4 of the 10 signatures listed in Table 2. Panel 2A is for HER2+/HR−, the graduating signature for neratinib. Estimated pCR Rate is the mean of the respective distribution. Predictive Probability in Phase 3 is a calculation based on the respective pair of histograms and is explained in the text.