Neoadjuvant Veliparib/Carboplatin and Neratinib ‘Graduate’ From Adaptive Randomization I-SPY 2 Trial in Early Breast Cancer


Key Points

  • The addition of veliparib/carboplatin to standard treatment met predictive success criteria in triple-negative breast cancer.
  • The addition of neratinib to standard treatment met predictive success criteria in HER2-positive, hormone receptor–negative breast cancer.

As reported by Rugo et al and Park et al in The New England Journal of Medicine, the adaptive randomization phase II I-SPY 2 trial has shown that the addition of veliparib/carboplatin and the addition of neratinib to standard neoadjuvant therapy have met criteria predictive of success in a phase III trial of the same comparators in early breast cancer patients with specific biomarker signatures.

I-SPY 2 Details

In the I-SPY 2 trial, adaptive randomization is being used to evaluate the effectiveness of multiple new agents added to standard neoadjuvant chemotherapy in producing pathologic complete response in high-risk stage II to III breast cancer based on biomarker subtypes. The aim of the adaptive-randomization scheme is to more rapidly and accurately identify experimental regimens with a higher likelihood of success in phase III trials that can include smaller numbers of patients.

The breast cancers are categorized into 8 biomarker subtypes based on HER2, hormone receptor, and 70-gene assay status. Patients undergo adaptive randomization within each biomarker subtype to receive regimens that perform better than standard therapy. The regimens are evaluated across 10 biomarker signatures, consisting of predefined combinations of biomarker subtypes. A regimen leaves the trial (“graduates”) when it reaches an 85% Bayesian predictive probability of success in a simulated 300-patient equally randomized phase III trial of the same comparators within a biomarker signature.

Veliparib/Carboplatin in Triple-Negative Disease

As reported by Rugo et al in The New England Journal of Medicine, veliparib/carboplatin became the first regimen to graduate from the trial. The veliparib/carboplatin regimen was considered only for HER2-negative tumors and was thus evaluated in the three biomarker signatures of HER2-negative, hormone receptor–positive and HER2-negative, and triple-negative.

All patients in the trial received standard weekly paclitaxel alone (or with trastuzumab [Herceptin] in HER2-positive disease) or in combination with an experimental regimen, and all subsequently received standard doxorubicin and cyclophosphamide. Overall, 75 patients were randomized to receive veliparib (50 mg twice daily) plus carboplatin (AUC [area under the curve] = 6 on weeks 1, 4, 7, and 10) plus standard treatment; 46 were randomized to receive paclitaxel; and 18 were randomized to receive paclitaxel/trastuzumab as control treatment. Veliparib/carboplatin was not assigned to patients with HER2-positive tumors. Comparisons were made among 72 patients receiving veliparib/carboplatin and 44 control patients receiving paclitaxel without trastuzumab.

The predefined threshold for efficacy for veliparib/carboplatin was achieved among patients with triple-negative disease, with pathologic complete response rates of 51% vs 26%; the probability that veliparib/carboplatin was superior to the control was 99%, and the probability of statistical success in an equally randomized phase III trial including 300 patients was 88%. Although not meeting the predefined threshold for efficacy, the addition of veliparib/carboplatin showed evidence of benefit among all patients with HER2-negative tumors (33% vs 22%; 91% probability of superiority, 53% predicted probability of success in a phase III trial). Estimated rates of pathologic complete response were 14% vs 19% in patients with HER2-negative, hormone receptor–positive disease.

The investigators concluded: “The process used in our trial showed that veliparib/carboplatin added to standard therapy resulted in higher rates of pathological complete response than standard therapy alone, specifically in triple-negative breast cancer.”

Neratinib in HER2-Positive, Hormone Receptor–Negative Disease

As reported by Park et al in The New England Journal of Medicine, all patients, again, received standard paclitaxel (with trastuzumab in HER2-positive patients) followed by doxorubicin and cyclophosphamide. Neratinib was given at 240 mg/d for the first 12 weeks in addition to standard chemotherapy. Overall, 115 patients received neratinib, and 78 received control treatment (paclitaxel alone in 56 patients and with trastuzumab in 22 patients).

Among the 10 biomarker signatures evaluated, the neratinib group achieved the predefined threshold for efficacy in patients with HER2-positive, hormone receptor–negative disease; in these patients, pathologic complete response was observed in 56% vs 33% of patients. The probability that neratinib was superior to control was 95%, and the probability of the success of neratinib in a phase III trial in 300 patients was 79% (the 85% threshold had been reached, but the probability was reduced somewhat when all randomized patients had completed neoadjuvant treatment).

Although not achieving the prespecified threshold for efficacy, the addition of neratinib showed evidence of benefit over control treatment in HER2-positive, hormone receptor–positive disease (30% vs 17%; 91% probability of superiority, 65% predicted probability of success in a phase III trial) and in HER2-positive disease irrespective of hormone receptor status (39% vs 23%; 95% probability of superiority, 73% predicted probability of success in a phase III trial).

The investigators concluded: “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.”

The study was funded by QuantumLeap Healthcare Collaborative and others.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.