The rate of grade 3 or greater hematologic toxic effects in this trial arm was higher in patients treated with veliparib-carboplatin, with neutropenia rates of 71% versus 2% for controls. Adverse events occurring only in patients on veliparib-carboplatin were thrombocytopenia in 21%, anemia in 28%, and febrile neutropenia in 1%. Among patients who had received the combination, toxic effects were higher during doxorubicin-cyclophosphamide therapy.
HR-negative disease
Patients with hormone receptor–negative disease received standard neoadjuvant chemotherapy with 12 weekly cycles of paclitaxel followed by 4 cycles of doxorubicin and cyclophosphamide as described before, with or without oral neratinib 240 mg per day. Patients in the control group who had HER2-positive cancers also received trastuzumab for the first 12 weeks with a loading dose of 4 mg per kilogram of body weight in the first cycle, followed by a maintenance dose of 2 mg per kilogram in cycles 2 through 12.
Surgery, including sentinel-node dissection in patients with node-negative cancer and axillary-node dissection in those with node-positive cancer at diagnosis, was performed according to NCCN and local practice guidelines, and adjuvant radiation and endocrine therapy were recommended according to standard guidelines.
The protocol was modified to included diarrhea prophylaxis with loperamide among patients assigned to receive neratinib.
A total of 127 patients were assigned to neratinib, and 115 of these patients were evaluable for response. Controls included 84 patients, of whom 78 were evaluable. At baseline, more patients in the neratinib group had HER2-positive tumors. Neratinib reached the prespecified efficacy threshold only within the HER2-positive, HR-negative group.
Diarrhea was the most common adverse event, with grade 3 or greater diarrhea occurring among 38% of patients assigned to neratinib. Vomiting and elevated liver enzymes were also more frequent with neratinib.
I-SPY 2 is supported by QuantumLeap Healthcare Collaborative, the Foundation for the National Institutes of Health (from 2010 through 2012) and the National Cancer Institute. Dr. Park reported receiving lecture fees and travel support from Genentech and Pfizer, and receiving royalties from patents. Dr. Rugo reported grants to her institution from BioMarin, and unpaid steering committee participation for BioMarin and AbbVie. Multiple co-authors reported financial relationships of various kinds.