A phase 1 study of veliparib (ABT-888) plus weekly carboplatin and paclitaxel in advanced solid malignancies, with an expansion cohort in triple negative breast cancer (TNBC) (ETCTN 8620).

BACKGROUND: Veliparib is a poly-ADP-ribose polymerase (PARP) inhibitor, and it has clinical activity with every 3 weeks carboplatin and paclitaxel. In breast cancer, weekly paclitaxel is associated with improved overall survival. We aimed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of veliparib with weekly carboplatin and paclitaxel as well as safety, pharmacokinetics, and preliminary clinical activity in triple negative breast cancer (TNBC). METHODS: Patients with locally advanced/metastatic solid tumors and adequate organ function were eligible. A standard 3 + 3 dose-escalation design was followed by a TNBC expansion cohort. Veliparib doses ranging from 50 to 200 mg orally bid were tested with carboplatin (AUC 2) and paclitaxel (80 mg/m2) given weekly in a 21-day cycle. Adverse events (AE) were evaluated by CTCAE v4.0, and objective response rate (ORR) was determined by RECIST 1.1. RESULTS: Thirty patients were enrolled, of whom 22 had TNBC. Two dose-limiting toxicities were observed. The RP2D was determined to be 150 mg PO bid veliparib with weekly carboplatin and paclitaxel 2 weeks on, 1 week off, based on hematologic toxicity requiring dose reduction in the first 5 cycles of treatment. The most common grade 3/4 AEs included neutropenia, anemia, and thrombocytopenia. PK parameters of veliparib were comparable to single-agent veliparib. In 23 patients with evaluable disease, the ORR was 65%. In 19 patients with TNBC with evaluable disease, the ORR was 63%. CONCLUSION: Veliparib can be safely combined with weekly paclitaxel and carboplatin, and this triplet combination has promising clinical activity.

The evolving management of metastatic triple negative breast cancer.

Advanced triple negative breast cancer (TNBC) is an incurable disease classified by its lack of expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2. Due to its lack of therapeutic targets, it has historically been treated with single agent chemotherapy, with combination cytotoxic therapy typically reserved for patients with high disease burdens, symptomatic disease, and/or impending visceral crisis. Recent molecular analyses have revealed that this clinical group of TNBCs is in fact quite biologically heterogeneous, with multiple TNBC subtypes defined by distinct biology and clinical behavior. Building on this biology, 2 targeted strategies are now approved for selected patients with advanced TNBC: the poly (ADP-ribose) polymerase inhibitors for advanced TNBC with a germline mutation in BRCA1/2, and the combination of the programmed death ligand 1-specific antibody atezolizumab with nab-paclitaxel for advanced TNBC that expresses programmed death ligand 1 on immune cells within the tumor. These targeted agents tend to be associated with a more favorable side effect profile and longer disease control than standard chemotherapy. A number of other targeted therapies have shown promise in early clinical trials, and several are now in definitive phase 3 testing for advanced TNBC. These include the antiapoptotic kinase inhibitors ipatisertib and capivasertib, and the antibody-drug conjugate sacituzumab govitecan-hziy. Approved biomarker-driven treatment options for this disease are thus likely to expand in the near-term. Here we review current treatment options and emerging targeted therapies for advanced TNBC. For patients who do not meet criteria for approved targeted therapies, participation in clinical trials evaluating precision medicines with candidate predictive biomarkers in advanced TNBC should be encouraged.