Veliparib Falls Short in Phase III NSCLC, TNBC Trials

Gary Gordon, MD, PhD

Veliparib failed to meet the primary endpoint in phase III non—small cell lung cancer (NSCLC) and triple-negative breast cancer (TNBC) trials, according to AbbVie, the company developing the PARP inhibitor.

Both trials examined the use of veliparib in combination with carboplatin and paclitaxel. AbbVie noted in a statement that the complete data from the studies will be presented at an upcoming medical meeting or published in a peer-reviewed journal.

"Research shows there is a role for PARP inhibitors in cancers associated with DNA repair deficits, such as those with BRCA mutations. In these clinical trials, we wanted to explore whether a PARP inhibitor could augment chemotherapy in patients with squamous non—small cell lung cancer and triple-negative breast cancer by disrupting the repair of cancer cells," Gary Gordon, MD, PhD, vice president, oncology clinical development, AbbVie, said in a statement. "Unfortunately, these data do not support the use of veliparib in combination with chemotherapy in these patients."

The double-blind, multicenter phase III NSCLC trial randomized 970 treatment-naive patients with metastatic or advanced squamous NSCLC to veliparib or placebo, in combination with carboplatin and paclitaxel. Patients were stratified by smoking history. The primary endpoint was improvement in overall survival (OS) among patients who had smoked within the past 12 months and had more than 100 smoking events in their lifetime.

In the double-blind, multicenter TNBC trial, 312 patients with early-stage disease were randomized to veliparib plus carboplatin/paclitaxel, placebo plus carboplatin/paclitaxel, or placebo plus paclitaxel. All 3 regimens were followed by doxorubicin plus cyclophosphamide. Complete pathologic response was the primary endpoint.

Phase III data for veliparib in TNBC had been anticipated since mixed results for the PARP inhibitor from the phase II BROCADE trial were presented at the 2016 San Antonio Breast Cancer Symposium (SABCS).

In the phase II study, treatment with veliparib plus chemotherapy elicited an ORR of 77.8%; however, progression-free survival (PFS) was not statistically significantly prolonged. The median PFS was 14.1 months (95% CI, 11.5-16.2) for the veliparib arm and 12.3 months (95% CI, 9.3-14.5) for the placebo group (HR, 0.789; 95% CI, 0.536-1.162; P = .231). The median OS was 28.3 months (95% CI, 26.9-NR) versus 25.9 months (95% CI, 20.4-31.8) with veliparib versus placebo, respectively (HR, 0.750; .503-1.117; P = .157), although these data were not fully mature.

The study included 290 women with histologically or cytologically confirmed locally recurrent or metastatic breast cancer who harbored a deleterious BRCA1 or BRCA2 germline mutation. Patients were allowed to have received 2 or fewer prior lines of chemotherapy in the metastatic setting. Individuals with prior PARP inhibitor treatment or CNS metastases were ineligible.

The 3-arm trial randomized patients in a 1:1:1 ratio to veliparib (120 mg twice daily on days 1-7) plus carboplatin (AUC 6)/paclitaxel (175 mg/m²) every 3 weeks (n = 97); the same chemotherapy regimen plus placebo (n = 99); or veliparib (40 mg twice daily on days 1-7) plus temozolomide (150-200 mg/m² each day on days 1-5) every 4 weeks (n = 94).

The findings reported at SABCS were for the first 2 arms. Tumor response was assessed in patients with measurable disease, which included 72 patients in the veliparib arm and 80 patients in the placebo arm. The overall response rate was 77.8% (95% CI, 66.4-86.7) in the veliparib arm and 61.3% (95% CI, 49.7-71.9) in the placebo group.

The complete and partial response rates in the veliparib versus placebo arms were 5.6% (n = 4) versus 3.8% (n = 3) and 72.2% (n = 52) versus 57.5% (n = 46), respectively. The clinical benefit rate (progression-free rate at 18 weeks) was 90.7% versus 87.0%, respectively. The median duration of response was 11.7 months (95% CI, 8.5-14.1) in the veliparib arm and 11.1 months (95% CI, 9.5-15.7) in the placebo arm.

The safety profile of veliparib plus carboplatin/paclitaxel was comparable to that of carboplatin/paclitaxel alone. All-grade adverse events (AEs) occurred in 100% of the veliparib arm and 97.9% of the placebo arm.

The most common nonhematologic AEs in the veliparib versus the placebo arm included alopecia (66.7% vs 57.3%), arthralgia (36.6% vs 32.3%), back pain (30.1% vs 22.9%), constipation (38.7% vs 29.2%), diarrhea (38.7% vs 28.1%), fatigue (50.5% vs 59.4%), headache (35.5% vs 32.3%), and peripheral neuropathy (68.8% vs 59.4%).

Common hematologic malignancies included anemia (57% with veliparib versus 51% with placebo), leukopenia (30.1% vs 28.1%), neutropenia (74.2% vs 74%), and thrombocytopenia (71% vs 69.8%).

Veliparib continues to be explored in ongoing phase III trials in ovarian cancer, BRCA1/2-positive breast cancer, and nonsquamous NSCLC.

"We have a comprehensive and innovative oncology pipeline that will help bring to market meaningful therapies for hematologic malignancies and solid tumors, especially where there continues to be a significant unmet need," Michael Severino, MD, executive vice president, research and development, and chief scientific officer, AbbVie, said in a statement.

Han HS , Diéras V, Robson M, et al. Efficacy and tolerability of veliparib (V; ABT-888) in combination with carboplatin (C) and paclitaxel (P) vs placebo (Plc)+C/P in patients (pts) with BRCA1 or BRCA2 mutations and metastatic breast cancer: a randomized, phase 2 study. Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Abstract S2-05.

The median PFS was 14.1 months (95% CI, 11.5-16.2) for the veliparib arm and 12.3 months (95% CI, 9.3-14.5) for the placebo group (HR, 0.789; 95% CI, 0.536-1.162; P = .231). The median OS was 28.3 months (95% CI, 26.9-NR) versus 25.9 months (95% CI, 20.4-31.8) with veliparib versus placebo, respectively (HR, 0.750; .503-1.117; P = 0.157).