Napabucasin Plus Paclitaxel Shows Efficacy in Platinum-Resistant Ovarian Cancer

Carlos Becerra, MD

Napabucasin, a first-in-class cancer stemness inhibitor, can be safely combined with full-dose weekly paclitaxel to treat patients with advanced, platinum-resistant ovarian cancer. In this heavily pretreated patient population, for whom new therapeutic options are needed, responses, including complete responses (CRs) and partial responses (PRs), were seen, and progression-free survival (PFS) and overall survival (OS) results were encouraging, according to a poster presented during the 2017 ASCO Annual Meeting.

Napabucasin, which inhibits the STAT3-driven gene transcription pathway and spherogenesis of cancer stem cells, showed synergistic antitumor activity with paclitaxel in preclinical studies. Napabucasin plus weekly paclitaxel was shown to be well tolerated in a phase Ib dose-escalation study in patients with solid tumors, leading to the opening of a phase II expansion cohort for patients with platinum-resistant ovarian cancer (NCT01325441).

The objective of this study was to evaluate the preliminary antitumor activity of napabucasin plus weekly paclitaxel in patients with platinum-resistant ovarian cancer. The recommended phase II dose of the combination of napabucasin plus paclitaxel was first determined in an open-label dose-escalation phase. In the phase II portion of this study, patients were enrolled into disease-specific cohorts. Objective tumor responses were assessed every 8 weeks using RECIST v1.1 criteria.

Cohort size was determined to be 98 patients assuming a disease control rate (DCR) of 60% to 80%, with the bounds of the 90% confidence intervals (CI) set at ±10% to 14%. Enrolled patients had a diagnosis of advanced ovarian cancer with disease progression either during or in the 6 months following platinum-based systemic therapy.

Napabucasin was administered orally at 500 mg, 480 mg, or 240 mg twice a day. Full-dose paclitaxel was administered intravenously at 80 mg/m²once weekly on 3 of every 4 weeks.

The median age of the 98 women who were enrolled was 61.5 years (range, 40-86); 79% were white, 8% were Hispanic, 3% were black, and 7% were Asian. The patients were all heavily pretreated with 43% having had ≥5 prior lines of therapy. All patients had prior platinum exposure, and 44% had ≥3 prior lines of platinum. Other prior therapies included taxanes in 99%, anthracyclines in 70%, gemcitabine in 56%, bevacizumab (Avastin) in 53%, and topotecan in 20%.

Most adverse events (AEs) were grade 1 or 2. There were 2 grade 4 AEs, including 1 incident each of intestinal perforation and pulmonary embolism. Grade 3 AEs included diarrhea (12.2%), vomiting (5.1%), nausea (4.1%), abdominal pain, fatigue, anemia, hypokalemia (3.1% each), hypophosphatemia, hyponatremia (2% each), dehydration, and ascites (1% each).

For the entire intent-to-treat (ITT) population of 98 patients, the DCR (the proportion with stable disease at 8 weeks plus PR plus CR) was 50%; at 24 weeks the DCR was 20%. Among the 75 patients whose tumors were evaluated using RECIST criteria, the DCR was 65% at 8 weeks and 27% at 24 weeks. The objective response rate (PR plus CR) was 15% for the ITT patient population, and 20% in the patients evaluated using RECIST. There was a CR in 2 patients (2%).

In the entire ITT population, median PFS was 3.3 months and median OS was 9.9 months. The timing of prior taxane therapy affected both PFS and OS. For the 37 patients who received prior taxanes early in disease course, defined as prior taxane with upfront therapy only, median PFS was 4.4 months, and median OS was 13.3 months. Note that this group included 1 patient who did not receive a prior taxane. However, for the 61 patients who received prior taxanes late in the disease course, defined as receiving a prior taxane upon disease occurrence after CR or curative resection, or late in the advanced setting with no disease-free interval, median PFS was lower at 2.1 months, and median OS likewise was lower at 8.5 months.

The study authors led by lead study author Carlos Becerra, MD, concluded that the safety of combination napabucasin plus full-dose weekly paclitaxel and the associated encouraging early antitumor activity in patients with heavily pretreated, platinum-resistant ovarian cancer warrant further evaluation of this combination in clinical trials.

Reference:

Becerra C, Garcia AA, Hays JL, et al. A phase 1b/2 study of napabucasin with weekly paclitaxel in advanced, previously treated platinum resistant ovarian cancer.J Clin Oncol.2017;35 (suppl; abstr 5548).