A randomized phase II study of paclitaxel alone versus paclitaxel plus sorafenib in second- and third-line treatment of patients with HER2-negative metastatic breast cancer (PASO)

Abstract

BackgroundWe conducted an open-label, randomized, two-arm multi-center study to assess the efficacy and safety of paclitaxel versus paclitaxel + sorafenib in patients with locally advanced or metastatic HER2-negative breast cancer.MethodsPatients were randomly assigned to receive either paclitaxel monotherapy (80 mg/m2) weekly (3 weeks on, 1 week off) plus sorafenib 400 mg orally, twice a day taken continuously throughout 28 day cycles. Sorafenib dose was gradually escalated from a starting dose of 200 mg twice a day. The primary endpoint was progression free survival (PFS).ResultsA pre-planned efficacy interim analysis was performed on the data of 60 patients, 30 patients in each treatment arm. Median PFS was estimated at 6.6 months (95% CI: 5.1 to 9.0) in patients randomized to single-agent paclitaxel (Arm A) and 5.6 months (95% CI: 3.8 to 6.5) in patients randomized to paclitaxel-sorafenib combination (Arm B) therapy. Contrary to the hypothesis, the treatment effect was statistically significant in favor of paclitaxel monotherapy (hazard ratio 1.80, 95% CI: 1.02 to 3.20; log-rank test P = 0.0409). It was decided to stop the trial early for futility. Median OS was also in favor of Arm A (20.7 months (95% CI: 16.4 to 26.7) versus 12.1 months (95% CI: 5.8 to 20.4) in Arm B. Clinical control was achieved in 28 patients (93.3%) in Arm A and in 21 patients 70.0% in Arm B. Overall response rate was met in 43.3% of patients in Arm A and in 40.0% in Arm B. Toxicities were increased in Arm B with higher rates of diarrhea, nausea, neutropenia, hand-foot skin reaction (HFSR) and anorexia, Grad 3 and 4 toxicities were rare.ConclusionsIn this pre-planned interim analysis, paclitaxel-sorafenib combination therapy was not found to be superior to paclitaxel monotherapy with regard to the primary end point, progression-free survival. The trial was therefore discontinued early. There was no indication of more favorable outcomes for combination therapy in secondary efficacy end points. As expected, the safety and toxicity profile of the combination therapy was less favorable compared to monotherapy. Overall, this trial did not demonstrate that adding sorafenib to second- or third-line paclitaxel provides any clinical benefit to patients with HER2-negative advanced or metastatic breast cancer. Cautious dosing using a sorafenib ramp up schedule might have contributed to negative results.Trial registrationThe study was registered at EudraCT (No 2009–018025-73) and retrospectively registered at Clinical trials.gov on March 17, 2011 (NCT01320111).

A multi-national, randomised, open-label, parallel, phase III non-inferiority study comparing NK105 and paclitaxel in metastatic or recurrent breast cancer patients

“…9–12,15–18 In this study, although the dose of NK105 was lower than that of PTX, there was not much difference between the two in the PFS, OS or ORR (median PFS: 8.4 months vs. 8.5 months; median OS: 31.2 months vs. 36.2 months; mean ORR: 31.6% vs. 39.8%).…”

“…According to several recent studies evaluating weekly single doses of PTX (80–90 mg/m 2 ) in breast cancer, PTX monotherapy affords a PFS of 6.89 months (3.38–8.8), 12,16–18 an OS of 20.99 months (10.35–25.2), 9–12,16–18 and an ORR of 26.73% (21.1–43.5). 9–12,15–18 In this study, although the dose of NK105 was lower than that of PTX, there was not much difference between the two in the PFS, OS or ORR (median PFS: 8.4 months vs. 8.5 months; median OS: 31.2 months vs. 36.2 months; mean ORR: 31.6% vs. 39.8%).…”

Role of Natural Phenolics in Hepatoprotection: A Mechanistic Review and Analysis of Regulatory Network of Associated Genes

“…Various hepatic problems are encountered with a number of synthetic as well as plant-based drugs. Nexavar is a chemotherapeutic drug generally prescribed for complex renal carcinoma (Ravaud et al, 2016; Decker et al, 2017). It is additionally used to treat liver carcinoma.…”

Comparative Effectiveness of Taxane‐Containing Regimens for Treatment of HER2‐Negative Metastatic Breast Cancer: A Network Meta‐analysis

“…Figure shows the study selection process. Among the 20 studies, 11 were randomized phase II trials, and 9 were randomized phase III trials . Three trials were three‐armed trials, and the other 17 had two arms.…”