Efficacy and Safety of nab-Paclitaxel vs Paclitaxel on Survival in Patients With Platinum-Refractory Metastatic Urothelial Cancer: The Canadian Cancer Trials Group BL.12 Randomized Clinical Trial

Abstract

Importance: Treatment options for platinum-refractory metastatic urothelial cancer (mUC) are limited, and outcomes remain poor. Nab-paclitaxel is an albumin-bound formulation of paclitaxel showing promising activity and tolerability in a prior single-arm trial.

Objectives: To evaluate the efficacy and safety of nab-paclitaxel vs paclitaxel in platinum-refractory mUC.

Design, setting, and participants: In this investigator-initiated, open-label, phase 2 randomized clinical trial conducted across Canada and Australia from January 2014 to April 2017, eligible patients had histologically confirmed, radiologically evident mUC of the urinary tract. Mixed histologic findings, except small cell, were permitted provided UC was the predominant histologic finding. All patients had received platinum-based chemotherapy either in the metastatic setting or were within 12 months of perioperative chemotherapy. Patients with prior taxane chemotherapy were not included. Patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 to 2 and adequate organ function.

Interventions: Patients were randomized to nab-paclitaxel, 260 mg/m2, or paclitaxel, 175 mg/m2, every 3 weeks.

Main outcomes and measures: The primary end point was progression-free survival (PFS).

Results: Among 199 patients, median age was 67 (range, 24-88) years; 144 (72%) were men; 167 (84%) were ECOG PS 0-1; 59 (30%) had liver metastases; and 110 (55%) were within 6 months of prior platinum-based chemotherapy. At a median follow-up of 16.4 months, there was no significant difference between nab-paclitaxel vs paclitaxel for median PFS (3.4 months vs 3.0 months; hazard ratio [HR], 0.92; 90% CI, 0.68-1.23; 1-sided P = .31). Median overall survival was 7.5 months for nab-paclitaxel vs 8.8 months for paclitaxel (HR, 0.95; 90% CI, 0.70-1.30; 1-sided P = .40); and objective response rate (ORR) was 22% for nab-paclitaxel vs 25% for paclitaxel (P = .97). Grade 3/4 adverse events were more frequent with nab-paclitaxel (64/97 [66%]) compared with paclitaxel (45/97 [46%]), P = .009; but peripheral sensory neuropathy was similar (all grades, 72/97 [74%] vs 64/97 [66%]; grade 3/4, 7/97 [7%] vs 3/97 [3%]; P = .27). There were no apparent differences in scores for health-related quality of life.

Conclusions and relevance: In this open-label, phase 2 randomized clinical trial of patients with platinum-refractory mUC, nab-paclitaxel had similar efficacy to paclitaxel; but worse toxic effects. The ORR with either taxane, however, was higher than previously reported and similar to those reported for the immune checkpoint inhibitors, suggesting that the taxanes remain a reasonable option in this setting.

Trial registration: ClinicalTrials.gov Identifier: NCT02033993.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Sridhar reports grants and personal fees from Merck, Roche, Pfizer, AstraZeneca, BMS, Janssen, and Bayer, outside the submitted work. Dr Tran reports personal financial interests from Amgen, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Janssen-Cilag, MSD, Novartis, Sanofi, Tolmar, Ipsen, Pfizer, Servier, and IQVIA; institutional financial interests from Amgen, Novartis, Aslan, GSK, Janssen-Cilag, MSD, Taiho, Akeso, Medimmune, AstraZeneca, Apteva, and Servier outside the submitted work. Dr. North reports grants and personal fees from Astellas, Janssen-Ortho, Merck, Novartis, Pfizer, Roche, Sanofi Canada, and AstraZeneca outside the submitted work. Dr Stockler reports grants from Specialised Therapeutics during the conduct of the study; grants from Astellas, Amgen, AstraZeneca, Bayer, Bionomics, Bristol Myers Squibb, Celgene, Medivation, Merck Sharp & Dohme, Pfizer, Roche, Sanofi, and Tilray outside the submitted work. Dr Chi reports grants and personal fees from Janssen, Astellas, Sanofi, Bayer, Roche, and AstraZeneca outside the submitted work. Dr. Fleshner reports personal fees from AbbVie, Amgen, Astellas, Bayer, Ferring, Hybridyne Imaging Technologies, Janssen, and Sanofi; and nonfinancial support from Hybridyne Imaging Technologies and Verity Pharmaceuticals outside of the submitted work. Dr Mukherjee reports personal fees from Roche, AstraZeneca, Novartis, and Merck outside the submitted work. Dr Winquist reports honoraria from Merck, Bayer, Eisai, Amgen, and Roche; and research funding from Roche/Genentech, AstraZeneca/MedImmune, Merck, Bristol Myers Squibb, Pfizer, and Eisai outside the submitted work. No other conflicts were reported.

Figures

Figure 1.. Consort Diagram

Figure 2.. Kaplan-Meier Curves

HR indicates hazard ratio. A, Estimates of progression-free survival distribution by treatment arm. B, Progression-free survival subgroup analysis by stratification factors.