A randomised Phase II trial of carboplatin and gemcitabine ± vandetanib in first-line treatment of patients with advanced urothelial cell cancer not suitable to receive cisplatin.

Robert Jones,Chao Huang,Tony Elliott,Alison Birtle,Jason Lester,Tracie‐Ann Madden,Satinder Jagdev,Gareth Griffiths,Robert Huddart,Simon Crabb,Linda Evans,John Chester,Angela Casbard

doi:10.1111/bju.15096

Abstract

To assess the efficacy and tolerability of the dual epidermal growth factor receptor/vascular endothelial growth factor receptor inhibitor, vandetanib, in combination with carboplatin and gemcitabine in the first-line treatment of patients with advanced transitional cell carcinomaurothelial cancer (UC) who were unsuitable for cisplatin. From 2011 to 2014, 82 patients were randomised from 16 hospitals across the UK into the TOUCAN double-blind, placebo-controlled randomised Phase II trial, receiving six 21-day cycles of intravenous carboplatin (targetarea under the concentration versus timecurve 4.5, day 1) and gemcitabine (1000mg/m2 days 1 and 8) combined with either oral vandetanib 100mg or placebo (once daily). Progression-free survival (PFS; primary endpoint), adverse events, tolerability and feasibility of use, objective response rate and overall survival (OS) were evaluated. Intention-to-treat and per-protocol analyses were used to analyse the primary endpoint. The 82 patients were randomised 1:1 to vandetanib (n = 40) or placebo (n = 42), and 25 patients (30%) completed six cycles of all allocated treatment. Toxicity Grade ≥3 was experienced in 80% (n = 32) and 76% (n = 32) of patients in the vandetanib and placebo arms, respectively. The median PFS was 6.8 and 8.8months for the vandetanib and placebo arms, respectively (hazard ratio [HR] 1.07, 95% confidence interval [CI] 0.65-1.76; P=0.71); the median OS was 10.8 vs 13.8months (HR 1.41, 95% CI 0.79-2.52; P=0.88); and radiological response rates were 50% and 55%. There is no evidence that vandetanib improves clinical outcome in this setting. Our present data do not support its adoption as the regimen of choice for first-line treatment in patients with UC who were unfit for cisplatin.

Highlights

There are ~10 000 patients newly diagnosed with urothelial cancer (UC) in the UK [1] and 118 000 in Europe [2] per annum
Much of the focus of clinical trials has been on improving outcomes in the cisplatin-fit population, but there is a need to improve outcomes in the sizable minority of patients currently treated with non-cisplatin containing regimens
Our present results are in contrast to the small benefits seen with vandetanib in combination with docetaxel in non-small cell lung cancer [19] and with a recently reported randomised Phase III trial using another anti-vascular endothelial growth factor receptors (VEGFRs) agent, ramucirumab, which demonstrated improved progression-free survival (PFS) and response rates in combination with docetaxel for patients with UC in the second-line setting [21]

Summary

Introduction

There are ~10 000 patients newly diagnosed with urothelial cancer (UC) in the UK [1] and 118 000 in Europe [2] per annum. Around 38% die within 1 year of diagnosis. The majority of UC deaths are caused by locally advanced or metastatic invasive bladder cancer. Advanced UC is a chemosensitive disease with response rates to cisplatincontaining regimens in previously untreated patients of. ~55% and with a median overall survival (OS) in the region of 14 months [3,4]. Cisplatin-based chemotherapy is not suitable for ~40% of patients [5], due to reasons such as insufficient renal function, performance status or comorbidity. Much of the focus of clinical trials has been on improving outcomes in the cisplatin-fit population, but there is a need to improve outcomes in the sizable minority of patients currently treated with non-cisplatin containing regimens

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Conclusion