UK ABC-03 Trial results published (NCT0939848)

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06.07.2018 kl 12:41
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published 21/06/2018

Full study results link:

https://www.nature.com/articles/s41416-018-0132-8#Sec18

Introduction

Novel therapeutic options, based on an improved understanding of underlying biology and response to therapy, are urgently needed for patients presenting with advanced biliary tract cancer (ABC). Whilst uncommon in the developed world, biliary tract cancer (BTC including cholangiocarcinoma [CCA], gallbladder and ampullary carcinoma) represent a significant global problem due to areas of high incidence, for instance of liver fluke-associated cholangiocarcinoma in Northern Thailand1 and of gallbladder cancer in Chile and India.2

Surgery is the cornerstone of curative therapy for BTC the use of adjuvant therapy has historically been based on meta-analyses of non-randomised series and prospective studies.3 The recently presented phase III, randomised, BilCap study has demonstrated an overall survival (OS) benefit from the use of adjuvant use of oral capecitabine following surgery versus surgery alone.4 Unfortunately, most patients are present with advanced (non-resectable or metastatic) disease and their survival is 𕟫 months, with best supportive care alone.5 In the ABC-02 study,6 the combination chemotherapy with cisplatin and gemcitabine achieved a median survival of 11.7 months, compared to gemcitabine monotherapy (8.0 months HR =𔁚.64, 95% confidence interval (CI) 0.52–0.80 P𔁚.001), findings which were confirmed in the Japanese BT22 study.7 Although this is the international reference regimen,8 there is a pressing need to improve the efficacy, given these modest outcomes.

Angiogenesis is one of the hallmarks of neoplasia the expression of vascular endothelial growth factor (VEGF) is associated with adverse clinical features including the presence of liver metastases in intra-hepatic cholangiocarcinoma (iCCA)9 and increased microvessel density (MVD) in both gallbladder cancer10 and CCA.11 In patients undergoing curative resection, MVD has been identified as an independent prognostic risk factor for OS in lymph node-negative iCCA12 and gallbladder cancer,13 as well as for disease-free survival (DFS)13 and OS14 in patients with extrahepatic cholangiocarcinoma (eCCA). These clinical observations are consistent with the demonstration of receptors for VEGF (VEGFR1 and VEGFR2) in tumour proximal endothelial cells15 along with the frequent (40–75%) expression of VEGF (particularly VEGFA) in BTC 9-,11 particularly at the invasive edge of the tumour.13

Cediranib is an oral VEGFR1, VEGFR2 and VEGFR3 tyrosine kinase inhibitor (TKI), with additional activity against platelet-derived growth factor (PDGF) receptors and c-KIT.16 In the prospective randomised double blind placebo-controlled phase II ABC-03 study, the cisplatin and gemcitabine combination was evaluated with either cediranib or placebo. Although an improved response rate was observed (44% vs. 19% with placebo P =𔁚.0036) along with an improved 6-month progression-free survival (PFS, 70.5% vs. 61.3% P𔁚.05) in cediranib-treated patients, the magnitude of this effect did not reach the pre-defined level of statistical significance (hazard ratio [HR] for PFS: 0.93, 80% CI 0.74–1.19 P =𔁚.72) for the primary endpoint. This may have been due to lack of efficacy, or alternatively, underpowering of the statistical plan, or because cediranib was not well tolerated in this combination.17

Recognising the challenge of serial tumour biopsy, an exploratory translational endpoint of the ABC-03 study was the prospective longitudinal profiling of circulating biomarkers associated with angiogenes is. We now present the findings of this work, set the findings in context and evaluate the implications for future clinical trials.
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