Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial

Abstract

Background: Advanced biliary tract cancer has a poor prognosis. Cisplatin and gemcitabine is the standard first-line chemotherapy regimen, but no robust evidence is available for second-line chemotherapy. The aim of this study was to determine the benefit derived from second-line FOLFOX (folinic acid, fluorouracil, and oxaliplatin) chemotherapy in advanced biliary tract cancer.

Methods: The ABC-06 clinical trial was a phase 3, open-label, randomised trial done in 20 sites with expertise in managing biliary tract cancer across the UK. Adult patients (aged ≥18 years) who had histologically or cytologically verified locally advanced or metastatic biliary tract cancer (including cholangiocarcinoma and gallbladder or ampullary carcinoma) with documented radiological disease progression to first-line cisplatin and gemcitabine chemotherapy and an Eastern Cooperative Oncology Group performance status of 0-1 were randomly assigned (1:1) centrally to active symptom control (ASC) and FOLFOX or ASC alone. FOLFOX chemotherapy was administered intravenously every 2 weeks for a maximum of 12 cycles (oxaliplatin 85 mg/m2, L-folinic acid 175 mg [or folinic acid 350 mg], fluorouracil 400 mg/m2 [bolus], and fluorouracil 2400 mg/m2 as a 46-h continuous intravenous infusion). Randomisation was done following a minimisation algorithm using platinum sensitivity, serum albumin concentration, and stage as stratification factors. The primary endpoint was overall survival, assessed in the intention-to-treat population. Safety was also assessed in the intention-to-treat population. The study is complete and the final results are reported. This trial is registered with ClinicalTrials.gov, NCT01926236, and EudraCT, 2013-001812-30.

Findings: Between March 27, 2014, and Jan 4, 2018, 162 patients were enrolled and randomly assigned to ASC plus FOLFOX (n=81) or ASC alone (n=81). Median follow-up was 21·7 months (IQR 17·2-30·8). Overall survival was significantly longer in the ASC plus FOLFOX group than in the ASC alone group, with a median overall survival of 6·2 months (95% CI 5·4-7·6) in the ASC plus FOLFOX group versus 5·3 months (4·1-5·8) in the ASC alone group (adjusted hazard ratio 0·69 [95% CI 0·50-0·97]; p=0·031). The overall survival rate in the ASC alone group was 35·5% (95% CI 25·2-46·0) at 6 months and 11·4% (5·6-19·5) at 12 months, compared with 50·6% (39·3-60·9) at 6 months and 25·9% (17·0-35·8) at 12 months in the ASC plus FOLFOX group. Grade 3-5 adverse events were reported in 42 (52%) of 81 patients in the ASC alone group and 56 (69%) of 81 patients in the ASC plus FOLFOX group, including three chemotherapy-related deaths (one each due to infection, acute kidney injury, and febrile neutropenia). The most frequently reported grade 3-5 FOLFOX-related adverse events were neutropenia (ten [12%] patients), fatigue or lethargy (nine [11%] patients), and infection (eight [10%] patients).

Interpretation: The addition of FOLFOX to ASC improved median overall survival in patients with advanced biliary tract cancer after progression on cisplatin and gemcitabine, with a clinically meaningful increase in 6-month and 12-month overall survival rates. To our knowledge, this trial is the first prospective, randomised study providing reliable, high-quality evidence to allow an informed discussion with patients of the potential benefits and risks from second-line FOLFOX chemotherapy in advanced biliary tract cancer. Based on these findings, FOLFOX should become standard-of-care chemotherapy in second-line treatment for advanced biliary tract cancer and the reference regimen for further clinical trials.

Funding: Cancer Research UK, StandUpToCancer, AMMF (The UK Cholangiocarcinoma Charity), and The Christie Charity, with additional funding from The Cholangiocarcinoma Foundation and the Conquer Cancer Foundation Young Investigator Award for translational research.

Conflict of interest statement

Declaration of interests AL has received travel and educational support from Ipsen, Pfizer, Bayer, AAA, SirtEx, Novartis, Mylan, and Delcath; speaker honoraria from Merck, Pfizer, Ipsen, and Incyte; advisory honoraria from EISAI, Nutricia Ipsen, QED, and Roche, outside of the submitted work. AL is also a member of the Knowledge Network and NETConnect Initiatives funded by Ipsen. DHP declares research grants from AstraZeneca, Bayer, Bristol-Myers Squibb, Nucana, and Sirtex; and consulting or advisory roles for AstraZeneca, Bayer, Bristol-Myers Squibb, Eisai, Merck Sharp & Dohme, Servier, and Roche, outside of the submitted work. HSW has participated in advisory boards for Incyte, Bayer, Roche/Genentech/Foundation Medicine, SIRTEX Medical, Celgene, and Zymeworks; has been a NICE expert for Bayer (uncompensated); and reports consultancies for ONCOSIL; speaker-related honoraria and travel support from BTG/Biocompatibles, Merck KGaA, and BMS; participation in trials steering committee for Pfizer and Zymeworks; creation of educational materials for AstraZeneca; and receipt of research funding from Sirtex, outside of the submitted work. PJR declares research grants from Sanofi and Bayer; consulting or advisory roles for Bayer, Bristol-Myers Squibb, Eisai, Sirtex, and Roche; speaker fees from Amgen, Roche, and Servier; and travel grants from Bayer, Roche, and Servier, outside of the submitted work. YTM declares speaker honoraria and advisory roles for Bayer, Eisai, and Roche, outside of the submitted work. JW declares research grants from AstraZeneca and Sanofi-Genzyme and consulting or advisory roles for Lilly, AstraZeneca, Sanofi Genyme, Eisai, AAA, Roche, Novartis, and Ipsen, outside of the submitted work. AM declares research grants from Pfizer, Bristol-Myers Squibb, and Bayer; speaker fees from Bristol-Myers Squibb, Bayer Ipsen, EUSA Pharma, Daiichi Sankyo, and Pfizer; and advisory roles for Bayer, Bristol-Myers Squibb, Leo, Pfizer, Merck, and Ipsen, outside of the submitted work. JSW has received educational support for travel and conference attendance from Mylan and Ipsen, and speaker honoraria from Mylan, outside of the submitted work. JR declares research grants, speaker fees, and advisory roles for Ipsen, Novartis, and AAA, outside of the submitted work. JAB declares consulting or advisory roles for Merck Serono, Servier, Roche, Bayer, AstraZeneca, Incyte, and Basilea; and travel support from MSD Oncology, Merck Serono, Servier, and Bristol-Myers Squibb, outside of the submitted work. JWV declares consulting or advisory roles for Agios, AstraZeneca, Delcath Systems, Keocyt, Genoscience Pharma, Incyte, Ipsen, Merck, Mundipharma EDO, Novartis, PCI Biotech, Pfizer, Pieris Pharmaceuticals, QED, and Wren Laboratories; speakers' bureau for Imaging Equipment, Ipsen, Novartis, and Nucana; and travel grants from Celgene and Nucana, outside of the submitted work. AAr, SF, RG, KP, AAn, TI, CH, SB, WDR, and LMD declare no competing interests.

Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1

Trial profile ASC=active symptom control. FOLFOX=folinic acid, fluorouracil, and oxaliplatin.

Figure 2

Overall survival The HR is adjusted for the three stratification factors (platinum sensitivity, serum albumin concentration, and disease stage). ASC=active symptom control. FOLFOX=folinic acid, fluorouracil, and oxaliplatin. HR=hazard ratio. *Numbers are cumulative.

Figure 3

Subgroup analyses of overall survival Hazard ratios were adjusted by the three stratification factors (platinum sensitivity, serum albumin concentration, and disease stage), or the remaining two stratification factors where the factor of interest was itself a stratification factor. ASC=active symptom control. ECOG=Eastern Cooperative Oncology Group. FOLFOX=folinic acid, fluorouracil, and oxaliplatin. *ECOG performance status information was missing for one participant (death) in the ASC alone group.

Figure 4

Grade 3–5 adverse events and chemotherapy-related toxicity Grade 3–5 adverse events reported at least in 1% of patients in the ASC plus FOLFOX group that were considered to be chemotherapy related are summarised, alongside the incidence in each study group regardless of causality. Percentages are calculated in the intention-to-treat population. ASC=active symptom control. FOLFOX=folinic acid, fluorouracil, and oxaliplatin. *Includes liver infection, increased bilirubin or alkaline phosphatase, and hepatitis.