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. MethodsThe 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.

Locoregional therapies in patients with intrahepatic cholangiocarcinoma: A systematic review and pooled analysis

“…In contrast to ablation, results of EBRT and IAT suffered from high heterogeneity of the results and unclear superiority of outcomes, as compared with what could be expected from systemic chemotherapy in liver-only iCC (pooled objective response rates of 23.4% to 41.3%; and pooled mean OS ranging between 14.1 and 21.3 months with wide CIs). These results do not allow for strong recommendations, especially in the context of the efficacy demonstrated in phase III trials with systemic chemotherapy [3,12]. Comparison of efficacy between the three IAT modalities would prove difficult as the populations included differed.…”

Efficacy and Safety of Apatinib Treatment for Advanced Cholangiocarcinoma After Failed Gemcitabine-Based Chemotherapy: An Open-Label Phase II Prospective Study

“…Recently, emerging outputs from the multiple phase II trials demonstrated that fluoropyrimidine-based chemotherapy, considered as the second-line treatment, benefited patients with advanced cholangiocarcinoma refractory to first-line chemotherapy (19). In recent ABC-06 trial, second-line mFOLFOX (folinic acid, 5-fluorouracil, and oxaliplatin) plus active symptom control (ASC) improved OS compared with ASC alone (12 months versus 6 months), providing evidence for the promising survival benefits of the use of second-line chemotherapy after progression on the cisplatin-gemcitabine combination (mFOLFOX+ASC versus ASC: HR 0.69, 95% CI 0.50-0.97, P = 0.031) (20).…”

Biomarkers in Hepatobiliary Cancers: What Is Useful in Clinical Practice?

“…On the contrary, detecting actionable targets though theragnostic biomarkers is highly valuable in BTC: (1) the therapeutic arsenal of advanced BTC is limited in second line [ 172 ] with FOLFOX chemotherapy regimen. This only therapeutic second-line validated to date in a randomized Phase III trial, showed a very modest benefit over best supportive care, with a median OS of 6 months (one month OS gain in OS) and an ORR of 5% [ 31 ] overall responses, including long-lasting responses and/or complete responses, are frequent with IDH1/2 and FGFR2 inhibitors; (2) most molecular profiling panels would also detect rare targets, such as NTRK fusions, interesting since NTRK inhibitors are approved regardless of the tumor type, or other rare fusion genes for which clinical trials are available; (3) besides tumors with known prevalent oncogenic driver such as gastro-intestinal stromal tumor (GIST, c-kit mutations) or melanoma (BRAF mutations), BTC are among the tumors with one of the highest frequency of actionable molecular alterations. Therefore, molecular screening with NGS is becoming a standard of care for BTC; (4) even if looking for IDH1 and/or FGFR fusion is more relevant in iCCA, NGS allows an identification of several potential actionable targets and it is interesting to be performed regardless of primary tumor localization (e.g., EGFR and HER2 in eCCA and GBC); (5) in addition to solid tissue biopsies, the place of ‘liquid biopsies’ (ctDNA), allowing repeated molecular profiling in a less invasive way, still needs to be validated in BTC.…”

“…No predictive biomarkers are used yet to select patients for antiangiogenic therapy in HCC with the exception of AFP level for ramucirumab. For BTC, first-line standard chemotherapy is cisplatine-gemcitabine regimen with a median OS of 11.7 months [ 30 ] and in second line, a combination of 5-fluorouracil and oxaliplatine can be proposed [ 31 ]. The poor results obtained with systemic chemotherapy in BTC stress a need for efficient targeted therapies and the need for molecular profiling.…”