Regorafenib after failure of gemcitabine and platinum-based chemotherapy for locally advanced/metastatic biliary tumors: REACHIN, a randomized, double-blind, phase II trial

Background: There is a high unmet clinical need for treatments of advanced/metastatic biliary tract cancers after progression on first-line chemotherapy. Regorafenib has demonstrated efficacy in some gastrointestinal tumors that progress on standard therapies. Patients and methods: REACHIN was a multicenter, double-blind, placebo-controlled, randomized phase II study designed to evaluate the safety and efficacy of regorafenib in patients with nonresectable/metastatic biliary tract cancer that progressed after gemcitabine/platinum chemotherapy. Patients were randomly assigned 1: 1 to best supportive care plus either regorafenib 160 mg once daily 3 weeks on/1 week off or placebo until progression or unacceptable toxicity. No crossover was allowed. The primary objective was progression-free survival (PFS). Secondary objectives were response rate, overall survival, and translational analysis. Results: Sixty-six patients with intrahepatic (n = 42), perihilar (n = 6), or extrahepatic (n = 9) cholangiocarcinoma, or gallbladder carcinoma (n = 9) were randomized, 33 to each treatment group (33 per group). At a median follow-up of 24 months, all patients had progressed and six patients were alive. Median treatment duration was 11.0 weeks [95% confidence interval (CI): 6.0–15.9] in the regorafenib group and 6.3 weeks (95% CI: 3.9–7.0) in the placebo group (P = 0.002). Fourteen of 33 patients (42%) in the regorafenib group had a dose reduction. Stable disease rates were 74% (95% CI: 59–90) in the regorafenib group and 34% with placebo (95% CI: 18–51; P = 0.002). Median PFS in the regorafenib group was 3.0 months (95% CI: 2.3–4.9) and 1.5 months (95% CI: 1.2–2.0) in the placebo group (hazard ratio 0.49; 95% CI: 0.29–0.81; P = 0.004) and median overall survival was 5.3 months (95% CI: 2.7–10.5) and 5.1 months (95% CI: 3.0–6.4), respectively (P = 0.28). There were no unexpected/new safety signals. Conclusion: Regorafenib significantly improved PFS and tumor control in patients with previously treated metastatic/unresectable biliary tract cancer in the second- or third-line setting. Clinical Trial Registration: The trial is registered in the European Clinical Trials Register database (EudraCT 2012-005626-30) and at ClinicalTrials.gov (NCT02162914).SCOPUS: ar.jinfo:eu-repo/semantics/publishe