Regorafenib after failure of gemcitabine and platinum-based chemotherapy for locally advanced/metastatic biliary tumors: a randomized, double-blind, phase 2 trial - REACHIN.

ABSTRACT Background There is a high unmet clinical need for treatments for advanced/metastatic biliary tract cancers (BTC) 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 2 study designed to evaluate the safety and efficacy of regorafenib in patients with nonresectable/metastatic BTC 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/one 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 (OS), and translational analysis. Results Sixty-six patients with intra-hepatic (n=42), peri-hilar (n=6), or extra-hepatic (n=9) cholangiocarcinoma, or gallbladder carcinoma (n=9) were randomized, 33 to each treatment group. At a median follow-up of 24 months, all patients had progressed and 6 patients were alive. Median treatment duration was 11.0 weeks (95%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 OS 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 BTC in the second- or third-line setting.