Regorafenib monotherapy as second-line treatment of patients with RAS-mutant advanced colorectal cancer (STREAM): an academic, multicenter, single-arm, two-stage, phase II study

BACKGROUND: Maintaining angiogenesis inhibition and switching the chemotherapy backbone represent the current second-line therapy in patients with RAS-mutant metastatic colorectal cancer (mCRC). Regorafenib, an oral multikinase inhibitor, prolonged overall survival (OS) in the chemorefractory setting. MATERIALS AND METHODS: STREAM was an academic, multicenter, single-arm phase II trial, evaluating the activity of regorafenib in RAS-mutant mCRC, in terms of the rate of patients who were progression-free after 6 months from study entry (6mo-PF). Patients were pretreated with fluoropyrimidine, oxaliplatin, and bevacizumab. According to Simon’s two-stage design, ≥18 patients 6mo-PF were needed in the overall population (N = 46). Secondary endpoints were safety, objective response rate (ORR), progression-free survival (PFS), and OS. Early metabolic response by [(18)F]2-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography ([(18)F]-FDG PET/CT) scan was an exploratory endpoint. EudraCT Number: 2015-001105-13. RESULTS: The number of patients 6mo-PF was 8/22 at the first stage and 14/46 in the overall population. The ORR was 10.9%, disease control rate was 54.6%, median (m)PFS was 3.6 months [95% confidence interval (CI) 1.9-6.7 months], mOS was 18.9 months (95% CI 10.3-35.3 months), and mPFS2 (from study entry to subsequent-line progression) was 13.3 months (95% CI 8.4-19.7 months). Long benefiter patients (>6mo-PF) significantly more often had a single metastatic site and lung-limited disease. No unexpected toxicity was reported. Grade ≥3 events occurred in 39.1% of patients, with hand–foot syndrome (13%), fatigue, and hyperbilirubinemia (6.5%) occurring mostly. Baseline metabolic assessment was associated with OS in the multivariate analysis, while early metabolic response was not associated with clinical outcomes. CONCLUSIONS: The study did not meet its primary endpoint. However, regorafenib was well tolerated and did not preclude subsequent treatments. Patients with good prognostic features (single metastatic site and lung-limited disease) reported clinical benefit with regorafenib. The exploratory metabolic analysis suggests that baseline [(18)F]-FDG PET/CT might be useful to select patients with a favorable outcome. A chemotherapy-free interval with regorafenib was associated with durable disease control in a selected group of patients with favorable clinical characteristics.