Regorafenib monotherapy as second-line treatment of patients with RAS-mutant advanced colorectal cancer (STREAM): an academic, multicenter, single-arm, two-stage, phase 2 study

<p><strong>Background</strong></p> <p>Maintaining angiogenesis inhibition and switching the chemotherapy backbone represent the current second-line therapy in patients with <em>RAS</em> mutant metastatic colorectal cancer (mCRC).</p> <p>Regorafenib, an oral multikinase inhibitor, prolonged overall survival (OS) in chemorefractory setting.</p> <p><strong>Methods</strong></p> <p>STREAM was an academic, multicenter, single-arm phase 2 trial, evaluating the activity of regorafenib in <em>RAS</em> mutant mCRC, in terms of the rate of patients who were progression-free after 6months from study entry (6mo-PF). Patients were pretreated with fluoropyrimidine, oxaliplatin and bevacizumab. According to Simon&rsquo;s two-stage design, &ge; 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 [18F]-FDG PET/CT scan was an exploratory endpoint. EudraCT Number:2015-001105-13</p> <p><strong>Results</strong></p> <p>The number of patients 6mo-PF was 8/22 at the first stage and 14/46 in the overall population. ORR was 10.9%, Disease Control Rate 54.6%, median (m)PFS 3.6 months (mo) (95%CI 1.9-6.7), mOS 18.9 mo (95%CI 10.3-35.3), mPFS2 (from study entry to subsequent-line progression) was 13.3mo (95%CI=8.4-19.7). Long responders patients (&gt;6mo-PF) significantly more often had a single metastatic site and lung-limited disease. No unexpected toxicity was reported. Grade&ge;3 events occurred in 39.1% patients, mostly hand-foot syndrome (13%), fatigue and hyperbilirubinemia (6.5%). Baseline metabolic assessment was associated with OS in multivariate analysis, while early metabolic response was not associated with clinical outcomes.&nbsp;</p> <p><strong>Conclusion</strong></p> <p>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 &nbsp;lung-limited disease) reported clinical benefit with regorafenib. The exploratory metabolic analysis suggests that baseline [18F]-FDG PET/CT might be useful to select patients with favorable outcome.</p> <p>A chemotherapy-free interval with regorafenib might be worth of further studies as second-line treatment in selected patients with RAS mutant mCRC.</p> <p>&nbsp;</p>