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.
Competing Interests: Disclosure CC declares personal honoraria for advisory board roles from Bayer. ADS declares personal honoraria for educational activities from Amgen. LA declares personal honoraria for educational activities from Pfizer. EM declares personal honoraria advisory board and speaker roles for Amgen, Bayer, Eisai, Merck Serono, Pierre Fabre, Roche, Servier, Incyte, ESMO; Travel grant: AstraZeneca, Pierre Fabre. FC declares personal honoraria advisor and speaker roles for Roche, Amgen, Merck Serono, Pfizer, Sanofi, Bayer, Servier, BMS, Cellgene, Lilly and institutional research grants from Bayer, Roche, Merck Serono, Amgen, AstraZeneca, Takeda. MCP declares personal honoraria for educational activities from Astellas, AstraZeneca, Pfizer, and institutional grants for support to research activities from AstraZeneca, Bayer, Roche. AA declares personal honoraria for advisory board roles from AstraZeneca, Amgen, MSD, Servier. All other authors have declared no conflicts of interest. Data sharing De-identified individual data might be available after publication upon reasonable request to the corresponding author by presenting a complete research proposal.
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