Regorafenib (BAY 73-4506) in advanced colorectal cancer: a phase I study

Abstract

Background: In a phase I dose-escalation study, regorafenib demonstrated tolerability and antitumour activity in solid tumour patients. The study was expanded to focus on patients with metastatic colorectal cancer (CRC).

Methods: Patients received oral regorafenib 60-220 mg daily (160 mg daily in the extension cohort) in cycles of 21 days on, 7 days off treatment. Assessments included toxicity, response, pharmacokinetics and pharmacodynamics.

Results: Thirty-eight patients with heavily pretreated CRC (median 4 prior lines of therapy, range 0-7) were enrolled in the dose-escalation and extension phases; 26 patients received regorafenib 160 mg daily. Median treatment duration was 53 days (range 7-280 days). The most common treatment-related toxicities included hand-foot skin reaction, fatigue, voice change and rash. Twenty-seven patients were evaluable for response: 1 achieved partial response and 19 had stable disease. Median progression-free survival was 107 days (95% CI, 66-161). At steady state, regorafenib and its active metabolites had similar systemic exposure. Pharmacodynamic assessment indicated decreased tumour perfusion in most patients.

Conclusion: Regorafenib showed tolerability and antitumour activity in patients with metastatic CRC. This expanded-cohort phase I study provided the foundation for further clinical trials of regorafenib in this patient population.

Figure 1

Maximum percentage change in target lesion sum from baseline (n=27).

Figure 2

Progression-free survival for individual patients, showing KRAS mutational status.

Figure 3

Concentration–time profile of regorafenib and its metabolites M2 (N-oxide metabolite) and M5 (N-oxide/N-desmethyl metabolite).

Figure 4

Dynamic contrast-enhanced magnetic resonance imaging: ratio to baseline of the area under the contrast agent concentration–time curve during the first 60 s after arrival of the contrast agent.