Early Development of Regorafenib: Was the Correct Dose Selected?

February 11, 2016
Special Reports, Gastrointestinal Cancers: mCRC (Issue 6), Volume 1, Issue 6

A first-in-human phase I dose-escalation study followed by a small expansion cohort, both of which were conducted solely in Germany, set the stage for what would soon become the FDA-approved dose for regorafenib (Stivarga) of 160 mg/day.

In the clinical trials leading to the approval, nearly two-thirds of patients required dose interruptions or modifications in order to manage the adverse events (AEs) associated with the medication. Moreover, following approval, reports suggested that as many as 80% of patients require dose modifications. Now, many recommend starting the treatment at 120 mg/day, or an even lower dose, in order to curb AEs.

Taken together, this has called for a re-examination of the recommended dose, and clinical trials are currently exploring whether a lower starting dose impacts efficacy.

Early Evidence of Efficacy

Regorafenib is an oral diphenylurea—based multikinase inhibitor that inhibits several angiogenic stromal and oncogenic kinases, including those in the RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, Trk2A, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl pathways. The agent initially showed promising antitumor activity in murine xenograft models before moving to clinical studies.

A first in human phase I dose-escalation study was initiated to explore regorafenib in patients with advanced solid tumors. In this study, the agent demonstrated an acceptable safety profile, coupled with a promising efficacy signal. Most importantly, the study identified what was considered the recommended dose.1

This open-label non-randomized dose-escalating study was conducted at a single center in Germany, the University Hospital in Freiburg. Inclusion criteria stipulated that all patients had to present with histologically or cytologically confirmed advanced solid tumors. Subsequent investigation with CT or MRI scan at baseline had to show evidence of progression after standard therapies for study enrollment. Patients had an ECOG performance status of 0 to 2, sufficient renal hepatic and bone marrow function, and a life expectancy of at least 3 months.

The study began in July 2005, and the date for data cutoff for the publication was June 29, 2009. There were 4 primary objectives: the safety profile, the maximum-tolerated dose (MTD), the pharmacokinetic profile of the oral dose, and the optimal dose of regorafenib for future studies. Secondary objectives included, the pharmacodynamics of the drug (plasma concentrations of VEGF and s VEGF), and the tumor responses.

The MTD was defined as a dose for which only 1 out of 6 patients experienced a dose limiting toxicity (DLT). There were 8 dose cohorts, each recruited at least 3 patients and evaluated doses of regorafenib from 10 mg to 220 mg.

The starting dose level of 10 mg had been calculated from results preclinical animal studies. Cohorts 1 to 5 administered regorafenib as a solution, which was replaced with a coprecipitate tablet formulation in cohorts 6 to 8. The quality of the safety data determined dose escalation. Study drug was administered in repeating 28-day cycles of 21 days on drug, and 7 days off drug. A more stepped approach was employed in cohort one, using the lowest (10 mg) dose. Treatment continued until disease progression, unacceptable toxicity or consent withdrawal. Adverse event levels were estimated in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events.

Patient Population and Results

The study enrolled 53 patients for whom the median age was 60 years (range, 22-77). The most common tumor type was colorectal (n = 16, 30%). The majority of patients were male, (n = 30, 57%) and all were Caucasian. Twenty-six patients (49%) had an ECOG score of 0, 25 a score of 1, and 2 had a score of 2. The patients had previously been treated with a median number of 3 different regimens (range, 0-9).

The median duration of treatment was 78 days. Across all cohorts, 94% of the patients received ≥50% of the scheduled dose, and a smaller percentage (72%) received ≥70%. At the time of data cut off, 51 patients had discontinued due to disease progression (n = 30), death from disease progression (n = 2), and consent withdrawal (n = 2).1

Forty-seven patients were available for efficacy assessment by RECIST.1Overall, 60% of patients had stable disease, 6% experienced partial responses, and 23% developed progressive disease. The authors assessed the efficacy as encouraging, and the safety profile as acceptable.

Maximum-Tolerated Dose and Safety

At least 1 treatment-related AE was experienced by 44 (83%) of the patients, and their frequency increased with dose levels. The most common treatment-related AEs were voice changes, hand-foot skin reaction, mucositis, diarrhea, and hypertension. The authors pointed out that the profile was consistent with the mechanism of action of the drug and not unusual when compared with the phase I safety profiles of other multikinase inhibitors.

The most common grade 3 or 4 treatment-related AEs were hand-foot skin reactions, hypertension, diarrhea, and rash/desquamation. The following treatment-related serious AEs were experienced by 30% of patients: hypertension, diarrhea, infection, abdominal pain, allergic reaction, cardiac ischemia/infarction, fatigue, weight loss, dehydration, CNS hemorrhage with underlying brain metastases, lipase elevation, somnolence, pain, bronchospasm, hand-foot skin reaction, rash/desquamation, and uticaria.

Overall the treatment emergent AEs were manageable, and some were resolved by dose adjustment. Grade ≤3 treatment-related AEs were responsible for treatment discontinuation in 17 patients.1

Determination of the MTD involved primarily the tolerability data in the context of the pharmacokinetic and pharmacologic findings. DLTs were unacceptable at the 220 mg dose level, but acceptable at the dose of 160 mg. Systemic exposure showed only small increases when the dose was increased from 160 mg to 220 mg. The authors pronounced the dose of 160 mg orally, once daily (tablet formulation) for 21 days on and 7 days off as the recommended dose.1

Pharmacokinetics and Pharmacodynamics

The pharmacokinetic analysis assessed levels of regorafenib and its 2 metabolites M-2 and M-5. The proportional systemic exposure/dose relationship was consistent, up until the 60 mg dose level. Proportionality was lost beyond that and the authors thought this was likely due to the limited solubility of regorafenib in the gastrointestinal fluids.

The terminal half-life of regorafenib was 20 to 40 hours, supporting the once daily recommended dosing. Accumulation of regorafenib also occurred with repeated dosing, and this was also observed for the M-2 and M-5 metabolites, indeed these rose to a level equivalent to that of the parent compound at a steady state. The authors stated that preclinical work demonstrated that the metabolites were pharmacologically active, and pointed out that the levels they achieve at the 160 mg dose may indicate they can indeed contribute to the clinical activity of regorafenib.1

Dynamic contrast-enhanced MRI (DCE-MRI) revealed a ≥40% decrease in tumor perfusion, consistent with the proposed antiangiogenic mechanism of action of regorafenib at doses of ≥120 mg.1This was in agreement with findings in preclinical models.2The authors also noted the plasma levels of VEGF gradually increased during the 21-day treatment period, and slowly returned to almost baseline levels during the 7 day off treatment periods.1

Phase I Expansion Study

The expansion study was conducted at 3 centers in Germany and enrolled 38 patients with heavily pretreated metastatic colorectal cancer. Twenty-six patients received regorafenib at the 160 mg/day dose level and 27 patients were evaluable for response.

The safety profile was acceptable, manageable, and similar to what was described in the dose escalation study. An efficacy signal was again evident. Median progression-free survival (PFS) was 107 days (95% CI, 66-161). The disease control rate was 74%, 70% of patients had stable disease, and 4% experienced a partial response.3

DCE-MRI revealed a reduction in tumor perfusion in patients treated with regorafenib, supporting an antiangiogenic mechanism. However, the authors found no correlation between change in DCE-MRI and PFS, and suggested that other mechanisms may be involved in the reduction in tumor perfusion, especially given the multikinase inhibition profile of the drug.3

Future Direction for Regorafenib

Quickly following the dose escalation and expansion study, the treatment successfully passed phase III testing and gained FDA approval as a treatment for patients with metastatic colorectal cancer following prior therapies. Adding to this indication, experts believe the agent could have further utility in earlier settings, particularly if a relevant biomarker can be identified.4

There are currently two clinical trials under way that were designed to evaluate the use of regorafenib with cytotoxic therapy as second-line treatment and as a monotherapy for patients with newly diagnosed metastatic colorectal cancer (NCT01298570 and NCT02023333 respectively). Additionally, a phase II trial is comparing a lower starting dose with the currently FDA approved 160 mg/day dose (NCT02368886).

Regorafenib is also being investigated in several other cancer types, placing further emphasis on the need to identify an optimal dose. Phase II trials are ongoing in patients with unsectable or metastatic esophagogastric cancer and in previously untreated patients with metastatic or unresectable renal cell cancer (NCT01913639 and NCT00664326, respectively).


  1. Mross K, Frost A, Steinbild S, et al. A phase I dose-escalation study of regorafenib (BAY 73-4506), an inhibitor of oncogenic, angiogenic, and stromal kinases, in patients with advanced solid tumors.Clin Cancer Res.2012;18(9):2658-2667
  2. Wilhelm SM, Dumas J, Adnane L, et al. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity.Int J Cancer.2011;129(1):245-255
  3. Strumberg D, Scheulen ME, Schultheis B, et al. Regorafenib (BAY 73-4506) in advanced colorectal cancer: a phase I study.Br J Cancer.2012;106(11):1722-1727
  4. Majithia N, Grothey A. Regorafenib in the treatment of colorectal cancer.Expert Opin Pharmacother. 2016;17(1):137-145