Regorafenib in the Treatment of Colorectal Cancer

George P. Kim, MD

Assistant Professor of Oncology, Department of

Hematology/Oncology, Mayo Clinic, Jacksonville, FL;

Kim.George@mayo.edu

Abstract

Regorafenib is a recently approved oral, multikinase inhibitor for refractory colorectal cancer. Although structurally similar to sorafenib, it more potently inhibits a broader spectrum of critical growth receptor pathways, including those regulating angiogenesis and aberrant cellular proliferation.

Regorafenib was evaluated in an international randomized, placebo-controlled, phase III study of 760 patients in the CORRECT trial. In the study, improvements in overall survival and progression-free survival were observed. The clinical activity with regorafenib was mainly cytostatic, with 41% of patients achieving disease stabilization and only 1% achieving response. Regorafenib proved tolerable, with side effects characteristic of other smallmolecule inhibitors.

Ongoing and future studies with regorafenib are testing its potential role combined with chemotherapy in first- and secondline therapy, as maintenance therapy, and in the postoperative setting. Regorafenib is a welcome, novel, targeted addition to the armamentarium for the treatment of colorectal cancer.

Background

Regorafenib (BAY 73-4506) is a novel, oral, multikinase inhibitor derived from efforts to optimize drug properties, breadth of activity, and potency using a diphenylurea backbone.¹Regorafenib is structurally similar to another drug in this class, sorafenib (Table^2-4), which is approved for the treatment of renal and hepatocellular cancers. Regorafenib contains a fluorine atom in the center of a phenyl ring, which results in similar yet distinct biochemical properties. Regorafenib is metabolized into two major human active metabolites M-2 (N-oxideregorafenib) and M-5 (N-oxide- and N-desmethylregorafenib), which are also potent but distinct from regorafenib in in vitro assays.⁵

M-2 inhibits key targets with similar IC₅₀values as regorafenib, while those for M-5 are slightly higher. In cell line studies, dose-dependent tumor growth inhibition was observed and was comparable to regorafenib. At steady state, both metabolites attain systemic exposure similar to the parent compound and contribute to clinical activity.⁶

Within the understanding of the hallmarks of cancer, cells self-perpetuate growth through aberrant signaling and by becoming resistant to growth inhibitory signals^.7Many growth factors and their associated receptors work in complementary, coordinated networks to regulate tumor growth. In addition, the tumor microenvironment is a critical accomplice in nurturing cancer cell processes such as angiogenesis. This complexity provides the rationale for concurrent targeting of multiple growth factors and receptor pathways to optimally develop anticancer therapies.

Regorafenib is a worthy candidate, as biochemical assays demonstrate its ability to inhibit a variety of tyrosine kinases.²The agent inhibits tumorigenic kinases such as BRAF, KIT, and RET. In addition, regorafenib inhibits the stromal and angiogenic kinases VEGFR-1, -2, -3, TIE2, PDGFR-beta, and FGFR at nanomolar (3 to 200 nM) concentrations. In in vivo experiments, antiproliferative effects are observed in both vascular and tumor cell lines: for example, VEGF-stimulated HUVECs, at an IC₅₀of 3 nM. Importantly, colon cell lines (SW620, Colo-205) tested had IC₅₀’s in the 970 nM to 3000 nM range. In colon and breast cancer xenograft models, regorafenib exhibited antiproliferative effects partly through the RAF/ MEK/ERK pathway, as well as antiangiogenic effects.

TABLE. Comparisons Between Regorafenib and Sorafenib

Regorafenib^2,3

Sorafenib⁴

Indications

Refractory CRC, refractory GI stromal tumors

Unresectable hepatocellular carcinoma, advanced RCC

Dosage

160 mg daily

400 mg BID

Schedule

Days 1 to 21 of 28-day cycle

Days 1 to 28 continuous

Targets IC50< 50 nM

VEGFR-1, -2, -3, RET, KIT, PDGFRbeta, RAF-1, B-RAF^WT, B-RAF^V600E

VEGFR-2, -3, RAF-1, B-RAF^WT, B-RAF^V600E

Pharmacokinetics Half-life Metabolism

Parent 28 h M1- 25 h, M2- 51 h CYP3A4, UGT1A9

25-48 h

CYP3A4, UGT1A9

Toxicities Grade 3 or higher

HFSR (17%), fatigue (10%), diarrhea (7%), hypertension (7%), rash/desquamation (6%)

Hypophosphatemia (11%), diarrhea (8%), HFSR (8%), hypertension (2%), abdominal pain (2%), thrombocytopenia (4%)

BID, twice daily; CRC, colorectal cancer; GI, gastrointestinal; h, hours; HFSR, hand-foot skin reaction; PDGFR, platelet-derived growth factor receptor; RAF^WT, RAF wild-type; RCC, renal cell carcinoma; VEGFR, vascular endothelial growth factor receptor.

Phase I Dose-Escalation Study of Regorafenib

In particular, pharmacodynamic effects, measured using dynamic contrast-enhanced (DCE)-MRI, were observed including both decreased contrast perfusion of tumors and decreased contrast extravasation from tumor vasculature, and were correlated with antitumor activity. In general, regorafenib demonstrated significant tumor growth inhibition in a wide range of xenografts derived from lung, melanoma, pancreatic, and ovarian tumor cell lines. Activity was seen at doses of 10 mg/kg to 30 mg/kg, which are readily achievable in clinical dosing. Regorafenib was well tolerated in mice at up to 100 mg/kg given daily without significant symptoms or death.Regorafenib was first tested in 53 patients with advanced solid tumors in a dose-escalation phase I study.⁶Safety, pharmacokinetics, pharmacodynamics, and efficacy were assessed. Patients were enrolled into eight cohorts at dosage levels ranging from 10 mg to 220 mg daily for 21 consecutive days of a 28-day cycle. The most frequent treatmentrelated adverse events (AEs) in 44 patients (83%) were hoarseness, mucositis, hand-foot skin reaction (HFSR), diarrhea, and hypertension, with the last three also being the most common grade 3/4 treatment- related events. Rash/desquamation was also a grade 3/4 event; no grade 5 treatment-related AE occurred. Serious treatment-related AEs (16 patients [30%]) included hypertension (n=3), diarrhea, infection, abdominal pain (2 each), cardiac ischemia/infarction (1), CNS hemorrhage with underlying brain metastases (1), and lipase elevation (1). Some of these events are observed with other antiangiogenic agents.

Expanded-Cohort Phase I Study of Regorafenib

This is in contrast to sorafenib, which at the maximum tolerated dose (MTD) and eventual standard dose (400 mg twice daily) resulted in grade 3 fatigue, anorexia, nausea, abdominal cramping, and HFSR.⁸In pharmacokinetic analyses, dose-dependent increases in systemic exposure were seen at the 60-mg dosage for regorafenib, and less than dose proportional increases were observed at dosages greater than 120 mg. Pharmacodynamic assessments, though, revealed antiangiogenic effects (at least 40% decreased tumor perfusion by DCE-MRI) at dosage levels of 120 mg or above. Ultimately, three evaluable patients achieved a partial response, including a patient with colorectal cancer (CRC).After the phase I trial defined the dose, schedule, and biologic activity, regorafenib was evaluated in advanced CRC—a thoughtful decision.⁹Antiangiogenic agents (bevacizumab, ziv-aflibercept) have been extensively investigated in metastatic disease and have consistently exhibited clinical benefit in several settings. For example, clinical trials demonstrate the benefit of using bevacizumab as maintenance therapy—a potential area of future research for other cytostatic agents, such as regorafenib, with favorable therapeutic indices.

The CORRECT Trial

Consequently, an expansion cohort of 23 additional patients with CRC was evaluated in addition to 15 subjects involved in the phase I trial, for a total of 38 patients. These patients were heavily pretreated with a median of four prior regimens for metastatic disease, including bevacizumab, oxaliplatin, irinotecan, and anti-EGFR antibodies. Overall, toxicities were consistent, with mainly grade 3 events (58%) consisting of HFSR, fatigue, and hypertension; one individual experienced grade 4 thrombocycotopenia. Dose reduction or delay of regorafenib was necessary in 25 patients (66%). Although only one partial response was seen, 19 patients had stable disease lasting at least 2 months, resulting in a disease control rate of 74%. Progression-free survival (PFS) was 107 days or about 3.6 months.⁹Formal evaluation of the impact of regorafenib in the treatment of CRC was conducted in an international randomized, placebo-controlled, phase III study, the CORRECT trial. A total of 760 patients were randomly assigned, in a 2:1 ratio, to receive oral regorafenib 160 mg daily for 21 consecutive days of a 28-day cycle (n=505) or placebo (n=255). The trial was designed to detect a 33% increase in overall survival (OS) with a hazard ratio (HR) of 0.75 with 90% power.³

Accrual to the trial was rapid, exceeding the target accrual within 10 months. In general, patient characteristics were balanced, although fewer patients withKRASmutations were in the regorafenib group versus the placebo group (54%vs 62%, respectively). Although it has been suggested that patients with mutantKRAStumors have a worse prognosis, it is unlikely that this imbalance impacted the final results. Importantly, 100% of patients received prior anti-VEGF treatment with bevacizumab.³

In terms of tolerability, grade 3 or higher AEs occurred in 54% of regorafenib-treated patients and included HFSR, fatigue, diarrhea, hypertension, and rash/desquamation, consistent with the phase I experience. Dose modifications were needed in 76% of patients, mainly consisting of holding at least one dose. Eight patients treated with regorafenib died while on study due to adverse events that included gastrointestinal bleeding, pulmonary hemorrhage, seizure, and sudden death. Side effects typical of antiangiogenic agents were seen, such as hypertension, whereas others, such as thromboembolism (2% in each arm), were not common.³

In terms of efficacy, the primary endpoint of the trial, OS, was met—6.4 months in the regorafenibtreated patients versus 5.0 months in the bestsupportive- care group. The HR was 0.77 (P=.0052), translating to a 23% risk reduction for death. The HR for PFS was 0.49(P<.0001), although the difference in median PFS was 0.2 months. The activity observed with regorafenib supports the drug being cytostatic, as 41% of patients had stable disease for at least 6 weeks and five patients (1%) achieved a partial response.³

Implications of the CORRECT Trial

In conclusion, the addition of regorafenib to best supportive care improved OS in patients with metastatic CRC refractory to all currently approved chemotherapy. In September 2012, the FDA approved regorafenib (Stivarga) for this indication.In addition to the CORRECT trial leading to the approval of regorafenib, the study is important for several other reasons. It is the first trial to demonstrate a survival benefit with a tyrosine kinase inhibitor (TKI) in CRC. In addition, the trial disproves the perception that drug approval cannot be achieved by testing agents in the refractory, last-line setting.

In reality, the CORRECT trial accrued patients at a rapid pace, and reservations regarding randomization to placebo were insignificant. In the community, it has been observed that greater numbers of patients with advanced CRC are exhausting available agents while still having excellent functional status. These patients actively seek subsequent treatment options, and after being considered for early drug development trials, there are now three agents available: regorafenib and the EGFR inhibitors cetuximab and panitumumab in patients withKRASwild-type disease.

The CORRECT trial and several other recently reported studies (TML 18147- phase III study that demonstrated continuation of bevacizumab from first- into second-line treatment improved survival10; VELOUR- phase III trial with the VEGF decoy receptor aflibercept and FOLFIRI, which demonstrated an OS benefit¹¹) with antiangiogenic agents also collectively debunk concerns regarding resistance to antiangiogenic therapy. In aggregate, these studies support use of antiangiogenic agents throughout the spectrum of treatment of patients with advanced CRC.

Both TML 18147 and VELOUR were second-line trials in which patients had received bevacizumab as a component of their first-line therapy. Despite this, in both studies improved survival was seen in patients administered a subsequent antiangiogenic therapy combined with cytotoxic chemotherapy. Similarly, in CORRECT, 100% of patients received prior bevacizumab, but subsequent exposure did not limit the observed benefit.

The Future for Regorafenib

These observations demonstrate that metastatic CRC maintains sensitivity to angiogenesis-targeting agents across the spectrum of multiple lines of treatment. Clearly, angiogenesis is a dynamic process, and when to optimize targeting it—for example, using serial biomarkers&mdash;remains to be elucidated. A caveat to this is that the degree of benefit from subsequent antiangiogenic treatment remains to be defined--a subset of bevacizumab-na&iuml;ve patients in the VELOUR trial appeared to benefit more than patients treated previously with bevacizumab. The test for interaction was negative (P=.57), although this can also be interpreted as merely having insufficient power to detect a difference.What is the future for regorafenib? As described, oncologists will use this agent in refractory patients who have progressed through approved treatments but have preserved performance status. As with sorafenib, toxicities will be encountered that collectively can be significant enough to require withholding of regorafenib. Importantly, the formulation of 40-mg tablets allows for greater flexibility in titrating to tolerability.

An update from the CORRECT trial reveals that at around cycle 3, the average dosage was 120 mg daily— roughly 75% of the trial-mandated 160-mg dose.12 Also in this analysis, focus on the time course of AEs reveals that the most common toxicities (fatigue, hypertension, HFSR, and rash/desquamation) peaked early in treatment&mdash;in cycle 1&mdash;and thereafter tapered in incidence. The incidence of diarrhea persisted at roughly 18% to 26% throughout treatment. No cumulative toxicity was observed.

As is common in drug development, regorafenib is being advanced in lines of therapy, and there are ongoing trials with FOLFIRI or FOLFOX. Recently, Schultheis and colleagues13 reported their efforts to define the safety profile of regorafenib in combination with FOLFOX or FOLFIRI. Standard dosages and schedules of chemotherapy were given, and regorafenib 160 mg was taken on days 4-10 and 18-24 of a 28-day cycle (33% less drug than in the CORRECT trial). This schedule was selected because regorafenib is a strong inhibitor of the glucuronosyltransferases, the enzymes that inactivate SN—38, the active metabolite of irinotecan, by glucuronidation.

Clinical Pearls

• Regorafenib (160 mg daily for 21 consecutive days of a 28-day cycle) is the first approved oral multikinase inhibitor with clinical activity in CRC
• Regorafenib improves OS in patients with refractory, metastatic CRC,with the majority of patients achieving disease stabilization
• The side effects with regorafenib are manageable and occur early in its usage; treatment initiation at 75% of dose or 120 mg per day may improve initial patient tolerance and compliance
• Regorafenib is a new standard of care for patients with refractory CRC and will be further tested in combination with chemotherapy, as maintenance therapy, and in the postoperative setting in patients undergoing metastectomy

Patients with metastatic CRC were treated in either the first-line (67%) or second-line setting. In the majority of patients (52% with FOLFOX and 65% with FOLFIRI), dose reduction or interruption of at least one of the chemotherapy components was required. Remarkably, compared with the CORRECT trial, fewer grade 3 or higher treatment-related AEs were observed, especially with regard to fatigue, diarrhea, HFSR, and rash/desquamation. In terms of pharmacokinetics, irinotecan and SN-38 exposure were significantly increased: 28% and 44%, respectively, despite the altered regorafenib dosing.¹³

Other trials with regorafenib and chemotherapy include a phase II trial with 54 patients combining FOLFOX with regorafenib as first-line therapy (ClinicalTrials. gov identifier: NCT01289821). Patients were allowed to continue treatment with regorafenib monotherapy if treatment-limiting toxicities, such as oxaliplatin-induced neuropathy, were experienced. The results of the study are awaited, but a planned phase III trial has been placed on hold. A randomized, multicenter phase II study in the second-line setting comparing FOLFIRI plus regorafenib to FOLFIRI plus placebo is accruing (ClinicalTrials.gov identifier: NCT01298570). The study is designed to compare PFS between the two arms in patients (N =240) withKRAS- orBRAF-mutant metastatic CRC previously treated with FOLFOX.

Summary

Based on these data and the history of challenges with combining small-molecule inhibitors and chemotherapy, regorafenib monotherapy approaches may prove more meaningful. It is important to again highlight that most of the clinical benefit in the CORRECT trial was disease stabilization: 41% had stable disease for 6 weeks, while only 1% of patients had partial responses. Certainly, taking pills at home on a daily basis while one&rsquo;s cancer is stable has virtue. Regorafenib is uniquely qualified to fulfill this role due to its cytostatic activity and manageable toxicities. The strategy of &ldquo;induction&rdquo; chemotherapy, typically FOLFOX followed by a maintenance treatment such as infusional 5FU or bevacizumab, is worthwhile and preserves quality of life, as seen in the OPTIMOX and CONCEPT trials. Regorafenib could readily be substituted into the maintenance phase. Another setting to consider incorporating regorafenib is as an adjuvant or after surgery, perhaps after resection of stage IV disease, where recurrence risk remains high.The addition of regorafenib to the CRC armamentarium represents an advance in the treatment of this disease. The drug is oral, can be taken at home, and has manageable side effects. Regorafenib will continue to be evaluated in other settings—combined with chemotherapy, as maintenance therapy, as adjuvant treatment after resected metastatic disease&mdash;allowing its full potential to impact outcomes in advanced CRC to be realized.

Author Disclosure

Dr. Kim has been a consultant for Bristol-Myers Squibb, Genentech, Regeneron Pharmaceuticals, Inc., and sanofi-aventis, and has conducted research for Amgen Inc., Genentech, and Eli Lilly and Company.

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