509792

research-article2013

AOPXXX10.1177/1060028013509792Annals of PharmacotherapyCrona et al

Review Article-New Drug Approvals

Regorafenib: A Novel Multitargeted Tyrosine Kinase Inhibitor for Colorectal Cancer and Gastrointestinal Stromal Tumors

Annals of Pharmacotherapy 47(12) 1685­–1696 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013509792 aop.sagepub.com

Daniel J. Crona, PharmD1, Meredith D. Keisler, PharmD2, and Christine M. Walko, PharmD, BCOP1,3

Abstract Objective: To review currently available literature on the oral multikinase inhibitor regorafenib and its role in the treatment of metastatic colorectal cancer (mCRC), and imatinib- and sunitinib-resistant gastrointestinal stromal tumors (GISTs). Data Sources: A comprehensive literature search was performed of PubMed/MEDLINE and American Society of Clinical Oncology (ASCO) abstracts (through August 2013). Study Selection/Data Extraction: Preclinical pharmacological and phase I to III trials data analyzing regorafenib efficacy and safety in mCRC or imatinib- and sunitinibresistant GIST patients were evaluated. All available English-language, peer-reviewed articles and ASCO abstracts with relevant information were reviewed. Data Synthesis: Regorafenib was approved for mCRC in September 2012 and for imatinib- and sunitinib-resistant GISTs in February 2013. Regorafenib is an inhibitor of stromal, angiogenic, and oncogenic receptor tyrosine kinases, as well as the RAF/MEK/ERK signaling pathway. Phase III CORRECT (Regorafenib Monotherapy for Previously Treated Metastatic Colorectal Cancer) trial data demonstrated an overall survival benefit for mCRC patients treated with regorafenib (6.4 vs 5.0 months; P = .0052). Phase III GRID (Gastrointestinal Stromal Tumors After Failure of Imatinib and Sunitinib) trial data revealed a progression-free survival benefit in imatinib- and sunitinib-resistant GIST patients (4.8 vs 0.9 months; P < .0001). Its adverse event (AE) profile is comparable to that of other multikinase inhibitors. The most commonly observed grade ≥3 AEs included hypertension, hand-foot skin reaction, rash, diarrhea, and fatigue. Conclusions: Regorafenib is a novel oral multikinase inhibitor that has shown promising results for patients with advanced, unresectable or metastatic treatment-refractory CRCs or imatinib- and sunitinib-resistant GISTs. Keywords regorafenib, colorectal cancer, gastrointestinal stromal tumors

Introduction Colorectal cancer (CRC) is the fourth most commonly diagnosed cancer, and the second leading cause of cancer death among both men and women, in the United States.1,2 Although systemic chemotherapy used for metastatic CRC (mCRC) has improved survival, it is rarely administered with curative intent for patients with stage IV disease.3 Combination regimens with a fluoropyrimidine backbone and leucovorin plus oxaliplatin and/or irinotecan, are the standard of care for patients with mCRC. Current guidelines from the National Comprehensive Cancer Network (NCCN) also suggest considering the addition of a monoclonal antibody (bevacizumab) targeting inhibition of the vascular endothelial growth factor (VEGF) pathway to certain frontline regimens, the option of using ziv-aflibercept in irinotecan-naïve patients receiving FOLFIRI (5-fluorouracil, leucovorin, and

irinotecan), or the addition of an antibody (cetuximab or panitumumab) targeting epidermal growth factor receptor (EGFR) inhibition in patients without KRAS-mutated tumors.4 However, there is an unmet therapeutic need for patients who progress despite treatment with standard 1

University of North Carolina (UNC) Eshelman School of Pharmacy, NC, USA 2 UNC Hospitals and Clinics, Chapel Hill, NC, USA 3 UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA Corresponding Author: Daniel J. Crona, PharmD, UNC Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, Institute for Pharmacogenomics and Individualized Therapy, 1023C Genetic Medicine Building, 120 Mason Farm Rd, CB #7361, Chapel Hill, NC 27599-7361, USA. Email: [email protected]

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first- and second-line therapies, and new agents are needed for mCRC patients who remain viable candidates for further treatment. Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the gastrointestinal tract, with approximately 60% originating in the stomach and 35% in the small intestine.5 Only 5000 new cases of GIST are diagnosed annually in the United States, but 95% of GIST tumors are positive for c-KIT (CD117) receptor tyrosine kinase (RTK), and 60% to 80% of GISTs harbor a c-KIT mutation.6,7 Thus, the development of targeted agents directed at c-KIT inhibition have become the primary treatment paradigm for GIST patients. Data from the preoperative and postoperative settings support the use of imatinib as the first-line agent of choice for treating GISTs.8-10 But, secondary resistance, predominantly developing from mutations in c-KIT exon 11, can occur in GIST patients on imatinib for at least 6 months.11 Imatinib resistance can be managed by dose escalation or through the use of sunitinib for these GIST patients.12 Prior to regorafenib approval, options were limited for patients who developed resistance to both imatinib and sunitinib. Regorafenib (BAY 73-4506; Stivarga; Bayer HealthCare Pharmaceuticals, Inc.) is an orally administered inhibitor of numerous kinases involved in oncogenesis, angiogenesis, and maintenance of the tumor microenvironment.13 In September 2012, the US Food and Drug Administration (FDA) approved regorafenib for the treatment of mCRC patients who had failed fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy regimens; an antiVEGF pathway therapy; and an anti-EGFR therapy (for KRAS wild-type patients). In February 2013, the FDA expanded the regorafenib label to include an indication for the treatment of locally advanced, unresectable or metastatic GIST in patients who had previously failed imatinib and sunitinib. This article reviews the preclinical and clinical literature that led to the approval of regorafenib and examines its place in therapy for the treatment of mCRC and GIST.

Data Sources and Selection A comprehensive literature search was performed of PubMed/MEDLINE and American Society of Clinical Oncology abstracts (through August 2013), using the primary search terms regorafenib, Stivarga, BAY 73-4506, colorectal cancer, and GIST. When possible, Medical Subject Headings (MeSH) were used as part of the search strategy. All English-language publications that described regorafenib pharmacology, pharmacokinetics (PK), pharmacodynamics (PD), clinical efficacy, and/or treatment-related adverse events (AEs) were reviewed. Special attention was paid to published clinical data from regorafenib trials that

enrolled either mCRC or imatinib- and sunitinib-resistant GIST patients. Prescribing information from Bayer HealthCare’s package insert was included in this review to complement preclinical and clinical trial data. Published and unpublished clinical trials were also identified in the national clinical trial registry, http://www.clinicaltrials.gov.

Pharmacology Regorafenib is an orally administered multikinase inhibitor of both intracellular and membrane-bound RTKs integral to angiogenesis, oncogenesis, maintenance of the tumor microenvironment, and tumor growth/proliferation signaling pathways. Regorafenib is a diphenylurea with a chemical structure and biochemical profile similar to that of sorafenib, a multikinase inhibitor approved for the treatment of advanced renal cell carcinoma and unresectable hepatocellular carcinoma. But the addition of a fluorine atom to regorafenib’s center phenyl ring leads to a pharmacologically more potent agent with a broader spectrum of antiangiogenic activity than sorafenib (Table 1).13 Its molecular formula is C21H15ClF4N4O3·H2O, and it has a molecular weight of 500.83.14 In vitro biochemical assays, using a standard 1-µM regorafenib dose, revealed potent inhibition of angiogenic and stromal RTKs, including VEGF receptors-1-3, plateletderived growth factor receptor-β (PDGFR-β), tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2, and fibroblast growth factor (FGF) receptor-1 at mean half maximal inhibitory concentration (IC50) values ranging from 4.2 to 311 nM. Regorafenib also inhibits oncogenic RTKs, such as RET and c-KIT, as well as the serine/threonine receptor kinase RAF-1, wild-type BRAF, and mutant BRAFV600E at mean IC50 values ranging from 1.5 to 28 nM (Table 1). Cellular kinase phosphorylation assays confirmed these biochemical assay results. Biochemical assays also revealed that regorafenib inhibits additional kinases (DDR2, Eph2A, PTK5, p38α, and p38β) with IC50 values >100 nM, but cellular assays were not performed to confirm these results.13 A series of in vitro experiments demonstrated the antiproliferative effects of regorafenib. It effectively inhibited proliferation of VEGF165 and FGF-2-stimulated human umbilical vascular endothelial and human aortic smooth muscle cells stimulated with the BB dimeric glycoprotein of PDGF (IC50 = 2.6 and 146 nM, respectively). Regorafenib also inhibited several additional tumor (breast, pancreas, thyroid, melanoma, GIST, and CRC) cell lines at mean IC50 values less than 1 µM. Notably, regorafenib inhibited GIST882 cells with the c-KITK642E mutant receptor (IC50 = 22 nM). Dose-dependent inhibition of tumor growth was also observed in CRC, breast cancer, and renal cell carcinoma mouse xenograft models,

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Crona et al Table 1. IC50 (nM) Values for Regorafenib and Sorafenib. Molecular Target Biochemical Activity

Sorafenib IC50 (nM) ± SD15

VEGFR-1 VEGFR-2 mVEGFR-2 mVEGFR-3 Raf-1 BRAF WT BRAFV600E FGFR-1 PDGFR-β c-KIT Flt-3 RET TIE2

NA 90 ± 15 15 ± 6 20 ± 6 6±3 22 ± 6 38 ± 9 580 ± 100 57 ± 20a 68 ± 21 58 ± 20 NA NA

Regorafenib IC50 (nM) ± SD13 13 ± 0.4 NA 4.2 ± 1.6 46 ± 10 2.5 ± 0.6 28 ± 10 19 ± 6 202 ± 18 22 ± 3 7±2 NA 1.5 ± 0.7 311 ± 46

Abbreviations: IC50, half maximal inhibitory concentration; SD, standard deviation, VEGFR, vascular endothelial growth factor receptor; BRAF WT, BRAF wild type; FGFR, fibroblast growth factor receptor; PDGFR, platelet-derived growth factor receptor; TIE2, tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2. a Murine PDGFR-β.

where daily regorafenib doses ranging from 10 to 100 mg/ kg were utilized. Furthermore, immunohistochemistry detected decreased pERK1/2, further demonstrating regorafenib’s antiproliferative effects through RAF/MEK/ ERK signaling cascade inhibition.13 Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with Gadomer-17 contrast was used to demonstrate the PD effects of regorafenib on tumor vasculature. Rat GS9L glioblastoma xenografts exposed to regorafenib revealed decreased tumor perfusion and decreased Gadomer-17 extravasation. In mice treated with 4 consecutive daily doses, antiangiogenic effects were observed for at least 4 days after the last dose. Decreased microvessel area, measured by immunohistochemistry, demonstrated regorafenib’s antiangiogenic effects on tumor vasculature in CRC and breast cancer xenografts.13

Pharmacokinetics Preclinical data and a 2-part phase I clinical trial drove the characterization of regorafenib’s PK profile.14,16,17 The initial part of the trial was the first-in-human, open-label, nonrandomized dose-escalation portion and evaluated the PK, PD, safety, and efficacy profiles of regorafenib in patients with advanced solid tumors. These patients received 10 to 220 mg of regorafenib daily. During the first cycle of the dose escalation study, regorafenib was not administered on day 2, which allowed for single-dose pharmacokinetic evaluations.16 An expansion cohort (n = 38)

was then enrolled to further investigate regorafenib solely in patients with mCRC. The 15 mCRC patients from the phase I dose-escalation study who were enrolled in the expansion cohort received daily doses ranging from 60 to 220 mg, whereas the remaining 23 patients received 160 mg of regorafenib daily.16,17 Plasma concentration versus time profiles revealed a multipeak shape for regorafenib, its active N-oxide metabolite (M-2), and its active N-oxide/N-desmethyl metabolite (M-5), which is indicative of extensive enterohepatic recycling. Peak plasma concentrations of regorafenib, M-2, and M-5 were first observed at 1 to 6 hours after administration, at 6 to 8 hours, and finally at approximately 24 hours.16 Maximum plasma concentration (Cmax) for patients administered a single 160-mg dose reached 2.5 mg/L and a mean area under the plasma concentration-time curve (AUC) of 70.4 mg h/L.14,16 At steady state, regorafenib, M-2, and M-5 achieved a Cmax of 3.9, 3.3, and 2.9 mg/L, respectively. Repeated doses resulted in plasma accumulation of the parent drug and active metabolites, as evidenced by 2- to 4-fold increases in Cmax.16 Dose-dependent increases in systemic regorafenib exposure (AUC0-24,md) were observed at doses ranging from 10 to 60 mg, whereas less-than-dose-proportional increases in exposure were detected at doses ≥120 mg. But, at steady state, systemic regorafenib exposure was comparable to M-2 and M-5 metabolites for patients in the dose-escalation study treated with 160 mg daily (58.3, 53.7, and 48.7 mg h/L, respectively).16 For expansion cohort patients treated with 160 mg, systemic exposure of M-2 (48 mg h/L) and M-5 (65–79 mg h/L) were similar to, if not slightly greater than, parent regorafenib (45-50 mg h/L).17 The mean bioavailability of regorafenib tablets is 69%. Regorafenib, M-2, and M-5 are highly bound to plasma proteins (≥99.5%). Cytochrome P450 (CYP) and uridine 5′-diphospho-glucuronosyltransferase (UDP glucuronosyltransferase, UGT) enzymes mediate regorafenib metabolism. Phase I CYP3A4-mediated oxidative metabolism results in the formation of M-2 and M-5, whereas phase II UGT1A9-mediated glucuronidation inactivates regorafenib. Regorafenib is primarily cleared through biliary elimination, with approximately 71% of a 120-mg radiolabeled dose recovered in the feces (47% as regorafenib, 24% as metabolites) and 19% excreted in the urine (17% as glucuronides).14 The terminal elimination half-life for regorafenib (26-28 hours) was similar to that for M-2 (25 hours), whereas M-5 was eliminated at a slower rate (51-64 hours).14,17

Dosage and Administration The FDA-approved dose of regorafenib for mCRC and GIST is 160 mg daily for the first 21 days of each 28-day

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Table 2.  Regorafenib Dose Modifications.14 Toxicity Gradea

Dose Modification

Hepatotoxicity   Grade 3 AST and/or ALT elevation   AST or ALT >20× ULN   AST or ALT >3× ULN and bilirubin >2× ULN   Reoccurrence of AST or ALT >5× ULN despite dose reduction to 120 mg Dermatological toxicity   Grade 2 HFSR of any duration   Grade 3 HFSR Additional AEs   Grade 2 hypertension   Additional grade 3 or 4 AEs   Gastrointestinal perforation or fistula   Severe or life-threatening hemorrhage  RPLS   Wound dehiscence   Failure to tolerate 80 mg dose for any reason

Withhold dose until recovered; consider resuming at 120 mg once dailyb Discontinue permanently Discontinue permanently Discontinue permanently 120 mg Once daily for first occurrencec Interrupt therapy for a minimum of 7 days; then, reduce dose to 120 mg once dailyd Interrupt therapy Interrupt therapy, and on recovery, reduce to 120 mg once dailye Discontinue permanently Discontinue permanently Discontinue permanently Discontinue permanently Discontinue permanently

Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotrasferase; ULN, upper limit of normal; HFSR, hand foot skin reaction; AE adverse events; RPLS, reversible posterior leukoencephalopathy syndrome. a National Cancer Institute Common Terminology Criteria for Adverse Events v3.0.18 b If recurrence of AST or ALT >5 times ULN despite dose reduction to 120 mg, discontinue permanently. c If grade 2 HFSR continues at 120 mg, then reduce to 80 mg once daily; if grade 2 HFSR continues at 80-mg dose for at least 7 days, then interrupt dose. d If grade 2 to 3 HFSR recurs at 120 mg, then reduce dose to 80 mg once daily on recovery; if grade 2 to 3 HFSR continues at 80 mg dose for at least 7 days, then interrupt dose. e If grade 3 to 4 AE occurs at 120 mg, then reduce dose to 80 mg once daily on recovery; for any grade 4 toxicity, ensure that the benefits of regorafenib outweigh safety risks before resuming; permanently discontinue if unable to tolerate 80-mg dose.

cycle. Regorafenib should be administered at the same time every day, preferably each morning with a low-fat breakfast (16 weeks

Not randomized

60-220 mg Daily (21 days on/7 days off); 26 patients received 160 mg

•  D  efine MTD, PK, and safety profile of regorafenib •  Evaluate PD end points and tumor response/progression

•  M  edian PFS = 3.6 months (95% CI = 2.2-5.6 months) •  PR in 1 patient, stable disease in 19 patients

Abbreviations: mCRC, metastatic colorectal cancer; GIST, gastrointestinal stromal tumor; CORRECT, Regorafenib Monotherapy for Previously Treated Metastatic Colorectal Cancer; OS, overall survival; PFS, progression-free survival; HR, hazard ratio; GRID, Gastrointestinal Stromal Tumors After Failure of Imatinib and Sunitinib; TTP, time to progression; ORR, objective response rate; CR, complete response; PR, partial response; MTD, maximum tolerated dose; PK, pharmacokinetics; PD, pharmacodynamics. a Primary end points are bolded. b Per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.22

patients enrolled on the dose-escalation study. Patients from the dose-escalation study were heavily pretreated, having received a median of 3 previous regimens. Data demonstrated that the daily160 mg dose of regorafenib was safe and tolerable to patients.16 Based on safety and efficacy data from the dose-escalation study, an expansion cohort of patients were enrolled (n = 23) in the second portion of the trial to evaluate regorafenib safety and efficacy solely in mCRC patients (n = 38; Table 3).17 The 15 patients from the dose-escalation study received daily regorafenib at doses ranging from 60 to 220mg, whereas the remaining 23 patients received 160 mg daily.16,17 Expansion cohort patients were also heavily pretreated, having received a median of 4 previous regimens. In addition, 59% of the patients had previous exposure to cetuximab, and 44% had previously received bevacizumab.17 Safety end points were assessed according to the National Cancer Institute’s Common Terminology Criteria for Adverse

Events (CTCAE) version 3.0.18 In the expansion cohort, 84% of the patients experienced treatment-related AEs. All regorafenib-related AEs were grade 3 or lower, with the exception of 1 reported case of asymptomatic grade 4 thrombocytopenia. No grade 5 toxicities were reported. Dose reductions were required in 66% of patients, and hand foot skin reaction (HFSR) was the AE most commonly responsible for dose reductions. Overall, 11 patients discontinued the trial because of regorafenib-related AEs, and 6 of them received 160 mg daily. Disease response, evaluated as a secondary end point, was defined based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0.23 Among the 27 patients who were evaluable at the conclusion of cycle 2, the disease control rate was 74%. A total of 19 patients (70%) experienced stable disease as their best response, whereas one confirmed partial response (PR) was achieved (4%). Tumor shrinkage was observed in 13 patients (48%). Median progression-free survival (PFS) was 107 days, and 13 patients

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achieved PFS >100 days.17 DCE-MRI evaluated PD end points, which included regorafenib’s effects on tumor perfusion and angiogenesis. DCE-MRI revealed reduced tumor perfusion by approximately 35% on day 21 of cycle 1 and then by approximately 50% on day 21 of cycle 2, thus demonstrating regorafenib’s effective inhibition of angiogenic kinases.17 Based on the phase I safety and efficacy data, the Regorafenib Monotherapy for Previously Treated Metastatic Colorectal Cancer (CORRECT) trial was conducted. This multinational, multicenter, randomized, placebo-controlled phase III trial (Table 3) enrolled 760 patients in a 2:1 ratio to either regorafenib 160 mg daily (n = 505) or placebo (n = 255). All patients also received best supportive care (BSC), and cross-over was not permitted during CORRECT. Primary and secondary end points were defined based on RECIST v1.1.22 The primary end point of the trial was overall survival (OS), defined as time from randomization to death from any cause. Secondary end points included the following: PFS (time from randomization to first radiographic or clinical observation of progression, or death from any cause), objective tumor response rate (ORR; proportion of patients with complete response [CR] or PR), disease control rate (proportion of patients with CR or PR, or stable disease), and toxicity. Tertiary trial end points included duration of response and stable disease, and health-related quality-of-life (QoL) and healthy utility values (using a European Organization for Research and Treatment of Cancer [EORTC] general health status and quality-of-life [QLQ-C30] questionnaire and the EuroQol five-dimension [EQ-5D] index questionnaire).19 All patients enrolled on CORRECT were heavily pretreated, having received prior treatment with a fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab. Wild-type KRAS patients had also received either cetuximab or panitumumab. Nearly half of all CORRECT patients had received 4 or more previous regimens. All baseline characteristics were comparable between the 2 trial arms, with the exception that a lower proportion of patients harbored a KRAS mutation in the regorafenib arm (54%) than in the placebo arm (62%).19 Results from CORRECT revealed significantly improved OS for regorafenib-treated patients (hazard ratio [HR] = 0.77; 95% CI = 0.64-0.94; P = .0052). Median OS was 6.4 months in the regorafenib arm, compared with 5.0 months in the placebo arm. Subgroup analyses revealed an OS benefit in regorafenib-treated patients

Regorafenib: a novel multitargeted tyrosine kinase inhibitor for colorectal cancer and gastrointestinal stromal tumors.

To review currently available literature on the oral multikinase inhibitor regorafenib and its role in the treatment of metastatic colorectal cancer (...
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