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REVIEW ARTICLE
Year : 2015  |  Volume : 52  |  Issue : 3  |  Page : 257-260
 

Regorafenib: A novel tyrosine kinase inhibitor: A brief review of its therapeutic potential in the treatment of metastatic colorectal carcinoma and advanced gastrointestinal stromal tumors


Department of Pharmacology, PGIMER, Chandigarh, India

Date of Web Publication18-Feb-2016

Correspondence Address:
H Singh
Department of Pharmacology, PGIMER, Chandigarh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.176690

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 » Abstract 

Regorafenib is a novel oral multitargeted tyrosine kinase inhibitor having both antitumor and anti-angiogenic activities. Regorafenib was recently approved by US Food and Drug Administration in February 25, 2013 in the treatment for patients with advanced gastrointestinal stromal tumor and for the treatment of patients with metastatic colorectal carcinoma after disease progression or intolerance to imatinib mesylate and sunitinib therapy. Oral regorafenib demonstrates a high level of efficacy with acceptable tolerability with the 160 mg daily for 3 weeks followed by 1 week off schedule; a continuous schedule could be of interest. Hypertension, mucositis, hand foot skin reaction, diarrhea and asthenia are the most common side-effects. Regardless of these encouraging results, studies investigating, adjuvant and neoadjuvant settings are awaited, as well as trials using regorafenib in combination with chemotherapy or other targeted therapies. Clinical trials investigating regorafenib in other tumor types are ongoing.


Keywords: Colorectal carcinoma, gastrointestinal stromal tumor, regorafenib, targeted therapy control


How to cite this article:
Thangaraju P, Singh H, Chakrabarti A. Regorafenib: A novel tyrosine kinase inhibitor: A brief review of its therapeutic potential in the treatment of metastatic colorectal carcinoma and advanced gastrointestinal stromal tumors. Indian J Cancer 2015;52:257-60

How to cite this URL:
Thangaraju P, Singh H, Chakrabarti A. Regorafenib: A novel tyrosine kinase inhibitor: A brief review of its therapeutic potential in the treatment of metastatic colorectal carcinoma and advanced gastrointestinal stromal tumors. Indian J Cancer [serial online] 2015 [cited 2019 Jun 19];52:257-60. Available from: http://www.indianjcancer.com/text.asp?2015/52/3/257/176690



 » Introduction Top


The various tyrosine kinase receptors namely platelet-derived growth factor receptors (PDGFRs), vascular endothelial growth factor receptors (VEGFRs), fibroblast growth factor receptors (FGFRs) and their ligands, have been shown to play important roles in the signaling pathway in the tumor growth and their vascular supply.[1] The development of antibodies in the inhibition of VEGF signaling [2] or VEGFR antagonists has demonstrated potent antitumor effects in cases of resistance to classical anticancer agents.[3] The humanized anti-VEGF monoclonal antibody, bevacizumab in combination with chemotherapy was associated with an increased survival in patients with advanced solid tumors most commonly involving the colon cancer.[4]

Regorafenib

Regorafenib (BAY 73-4506) is an orally active diphenylurea multikinase inhibitor developed by Bayer targeting angiogenic, oncogenic and the stromal component. The various molecular targets of this oral drug were C-RAF, BRAF and VEGFR-1, 2 and 3. The antitumor activity is mediated by the inhibition of VEGFR-1, VEGFR-2 and VEGFR-3, which is the angiogenic component, tyrosine-protein kinase receptor (TIE-2) protooncogene c-Kit, tyrosine-protein kinase receptor (RET), protooncogene RAF-1, BRAF and the p38 mitogen-activated protein (MAP) kinase, which were oncogenic component and basic FGFR-1 and PDGFR-b constituting the stromal component. Regorafenib appears to be pharmacologically more potent by the presence of the fluorine atom in the phenyl ring than structurally similar sorafenib with broader anti-angiogenic properties as shown in many in vitro biochemical studies. In addition, the inhibition of MAP kinase p38 in particular is a peculiar characteristic of regorafenib.[5],[6]


 » Pharmacokinetic Top


Absorption

The oral absorption is good with regorafenib. After a single dose of 160 mg maintaining the steady state concentration to have its anti-tumor activity, which was evident from the biochemical as well as the tumor response activity.[5],[6],[7]

Distribution

Regorafenib is highly bounded to human plasma proteins (99.5%), which undergo enterohepatic circulation maintaining 24-h dosing interval.

Metabolism

It is metabolized by microsomal enzymes CYP3A4 and UGT1A9 to metabolites M2 (N-oxide) and M5 (N-oxide and N-desmethyl). The metabolites M-2 and M-5 are highly protein bound (99.8% and 99.95%) respectively. Since it is metabolized by CYP3A4 and the drug which inhibit or induces its metabolism may lead to an increase/decrease in the plasma concentration of regorafenib and subsequent failure of treatment or toxicity.

Elimination

The elimination half-lives for regorafenib and its metabolite M2 in plasma are 28 h (14-58 h) and 25 h (14-32 h), respectively. The metabolite M5 has a longer elimination half-life of 32-70 h with a median of 51 h. Major route of excretion is in the feces (71%) and rest (19%) is excreted in the urine.

Preclinical and clinical data

In an in vitro preclinical study, the inhibitory concentration of 50% for the various targets of inhibition was determined by the kinase assay [Table 1]. The cell assay was done with 5-10 nM-10 µM concentration of regorafenib and in in vivo study, the drug was given orally in the dose of 3, 10, 30 and 100 mg/kg to rodents and the tumor response and the plasma concentration was determined.[5]
Table 1: IC50 values of ragorafenib for various targets determined by in vitro studies

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In a Phase I clinical study,[8] the safety, pharmacokinetics, pharmacodynamics and tumor response, regorafenib was administered in patients with advanced solid tumors for 21 days with 7 days off. The drug was given orally at a dose of 10-120 mg/day for 22 patients. It was well-tolerated at a dose of 60 mg/day, but with a dose of 120 mg/day, dose-limiting toxicities such as fever, hand-foot skin reactions, leukopenia and fatigue were identified.

A dose escalation study [9] was conducted in a total of 53 patients with advanced solid tumors and progressive disease (PD) who were given once daily oral regorafenib up to 220 mg. The most common drug-related adverse events (AEs) noticed were hoarseness, hand-foot skin reaction, mucositis, diarrhea, rash, fatigue and hypertension. The pharmacokinetic analysis done at day 1 and day 21 of each cycle revealed a similar exposure at steady state for the parent and two active metabolites in dose-dependent increase up to 160 mg and 220 mg in case of metabolites. From the result of dose escalation study, the recommended dose for Phase II study was 160 mg/day using the 21 days on/7 days off in treatment schedule.

In another Phase I dose-escalation study,[10] where this drug was administered continuously without a break for a total of 38 patients with advanced solid tumors in a dose of once daily 20-140 mg regorafenib orally, the median treatment duration was found to be 73 days. Drug-related AEs were comparable with that of break treatment with skin toxicity as the most common dose-limiting toxicity observed. Steady-state exposure of regorafenib was increased from 20 to 140 mg. The maximum tolerated dose for continuous oral daily administration was 100 mg.

Regorafenib in colorectal carcinoma

The objective tumor regression was noticed in patients with advanced CRC during the course of the first Phase I dose-escalation study,[11] in which regorafenib was administered for 21 days on/7 days off treatments providing the rationale for an extension cohort in patients refractory to previous treatments including bevacizumab (44%) and cetuximab (59%).

A total of 38 patients with actively progressing CRC were finally analyzed,[12] who were treated with regorafenib at doses of 60, 120, 160 and 220 mg once daily. The toxicities were comparable with the dose-escalation study. The treatment-related AEs leading to dose reduction, interruption or discontinuation were hand-foot skin reaction (26%), fatigue (18%), thrombopenia (8%) and hypertension (5%). Partial response was seen in one patient, stable disease was noticed in 21 patients with 15 had stable disease at least 7 weeks after the start of treatment and six for more than 23 weeks. The pharmacodynamics plasma bio-markers demonstrated a decrease in soluble VEGFR-2 and decreased gadolinium-diethylenetriamine penta-acetic acid uptake during the study.[13] The result from the evaluable patient showed promising clinical response with regorafenib in heavily pre-treated metastatic CRC (mCRC). This data provided the rationale to evaluate regorafenib for the treatment of patients with mCRC who have progressed after standard therapies in Phase III clinical trial.

In another Phase 1 study,[14] the combination of regorafenib sequentially administered with either FOLFOX or FOLFIRI regimes in patients of CRC was evaluated. In this study, a total of 45 patients with FOLFOX group (n = 25) and FOLFIRI group (n = 20) were enrolled. Regorafenib with this combination had no significant effect on the pharmacokinetics of platinum and 5-fluorouracil but the exposure of SN-38 (the active metabolite of irinotecan) increased by 32%. After analyzing the result, the authors concluded that regorafenib, when administered sequentially with standard chemotherapy, has shown acceptable tolerability and promising activity in first-and second-line patients with CRC.

In an international Phase III randomized 2:1, double-blinded, placebo-controlled trial (Study 14387) that enrolled 760 patients with previously treated mCRC,[15] patients received prior treatment with platinum compounds, antimetabolites and irinotecan-based chemotherapy and with the monoclonal antibody against VEGF, bevacizumab. One of patients with Kirsten rat sarcoma viral oncogene homolog (K-RAS) wild-type tumors received the anti-epidermal growth factor receptor therapies with antibodies panitumumab or the small molecule peptide cetuximab. In regorafenib arm, the patients received 160 mg regorafenib orally once daily for the 1st 21 days of each 28-day cycle with the best supportive care. In the control group, matching placebo with best supportive care was given. The primary end point was overall survival and progression free survival. A statistically significant prolongation in end point overall survival was observed in patients randomly assigned to regorafenib arm with a hazard ratio (HR) 0.77, 95% confidence intervals (CI): 0.64-0.94; P = 0.0102. The median survival time was 6.4 months in regorafenib (95% CI: 5.8, 7.3) versus 5.0 months (95% CI: 4.4, 5.8) in the placebo group. The progression free survival was also demonstrated statistically significant (HR 0.49 [95% CI: 0.42-0.58]; P < 0.0001). The median progression-free survival was 2.0 months (95% CI: 1.9-2.3) in the regorafenib group and 1.7 months (95% CI: 1.7-1.8) in the placebo group. Five patients (1%) in the regorafenib group and one patient (0.4%) in the placebo group experienced partial responses.

The safety population in this study comprised regarofenib group of 500 patients and 253 placebo group patients. The most frequently observed adverse drug reactions (in at least 30% of patients) in those receiving regorafenib were similar side effects obtained in Phase I clinical studies such as hand-foot skin reactions, rashes, mucositis, fatigue, diarrhea. The most serious adverse drug reactions in patients receiving regorafenib were hepatotoxicity, perforation and haemorrhage. Hence regorafenib was approved with a black boxed warning of risk of hepatotoxicity.[7] The dose for this trial was 160 mg oral once daily and this dose was recommended dose for mCRC with four 40 mg tablets.

Regorafenib in advanced gastrointestinal stromal tumors

GISTs are neoplasms of mesenchymal cells of the gastrointestinal tract (GIT) developing from the interstitial cells of Cajal, which is the pacemaker of the smooth muscle of intestine. The commonest mutation seen in around 85-95% of GISTs are the activating Kit mutations, the rest around 5% contains the PDGFR α mutations.[16],[17],[18] This rare malignancy constitute only around 1% of all the malignancy in the GIT but named commonest of the mesenchymal neoplasms. Distant metastases to the liver and peritoneum usually appear late in the course of the disease, lymph node being the rarest site in adult type but common in the pediatric. It was also seen that even after the complete resection of the primary tumor, 50% of patients develop recurrence or metastasis with at a median time of around 2 years. This recurrence rate was very high causing only an overall 5-year survival rate of about 50%.[19] Imatinib, a tyrosine kinase inhibitors targeting PDGFR α and Kit, was found to benefit clinically and was approved by US Food and Drug Administration (FDA) in 2002 for metastatic GIST and in 2008 for the adjuvant therapy of the GIST, which was primarily resected.[20] Advanced GIST provided the first clinical evidence for the efficacy of various kinase inhibitors in solid tumors by virtue of the ability of imatinib mesylate to block tumor signals from activated c-Kit.

The results of a Phase II study on regorafenib in patients with advanced GIST, following failure or intolerance of imatinib and failure of sunitinib, were reported.[21] Patients were given regorafenib 160 mg/day orally for 21 days on/7 days off cycle. A total of 32 patients were evaluable for tumor response. Partial response was observed in 3/32 patients (9%), stable disease was observed in 27/32 patients (82%) with 21 patients (64%) had stable disease for at least 16 weeks. The median progression free survival was 10 months. The most common treatment-related grade 3 AEs included hand-foot skin reaction, hypertension and hypophosphatemia, (21, 36 and 15% of patients respectively). Grade 4 AEs were rare. A pharmacodynamic biomarker study evaluated fluorodeoxyglucose-positron emission tomography/computed tomography in 26 patients of this Phase II trial after a 3 week on treatment with regorafenib, 16 patients exhibited metabolic partial response, stable disease in eight patients and PD noted in two patients. Most patients with metabolic partial response had stable disease as per response evaluation criteria in solid tumors criteria.

This Phase II trial was followed by the Phase III clinical trial evaluating the safety and efficacy in refractory GIST. This Phase III multicentric randomized, double blinded, placebo controlled trial consisting of 199 patients with histologically confirmed unresectable and metastatic tumor who showed disease progression in spite of previous imatinib treatment or intolerant to treatment and disease progression while on previous sunitinib were evaluated.[22] The patients were randomly assigned in the ratio of 2:1 to receive either oral regorafenib 160 mg daily (n = 133) or placebo (n = 66) for the 1st 21 days of each 4-week cycle along with best supportive care for managing side effects due to treatments and symptoms of cancer. The study patients took oral regorafenib or placebo until their cancer progressed or there was unacceptable toxicity. Patients were given the provision to switch to regorafenib when their cancer progressed. Progression free survival was the primary end point. Median progression free survival was 4.8 months (interquartile range [IQR] 1.4-9.2 months) for patients in regorafenib group and 0.9 months (IQR 0.9-1.8 months) for patients in placebo (HR of progression 0.27, 95% CI: 0.19, 0.39; P < 0.0001). After the disease progression, 56 patients from the placebo were crossed over to receive regorafenib treatment. Drug-related AEs were reported in 130 patients assigned to receive regorafenib (98%) and 45 patients assigned to receive placebo (68%). The most common regorafenib-related AEs of grade 3 or higher were hypertension, hand-foot skin reaction and diarrhea. Serious side-effects, which occurred in <1% of patients, were liver damage, severe bleeding, skin reactions, high blood pressure requiring emergency treatment, myocardial infarctions and perforations in the intestines leading to bleeding.[22]


 » Clinical Trials In Progress Top


NCT0128982

This is a Phase II study to evaluate the efficacy (effectiveness) and the safety of regorafenib when given in combination with chemotherapy mFOLFOX6 as first line therapy in patients with mCRC).[23]

NCT01298570

Another Phase II trial investigating regorafenib combined with FOLFIRI in patients with KRAS-or BRAF-mutant CRC after a FOLFOX regimen. This is a randomized (2:1), multicentric and placebo-controlled study is designed to compare progression free survival between regorafenib + FOLFIRI (ARM A) versus placebo + FOLFIRI (ARM B) in patients with mCRC and KRAS or BRAF mutations who were previously treated with a FOLFOX regimen.[24]


 » Conclusion Top


Regorafenib has demonstrated a high level of efficacy with acceptable tolerability in both mCRC and in advanced GIST after disease progression or intolerance to both imatinib mesylate and sunitinib therapy, leading to the recent expanded FDA approval indicated for its use in advanced GIST apart from mCRC. Regarofenib also shows promising activity in other tumors such as renal cell carcinoma and other solid tumors.[25] The actual requested schedule for regorafenib administration is 3 weeks on and 1 week off treatment until the tumor regress or unacceptable tolerability occurs. The results of regorafenib in GIST patients indicate that regorafenib has a greater efficacy in patients with primary Kit exon 11 mutations than in those with wild type exon nine mutations, suggesting that patients with Kit exon 11 mutations should receive regorafenib as first-line treatment. Hypertension, mucositis, diarrhea, hand foot skin reactions and asthenia are the most common side-effects reported at the recommended doses of regorafenib. The majority of patients treated with regorafenib for mCRC or GIST have stable disease with prolonged progression free survival. Considering the great efficacy of regorafenib in advanced CRC and GIST, trials to test the efficacy of regorafenib in the adjuvant or neoadjuvant setting for patients with high risk of recurrence tumors are greatly awaited. Regorafenib belongs to a new class of multi targeted compounds that have demonstrated a high level of efficacy in mCRC and advanced GIST after disease progression or intolerance to imatinib mesylate and sunitinib therapy. It also shows promising activity in other types of cancer. Adjuvant and neoadjuvant studies settings are awaited and the trials exploring the combination of regorafenib with other chemotherapeutic agents and other targeted therapies.

 
 » References Top

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Shimizu T, Tolcher AW, Patnaik A, Papadopoulos K, Christensen O, Lin T, et al. Phase I dose-escalation study of continuously administered regorafenib (BAY 73-4506), an inhibitor of oncogenic and angiogenic kinases, in patients with advanced solid tumors. J Clin Oncol 2010;28:3035.  Back to cited text no. 10
    
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Mross K, Frost A, Steinbild S, Hedbom S, Büchert M, Fasol U, et al. Phase I study of BAY 73-4506, an inhibitor of oncogenic and angiogenic kinases, in patients with advanced solid tumors: Final results of a dose-escalation study. J Clin Oncol 2008;26:2558-67.  Back to cited text no. 11
    
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Strumberg D, Scheulen ME, Schultheis B, Richly H, Frost A, Büchert M, et al. Regorafenib (BAY 73-4506) in advanced colorectal cancer: A phase I study. Br J Cancer 2012;106:1722-7.  Back to cited text no. 12
    
13.
Christensen O, Buechert M, Fasol U, Jeffers M, Krätzschmar J, Strumberg D, et al. Analysis of plasma biomarkers, DCE-MRI, and KRAS mutations in patients with advanced colorectal carcinoma (CRC) treated with the multikinase inhibitor regorafenib. Ann Oncol 2010; 21 Suppl 8:619.  Back to cited text no. 13
    
14.
Schultheis B, Folprecht G, Kuhlmann J, Ehrenberg R, Hacker UT, Köhne CH, et al. Phase I study of regorafenib sequentially administered with either FOLFOX or FOLFIRI in patients with first-/second line colorectal cancer. J Clin Oncol 2011;29:3585.  Back to cited text no. 14
    
15.
Grothey A, Sobrero AF, Siena S, Lenz HJ, Falcone A, Ychou M, et al. Results of a phase III randomized, double-blind, placebo-controlled, multicenter trial (CORRECT) of regorafenib plus best supportive care versus placebo plus BSC in patients with metastatic colorectal cancer who have progressed after standard therapies. J Clin Oncol 2012;30:385.  Back to cited text no. 15
    
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Kang HJ, Koh KH, Yang E, You KT, Kim HJ, Paik YK, et al. Differentially expressed proteins in gastrointestinal stromal tumors with KIT and PDGFRA mutations. Proteomics 2006;6:1151-7.  Back to cited text no. 16
    
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Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, Gelderblom H, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): An international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013;381:295-302.  Back to cited text no. 22
    
23.
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24.
NCT01298570. Multi-center, randomized, placebo-controlled phase II study of regorafenib in combination with FOLFIRI versus placebo with FOLFIRI as second-line therapy in patients with metastatic colorectal cancer. Available from: http://clinicaltrails.gov.in. [Last accessed on 2013 Apr 15].  Back to cited text no. 24
    
25.
Eisen T, Joensuu H, Nathan P, Harper P, Wojtukiewicz M, Nicholson S, et al. Phase II study of BAY 73-4506, a multikinase inhibitor, in previously untreated patients with metastatic or unresectable renal cell cancer. J Clin Oncol 2009;27:5033.  Back to cited text no. 25
    



 
 
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