Review Article Oncol Res Treat 2015;38:300–308 DOI: 10.1159/000382067
Received: February 02, 2015 Accepted: March 30, 2015 Published online: May 12, 2015
Improving Patient Outcomes with Regorafenib for Metastatic Colorectal Cancer – Patient Selection, Dosing, Patient Education, Prophylaxis, and Management of Adverse Events Ralf-Dieter Hofheinz a Dirk Arnold b Stefan Kubicka c Nicole Prasnikar d Arndt Vogel e a
Interdisciplinary Tumor Center Mannheim, University Hospital Mannheim, Germany; Department of Medical Oncology, Freiburg i.Br., Germany; c Department of Internal Medicine-Gastroenterology, Haemato-Oncology, Diabetology and Infectiology, Klinikum Ludwigsburg, Germany; d Cancer Center Reutlingen, Germany; e Department of Gastroenterology, Hepatology and Endocrinology, Hanover Medical School, Hanover, Germany b
Summary Regorafenib is the first tyrosine kinase inhibitor approved for metastatic colorectal cancer. In 2 phase III trials, regorafenib significantly improved progression-free and overall survival in patients who had been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-vascular endothelial growth factor therapy, and, if (K)RAS wild type, an antiepidermal growth factor receptor therapy. Its safety profile is in line with other multikin ase and/or tyrosine kinase inhibitors approved for different indications. Commonly reported adverse events specifically associated with regorafenib include hand-foot skin reaction and hypertension, whereas others such as fatigue, diarrhea, and liver dysfunction may occur during both targeted and cytotoxic treatments. These adverse events frequently occur within the first cycles of treatment, are transient, and decrease in incidence over time. Patient selection, education, and management, as well as close communication between oncologists or trained nurses and patients, are essential for prevention and mitigation
Ralf-Dieter Hofheinz and Dirk Arnold contributed equally.
© 2015 S. Karger GmbH, Freiburg 2296–5270/15/0386–0300$39.50/0 Fax +49 761 4 52 07 14 [email protected] www.karger.com
Accessible online at: www.karger.com/ort
of treatment toxicity as is rapid implementation of dose modifications and temporary discontinuations. Effective management of adverse events enables patients who are responding to stay on treatment for a substantial period of time and thereby receive the full benefit of regorafenib therapy. This review aims to provide guidance around prophylaxis and management of regorafenibassociated adverse events.
Introduction Within the last 15 years, remarkable progress has been made in extending median overall survival (OS) in patients with metastatic colorectal cancer (mCRC). To a large extent, this progress has been due to molecular targeted therapies which were first introduced in 2004. The concept and implementation of tumor growth inhibition with anti-angiogenic bevacizumab or inhibition of epidermal growth factor receptor (EGFR) signaling with cetuximab and panitumumab has substantially prolonged survival in mCRC compared to traditional chemotherapies alone [1–3]. With the recent approval of regorafenib (Stivarga®, Bayer HealthCare, Leverkusen, Germany), the range of treatment options for mCRC after failure of standard therapies in the first and second line has been broadened with a tyrosine kinase inhibitor (TKI) for the first time [4, 5]. Regorafenib inhibits tumor angiogenesis not only by targeting the receptor tyrosine kinases VEGFR (vascular endothelial growth factor receptor)-1, -2, and -3 but also by blockade of platelet-de-
Prof. Dr. Ralf-Dieter Hofheinz Interdisciplinary Tumor Center Mannheim University Hospital Mannheim Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany [email protected]
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Keywords Regorafenib · Metastatic colorectal cancer · Patient selection · Adverse event prophylaxis · Adverse event management
Fig. 1. Managing starting dose.
rived growth factor receptor (PDGFR) and epidermal growth factor homology domain 2 (TIE2) signaling that promote tumor neovascularization, vessel stabilization, lymphatic vessel formation, as well as stromal cell growth, all of which contribute to tumor development and metastasis formation [6]. Approval for regorafenib was based on the results of CORRECT, a pivotal phase III trial in which patients were randomized to receive regorafenib or placebo. An interim analysis showed the trial had met its primary endpoint of OS, and consequently, due to unequivocal benefit, the trial was terminated and placebo recipients were given the option of crossing over to the active treatment arm [7]. Some of these patients (19%) experienced progression-free survival (PFS) for more than 4 months [8]. However, as yet, no significant patient characteristics have been assigned to this subgroup. A second phase III trial in Asian patients (CONCUR) confirmed the significant survival prolongation with regorafenib (median OS 8.8 vs. 6.3 months; hazard ratio (HR) 0.550; p = 0.0002) [9]. Previous treatment with targeted therapies was not mandatory in this study and consequently led to fewer prior lines of therapy (62% ˯ 3 prior therapies vs. 52% in CORRECT) [7, 9]. The types of adverse events associated with regorafenib, a targeted therapy with a broad kinase activity profile, generally differ from those associated with other targeted agents with a more specific mechanism of action, such as selective VEGF inhibitors, as well as from those observed with traditional cytotoxic chemotherapy. Differences include time to onset, cumulative effects, and duration of adverse events, with adverse events associated with targeted treatments tending to be non-cumulative, transient, and usually occurring in the first cycles of treatment, with a reduction observed in later cycles [10, 11]. During the first cycle of the CORRECT trial, 32, 45, 21, and 23% of patients experienced any-grade hand-foot skin reaction (HFSR), fatigue, hypertension, and diarrhea, respectively; whereas during the 4th cycle the corresponding percentages were 24, 24, 4, and 26%, and in the 8th cycle the corresponding percentages were 5, 9, 5, and 14% [11]. These reduced adverse event rates in later cycles may also be partially due to effective patient management.
In CORRECT, 38 and 61% of regorafenib recipients required dose reductions and temporary treatment discontinuations, respectively, due to adverse events [7]. In REBECCA, a large non-interventional cohort study that provided early access to regorafenib, 500 (41%) patients required dose reductions [12]. Some oncologists are hesitant about prescribing regorafenib due to uncertainty about treatment-related toxicity despite the significant, albeit moderate, survival benefit associated with this therapy. Thus, patient education, prophylaxis, and management of adverse events as well as dose adjustments are crucial in enabling patients to benefit from regorafenib treatment.
Regorafenib: Patient Selection and Management of Adverse Events
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Patient Eligibility and Starting Dose for Regorafenib
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Based on the results of the phase III trial CORRECT, regorafenib is indicated for the treatment of patients with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, a VEGF inhibitor, and, for patients with wild-type (K)RAS disease, an EGFR inhibitor, or for those patients who are not suitable for standard therapies [4, 13]. Current clinical practice guidelines recommend use of regorafenib in the 3rd or 4th line [14]. To optimize treatment outcomes, it is crucial to assess patient eligibility. In our experience, regorafenib can be administered at the standard dose of 160 mg/day in mCRC patients who meet the inclusion criteria of the CORRECT trial, such as: i) no major comorbidities; ii) no unresolved toxicities National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0 grade 1 or higher [15]; iii) an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 1 or 0; and iv) adequate liver function (total bilirubin no higher than 1.5× the upper limit of normal (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) no higher than 2× ULN (no more than 5× ULN in patients with liver metastases), alkaline phosphatase no more than 2.5× ULN (no more than 5× ULN in patients with liver metastases)) [7].
Table 1. Incidence of selected regorafenib-associated adverse events in pivotal clinical trials and a cohort study [7, 9, 12]
Regorafenib-associated adverse events
Fatigue HFSR Skin rash/desquamation Stomatitis/oral mucositis Diarrhea Hypertension Elevated ALT Elevated AST Hyperbilirubinemia
Incidence in pivotal trials (% any-grade/% grade 3 or higher) CORRECT (phase III)
CONCUR (phase III)
REBECCA (cohort study)
47/9 47/17 26/6 27/3 34/7 28/7 5/2 7/2 9/2
22/3 74/16 12/4 10/ 8× ULN + concomitant increase in bilirubin (any increase vs. baseline), consider discontinuing treatment permanently
1st
2nd 1st
discontinue therapy permanently none
stop regorafenib therapy until symptoms resolve AND diastolic BP ≤ 100 mmHg; upon therapy re-initiation, decrease dose by 1 dose levelc if diastolic BP is not controlled (> 100 mmHg) with addition of more antihypertensive therapy, decrease regorafenib dose by another levelc
1st
1 2e
4 increase from baseline grade 0 to 1 or grade 1 to 2
stop therapy until symptoms resolve and diastolic BP is ≤ 100 mmHg; upon therapy re-initiation, decrease dose by 1 dose levelc if diastolic BP is not controlled (> 100 mmHg) with addition of more antihypertensive therapy, reduce regorafenib dose by another levelc
3rd any 1st
2nd
4th 1st
dose may be reduced by 1 level; if no improvement, stop therapy for at least 7 days until toxicity grade is 0 or 1
1st
2
3
none
any
1
HFSR
Regorafenib dose modificationsa,b
Grade
Adverse event
Occurrence
Table 2. Management of regorafenib-associated adverse events [7, 10, 23]
Table 2. Continued on next page
increase dose of antihypertensive medication(s) or add additional antihypertensive(s)
frequency of BP monitoring may be increased add antihypertensive(s)
immediately implement supportive measures to relieve symptoms; high-potency topical corticosteroids and topical lidocaine should be prescribed for painful areas
immediately implement supportive measures to relieve symptoms
Other management
Dose Adjustment Recommendations Dose reductions or temporary discontinuations are important measures for reducing side effects and may result in patients being able to remain longer on treatment if they are experiencing clinical benefit from regorafenib. Moreover, OS might even be improved as a result of patients being able to remain on regorafenib treatment for a longer period of time. Following initial dose delays and adjustments in the CORRECT and GRID trials, most patients were able to tolerate long-term regorafenib treatment, with some patients still on regorafenib at 3 years despite experiencing grade 3 toxicities during cycles 1 and 2 [10]. Further, in the GRID study it was shown that regorafenib provided a benefit in PFS, regardless of whether patients underwent temporary treatment discontinuations (median of 5.5 and 4.1 months in patients with and without temporary discontinuations, respectively) or dose reductions (median of 5.5 and 4.1 months in patients with and without dose reductions, respectively) [30] (table 2).
Conclusion Regorafenib has demonstrated a significant OS benefit in mCRC patients after failure of standard therapies or for whom standard therapy is contraindicated. As expected, regorafenib is also associated with clinically significant adverse events, albeit usually no worse than those associated with cytotoxic chemotherapy. Further, most regorafenib-associated adverse events are amenable to prophylactic measures and can be substantially mitigated if recognized and treated in a timely manner. Therefore, eligible patients should be monitored closely during the first cycles of regorafenib treatment, and, if necessary, doses should be adjusted. Effective prophylaxis and management of adverse events will allow patients to receive treatment with an effective drug, which can result in disease stabilization for several months.
Acknowledgement Medical writing assistance was provided by Melody Watson and Marc Esser at co.faktor GmbH, with financial support from Bayer Vital GmbH.
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Patients requiring a dose reduction of more than 2 levels should discontinue treatment permanently. Dose level 0 (maximum dose level): 160 mg once daily; dose level 1: 120 mg once daily; dose level 2: 80 mg once daily. c Dose re-escalation is permitted at the discretion of the oncologist after resolution to NCI CTCAE v3.0 grade 0 or 1 (HFSR) or after 1 cycle (hypertension). d After re-escalation or discontinuation, AST, ALT, and bilirubin levels should be checked twice weekly for 2 weeks and then either weekly for at least 4 weeks (re-escalation) or weekly until laboratory values return to baseline levels (discontinuation). e Asymptomatic (recurrent or persistent (for ≥ 24 h) increase by > 20 mmHg (diastolic) or to > 150/100 mmHg). f Symptomatic (increase by > 20 mmHg (diastolic) or to 150/100 mmHg). HFSR = Hand-foot skin reaction; BP = blood pressure; ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN=upper limit of normal. b
a
if grade ≥ 3 following re-escalation, permanently reduce dose stop treatment until grade 0 or 1; upon therapy re-initiation, decrease dose by 1 levelc permanent discontinuation can be considered at the oncologist’s discretion 2nd 1st 4
none
1st
stop treatment until grade 0 or 1; if interruption is > 4 weeks, iscontinue treatment permanently upon therapy re-initiation, decrease dose by 1 level
any
3
2 1st increase from baseline grade 0 to 4
1 or 2
Adverse events, aside from nonrefractory nausea and vomiting, alopecia, asymptomatic laboratory abnormalities and non-refractory hypersensitivity
discontinue treatment permanently discontinue treatment permanentlyd
Other management d nd
Regorafenib dose modificationsa,b Occurrence Grade Adverse event
Table 2. Continued
Regorafenib: Patient Selection and Management of Adverse Events
Liver Dysfunction Liver dysfunction, particularly elevated ALT, AST, and bilirubin levels, is another commonly reported adverse event which generally presents as asymptomatic laboratory abnormalities, with clinically significant liver dysfunction being rare. However, 1 case of fatal liver dysfunction possibly associated with regorafenib was reported in CORRECT (0.2% of regorafenib recipients) as well as in GRID (0.8% of regorafenib recipients) [7, 18]. Therefore, ALT, AST, and bilirubin should be assessed every 2 weeks for the first 2 cycles of treatment [10, 16]. In the case of increasing transaminases and bilirubin levels, dose modifications or treatment discontinuation is mandatory depending on severity and persistence.
Disclosure Statement Dirk Arnold: Roche, sanofi-aventis, Amgen, Bayer Healthcare, Eli Lilly: honoraria (presentations); Roche, Merck, sanofi-aventis, Bayer Healthcare, Terumo: travel support; Roche, Bayer Healthcare, sanofi-aventis, Astellas: research support (to the institution). Stephan Kubicka: Sanofi-Aventis: consultant honoraria, honoraria for advisory board meetings; Merck: consultant honoraria, honoraria for advisory board meetings; Roche: consultant honoraria, honoraria for advisory board meetings, congress-related travel; Bayer: consultant honoraria, honoraria for advisory board meetings, congress-related travel; Lilly: consultant honoraria, honoraria for advisory board meetings, congress-related travel; Boehringer: consultant honoraria, congress-related travel.
Arndt Vogel: Roche, Bayer, Sanofi, Amgen, Merck und Lilly: lecture honoraria and honoraria for advisory board meetings. Nicole Prasnikar: Celgene: consultant honoraria, congress-related travel; Amgen: consultant honoraria; Lilly: honoraria for advisory board meetings; Bayer: honoraria for advisory board meetings. Ralf Hofheinz: Sanofi-Aventis: consultant honoraria, honoraria for advisory board meetings; Merck:consultant honoraria, honoraria for advisory board meetings; Roche: consultant honoraria, honoraria for advisory board meetings, congress-related travel; Bayer: consultant honoraria, honoraria for advisory board meetings, congress-related travel; Lilly: consultant honoraria, honoraria for advisory board meetings, congress-related travel; Boehringer: consultant honoraria, congress-related travel.
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1 Kirstein MM, Lange A, Prenzler A, Manns MP, Kubicka S, Vogel A: Targeted therapies in metastatic colorectal cancer: a systematic review and assessment of currently available data. Oncologist 2014; 19: 1156–1168. 2 Arnold D, Stein A: New developments in the secondline treatment of metastatic colorectal cancer: potential place in therapy. Drugs 2013; 73: 883–891. 3 Ibrahim EM, Abouelkhair KM: Clinical outcome of panitumumab for metastatic colorectal cancer with wild-type KRAS status: a meta-analysis of randomized clinical trials. Med Oncol 2011; 28(suppl 1):S310–S317. 4 www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm321378.htm 5 www.ema.europa.eu/docs/en_GB/document_library/ Summary_of_opinion_–_Initial_authorisation/human/ 002573/WC500144844.pdf 6 Wilhelm S, Adnane J, Lynch M, Hornberg J, Schütz G, Thierauch K-H, Zopf D: Regorafenib: a new oral multikinase inhibitor of angiogenic, stromal and oncogenic (receptor tyrosine) kinases with potent preclinical antitumor activity. Mol Cancer Ther 2009; 8(12 suppl):B4. 7 Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouché O, Mineur L, Barone C, Adenis A, Tabernero J, Yoshino T, Lenz HJ, Goldberg RM, Sargent DJ, Cihon F, Cupit L, Wagner A, Laurent D: Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicenter, randomized, placebo-controlled, phase 3 trial. Lancet 2013; 381: 303–312. 8 Grothey A, Falcone A, Humblet Y, Bouche O, Mineur L, Adenis A, Tabernero J, Yoshino T, Lenz H-J, Goldberg RM, Xu L, Wagner A, Van Cutsem E: Subgroup analysis of patients with metastatic colorectal cancer (mCRC) treated with regorafenib (REG) in the CORRECT trial who had progression-free survival (PFS) longer than 4 months. J Clin Oncol 2015;suppl 3:abstr 710. Presented at the 2015 Gastrointestinal Cancers Symposium, San Francisco, CA, 15–17 January 2015. 9 Pan H, Xu J, Bai Y, Chi Y, Wang L, Bi F, Le AT, Liu T, Ma D, Kappeler C, Kalmus J, Kim TW: CONCUR: a randomized, double-blind, placebo-controlled phase 3 study of regorafenib monotherapy in Asian patients with previously treatment metastatic colorectal cancer (mCRC). Ann Oncol 2014; 25(suppl 2):ii105–ii117. 10 Grothey A, George S, van Cutsem E, Blay J-Y, Sobrero A, Demetri GD: Optimizing treatment outcomes with regorafenib: personalized dosing and other strategies to support patient care. Oncologist 2014; 19: 669–680. 11 Grothey A, Van Cutsem E, Sobrero AF, Siena S, Falcone A, Ychou M, Humblet Y, Bouche O, Mineur L, Barone C, Adenis A, Tabernero J, Yoshino T, Lenz H-J, Goldberg RM, Sargent DJ, Cihon F, Wagner A, Laurent D, Cupit L: Time course of regorafenib-associated adverse events in the phase III CORRECT study. J Clin Oncol 2013;suppl 4:abstr 467.
Received: February 02, 2015 Accepted: March 30, 2015 Published online: May 12, 2015
Improving Patient Outcomes with Regorafenib for Metastatic Colorectal Cancer – Patient Selection, Dosing, Patient Education, Prophylaxis, and Management of Adverse Events Ralf-Dieter Hofheinz a Dirk Arnold b Stefan Kubicka c Nicole Prasnikar d Arndt Vogel e a
Interdisciplinary Tumor Center Mannheim, University Hospital Mannheim, Germany; Department of Medical Oncology, Freiburg i.Br., Germany; c Department of Internal Medicine-Gastroenterology, Haemato-Oncology, Diabetology and Infectiology, Klinikum Ludwigsburg, Germany; d Cancer Center Reutlingen, Germany; e Department of Gastroenterology, Hepatology and Endocrinology, Hanover Medical School, Hanover, Germany b
Summary Regorafenib is the first tyrosine kinase inhibitor approved for metastatic colorectal cancer. In 2 phase III trials, regorafenib significantly improved progression-free and overall survival in patients who had been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-vascular endothelial growth factor therapy, and, if (K)RAS wild type, an antiepidermal growth factor receptor therapy. Its safety profile is in line with other multikin ase and/or tyrosine kinase inhibitors approved for different indications. Commonly reported adverse events specifically associated with regorafenib include hand-foot skin reaction and hypertension, whereas others such as fatigue, diarrhea, and liver dysfunction may occur during both targeted and cytotoxic treatments. These adverse events frequently occur within the first cycles of treatment, are transient, and decrease in incidence over time. Patient selection, education, and management, as well as close communication between oncologists or trained nurses and patients, are essential for prevention and mitigation
Ralf-Dieter Hofheinz and Dirk Arnold contributed equally.
© 2015 S. Karger GmbH, Freiburg 2296–5270/15/0386–0300$39.50/0 Fax +49 761 4 52 07 14 [email protected] www.karger.com
Accessible online at: www.karger.com/ort
of treatment toxicity as is rapid implementation of dose modifications and temporary discontinuations. Effective management of adverse events enables patients who are responding to stay on treatment for a substantial period of time and thereby receive the full benefit of regorafenib therapy. This review aims to provide guidance around prophylaxis and management of regorafenibassociated adverse events.
Introduction Within the last 15 years, remarkable progress has been made in extending median overall survival (OS) in patients with metastatic colorectal cancer (mCRC). To a large extent, this progress has been due to molecular targeted therapies which were first introduced in 2004. The concept and implementation of tumor growth inhibition with anti-angiogenic bevacizumab or inhibition of epidermal growth factor receptor (EGFR) signaling with cetuximab and panitumumab has substantially prolonged survival in mCRC compared to traditional chemotherapies alone [1–3]. With the recent approval of regorafenib (Stivarga®, Bayer HealthCare, Leverkusen, Germany), the range of treatment options for mCRC after failure of standard therapies in the first and second line has been broadened with a tyrosine kinase inhibitor (TKI) for the first time [4, 5]. Regorafenib inhibits tumor angiogenesis not only by targeting the receptor tyrosine kinases VEGFR (vascular endothelial growth factor receptor)-1, -2, and -3 but also by blockade of platelet-de-
Prof. Dr. Ralf-Dieter Hofheinz Interdisciplinary Tumor Center Mannheim University Hospital Mannheim Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany [email protected]
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Keywords Regorafenib · Metastatic colorectal cancer · Patient selection · Adverse event prophylaxis · Adverse event management
Fig. 1. Managing starting dose.
rived growth factor receptor (PDGFR) and epidermal growth factor homology domain 2 (TIE2) signaling that promote tumor neovascularization, vessel stabilization, lymphatic vessel formation, as well as stromal cell growth, all of which contribute to tumor development and metastasis formation [6]. Approval for regorafenib was based on the results of CORRECT, a pivotal phase III trial in which patients were randomized to receive regorafenib or placebo. An interim analysis showed the trial had met its primary endpoint of OS, and consequently, due to unequivocal benefit, the trial was terminated and placebo recipients were given the option of crossing over to the active treatment arm [7]. Some of these patients (19%) experienced progression-free survival (PFS) for more than 4 months [8]. However, as yet, no significant patient characteristics have been assigned to this subgroup. A second phase III trial in Asian patients (CONCUR) confirmed the significant survival prolongation with regorafenib (median OS 8.8 vs. 6.3 months; hazard ratio (HR) 0.550; p = 0.0002) [9]. Previous treatment with targeted therapies was not mandatory in this study and consequently led to fewer prior lines of therapy (62% ˯ 3 prior therapies vs. 52% in CORRECT) [7, 9]. The types of adverse events associated with regorafenib, a targeted therapy with a broad kinase activity profile, generally differ from those associated with other targeted agents with a more specific mechanism of action, such as selective VEGF inhibitors, as well as from those observed with traditional cytotoxic chemotherapy. Differences include time to onset, cumulative effects, and duration of adverse events, with adverse events associated with targeted treatments tending to be non-cumulative, transient, and usually occurring in the first cycles of treatment, with a reduction observed in later cycles [10, 11]. During the first cycle of the CORRECT trial, 32, 45, 21, and 23% of patients experienced any-grade hand-foot skin reaction (HFSR), fatigue, hypertension, and diarrhea, respectively; whereas during the 4th cycle the corresponding percentages were 24, 24, 4, and 26%, and in the 8th cycle the corresponding percentages were 5, 9, 5, and 14% [11]. These reduced adverse event rates in later cycles may also be partially due to effective patient management.
In CORRECT, 38 and 61% of regorafenib recipients required dose reductions and temporary treatment discontinuations, respectively, due to adverse events [7]. In REBECCA, a large non-interventional cohort study that provided early access to regorafenib, 500 (41%) patients required dose reductions [12]. Some oncologists are hesitant about prescribing regorafenib due to uncertainty about treatment-related toxicity despite the significant, albeit moderate, survival benefit associated with this therapy. Thus, patient education, prophylaxis, and management of adverse events as well as dose adjustments are crucial in enabling patients to benefit from regorafenib treatment.
Regorafenib: Patient Selection and Management of Adverse Events
Oncol Res Treat 2015;38:300–308
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Based on the results of the phase III trial CORRECT, regorafenib is indicated for the treatment of patients with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, a VEGF inhibitor, and, for patients with wild-type (K)RAS disease, an EGFR inhibitor, or for those patients who are not suitable for standard therapies [4, 13]. Current clinical practice guidelines recommend use of regorafenib in the 3rd or 4th line [14]. To optimize treatment outcomes, it is crucial to assess patient eligibility. In our experience, regorafenib can be administered at the standard dose of 160 mg/day in mCRC patients who meet the inclusion criteria of the CORRECT trial, such as: i) no major comorbidities; ii) no unresolved toxicities National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0 grade 1 or higher [15]; iii) an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 1 or 0; and iv) adequate liver function (total bilirubin no higher than 1.5× the upper limit of normal (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) no higher than 2× ULN (no more than 5× ULN in patients with liver metastases), alkaline phosphatase no more than 2.5× ULN (no more than 5× ULN in patients with liver metastases)) [7].
Table 1. Incidence of selected regorafenib-associated adverse events in pivotal clinical trials and a cohort study [7, 9, 12]
Regorafenib-associated adverse events
Fatigue HFSR Skin rash/desquamation Stomatitis/oral mucositis Diarrhea Hypertension Elevated ALT Elevated AST Hyperbilirubinemia
Incidence in pivotal trials (% any-grade/% grade 3 or higher) CORRECT (phase III)
CONCUR (phase III)
REBECCA (cohort study)
47/9 47/17 26/6 27/3 34/7 28/7 5/2 7/2 9/2
22/3 74/16 12/4 10/ 8× ULN + concomitant increase in bilirubin (any increase vs. baseline), consider discontinuing treatment permanently
1st
2nd 1st
discontinue therapy permanently none
stop regorafenib therapy until symptoms resolve AND diastolic BP ≤ 100 mmHg; upon therapy re-initiation, decrease dose by 1 dose levelc if diastolic BP is not controlled (> 100 mmHg) with addition of more antihypertensive therapy, decrease regorafenib dose by another levelc
1st
1 2e
4 increase from baseline grade 0 to 1 or grade 1 to 2
stop therapy until symptoms resolve and diastolic BP is ≤ 100 mmHg; upon therapy re-initiation, decrease dose by 1 dose levelc if diastolic BP is not controlled (> 100 mmHg) with addition of more antihypertensive therapy, reduce regorafenib dose by another levelc
3rd any 1st
2nd
4th 1st
dose may be reduced by 1 level; if no improvement, stop therapy for at least 7 days until toxicity grade is 0 or 1
1st
2
3
none
any
1
HFSR
Regorafenib dose modificationsa,b
Grade
Adverse event
Occurrence
Table 2. Management of regorafenib-associated adverse events [7, 10, 23]
Table 2. Continued on next page
increase dose of antihypertensive medication(s) or add additional antihypertensive(s)
frequency of BP monitoring may be increased add antihypertensive(s)
immediately implement supportive measures to relieve symptoms; high-potency topical corticosteroids and topical lidocaine should be prescribed for painful areas
immediately implement supportive measures to relieve symptoms
Other management
Dose Adjustment Recommendations Dose reductions or temporary discontinuations are important measures for reducing side effects and may result in patients being able to remain longer on treatment if they are experiencing clinical benefit from regorafenib. Moreover, OS might even be improved as a result of patients being able to remain on regorafenib treatment for a longer period of time. Following initial dose delays and adjustments in the CORRECT and GRID trials, most patients were able to tolerate long-term regorafenib treatment, with some patients still on regorafenib at 3 years despite experiencing grade 3 toxicities during cycles 1 and 2 [10]. Further, in the GRID study it was shown that regorafenib provided a benefit in PFS, regardless of whether patients underwent temporary treatment discontinuations (median of 5.5 and 4.1 months in patients with and without temporary discontinuations, respectively) or dose reductions (median of 5.5 and 4.1 months in patients with and without dose reductions, respectively) [30] (table 2).
Conclusion Regorafenib has demonstrated a significant OS benefit in mCRC patients after failure of standard therapies or for whom standard therapy is contraindicated. As expected, regorafenib is also associated with clinically significant adverse events, albeit usually no worse than those associated with cytotoxic chemotherapy. Further, most regorafenib-associated adverse events are amenable to prophylactic measures and can be substantially mitigated if recognized and treated in a timely manner. Therefore, eligible patients should be monitored closely during the first cycles of regorafenib treatment, and, if necessary, doses should be adjusted. Effective prophylaxis and management of adverse events will allow patients to receive treatment with an effective drug, which can result in disease stabilization for several months.
Acknowledgement Medical writing assistance was provided by Melody Watson and Marc Esser at co.faktor GmbH, with financial support from Bayer Vital GmbH.
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Patients requiring a dose reduction of more than 2 levels should discontinue treatment permanently. Dose level 0 (maximum dose level): 160 mg once daily; dose level 1: 120 mg once daily; dose level 2: 80 mg once daily. c Dose re-escalation is permitted at the discretion of the oncologist after resolution to NCI CTCAE v3.0 grade 0 or 1 (HFSR) or after 1 cycle (hypertension). d After re-escalation or discontinuation, AST, ALT, and bilirubin levels should be checked twice weekly for 2 weeks and then either weekly for at least 4 weeks (re-escalation) or weekly until laboratory values return to baseline levels (discontinuation). e Asymptomatic (recurrent or persistent (for ≥ 24 h) increase by > 20 mmHg (diastolic) or to > 150/100 mmHg). f Symptomatic (increase by > 20 mmHg (diastolic) or to 150/100 mmHg). HFSR = Hand-foot skin reaction; BP = blood pressure; ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN=upper limit of normal. b
a
if grade ≥ 3 following re-escalation, permanently reduce dose stop treatment until grade 0 or 1; upon therapy re-initiation, decrease dose by 1 levelc permanent discontinuation can be considered at the oncologist’s discretion 2nd 1st 4
none
1st
stop treatment until grade 0 or 1; if interruption is > 4 weeks, iscontinue treatment permanently upon therapy re-initiation, decrease dose by 1 level
any
3
2 1st increase from baseline grade 0 to 4
1 or 2
Adverse events, aside from nonrefractory nausea and vomiting, alopecia, asymptomatic laboratory abnormalities and non-refractory hypersensitivity
discontinue treatment permanently discontinue treatment permanentlyd
Other management d nd
Regorafenib dose modificationsa,b Occurrence Grade Adverse event
Table 2. Continued
Regorafenib: Patient Selection and Management of Adverse Events
Liver Dysfunction Liver dysfunction, particularly elevated ALT, AST, and bilirubin levels, is another commonly reported adverse event which generally presents as asymptomatic laboratory abnormalities, with clinically significant liver dysfunction being rare. However, 1 case of fatal liver dysfunction possibly associated with regorafenib was reported in CORRECT (0.2% of regorafenib recipients) as well as in GRID (0.8% of regorafenib recipients) [7, 18]. Therefore, ALT, AST, and bilirubin should be assessed every 2 weeks for the first 2 cycles of treatment [10, 16]. In the case of increasing transaminases and bilirubin levels, dose modifications or treatment discontinuation is mandatory depending on severity and persistence.
Disclosure Statement Dirk Arnold: Roche, sanofi-aventis, Amgen, Bayer Healthcare, Eli Lilly: honoraria (presentations); Roche, Merck, sanofi-aventis, Bayer Healthcare, Terumo: travel support; Roche, Bayer Healthcare, sanofi-aventis, Astellas: research support (to the institution). Stephan Kubicka: Sanofi-Aventis: consultant honoraria, honoraria for advisory board meetings; Merck: consultant honoraria, honoraria for advisory board meetings; Roche: consultant honoraria, honoraria for advisory board meetings, congress-related travel; Bayer: consultant honoraria, honoraria for advisory board meetings, congress-related travel; Lilly: consultant honoraria, honoraria for advisory board meetings, congress-related travel; Boehringer: consultant honoraria, congress-related travel.
Arndt Vogel: Roche, Bayer, Sanofi, Amgen, Merck und Lilly: lecture honoraria and honoraria for advisory board meetings. Nicole Prasnikar: Celgene: consultant honoraria, congress-related travel; Amgen: consultant honoraria; Lilly: honoraria for advisory board meetings; Bayer: honoraria for advisory board meetings. Ralf Hofheinz: Sanofi-Aventis: consultant honoraria, honoraria for advisory board meetings; Merck:consultant honoraria, honoraria for advisory board meetings; Roche: consultant honoraria, honoraria for advisory board meetings, congress-related travel; Bayer: consultant honoraria, honoraria for advisory board meetings, congress-related travel; Lilly: consultant honoraria, honoraria for advisory board meetings, congress-related travel; Boehringer: consultant honoraria, congress-related travel.
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