Proactive strategies for regorafenib in metastatic colorectal cancer: implications for optimal patient management

Figures & data

Figure 1 Regorafenib inhibits oncogenesis, angiogenesis, and the tumor microenvironment in metastatic colorectal cancer. Regorafenib is a multikinase inhibitor that targets several receptor tyrosine kinases (eg, fibroblast growth factor receptor [FGFR], platelet-derived growth factor receptor-β [PDGFR-β], vascular endothelial growth factor receptor [VEGFR], and tyrosine kinase with immunoglobulin and epidermal growth factor homology domain [TIE2]) that regulate angiogenesis and the tumor microenvironment in colorectal tumor cells. Regorafenib also inhibits oncogenesis, in part, by selectively targeting the intracellular kinases BRAF and RAF1, an activator of downstream mitogen-activated protein kinases (MEK and ERK) that promote cell proliferation.

Abbreviation: ANG-2, angiopoietin-2.

Figure 2 Kaplan–Meier curves for overall survival (A) and progression-free survival (B) in the study population.

Notes: The hazard ratio (HR) for overall survival at final analysis was 0.79 (95% CI: 0.66–0.94; P=0.0038). Reprinted from The Lancet, 381, Grothey et al, Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial, 303–312, Copyright © 2013, with permission from Elsevier.¹¹

Abbreviations: CI, confidence interval; IQR, interquartile range; PFS, progression-free survival.

Table 1 Incidence of adverse events (≥10%) reported in patients treated with regorafenib in the CORRECT study and reported more commonly than in patients receiving placebo

Adverse event	Regorafenib (N=500)		Placebo (N=253)
	All grades (%)	Grade ≥3 (%)	All grades (%)	Grade ≥3 (%)
Asthenia/fatigue	64	15	46	9
Decreased appetite and food intake	47	5	28	4
HFSR/PPE	45	17	7	0
Diarrhea	43	8	17	2
Mucositis	33	4	5	0
Weight loss	32	<1	10	0
Infection	31	9	17	6
Hypertension	30	8	8	<1
Dysphonia (voice changes)	30	0	6	0
Pain	29	3	21	2
Fever	28	2	15	0
Rasha	26	6	4	<1
Hemorrhage	21	2	8	<1
Headache	10	<1	7	0

Notes:

a Rash represents events of drug eruption, rash, erythematous rash, generalized rash, macular rash, maculo-papular rash, popular rash, and pruritic rash. Data taken from Stivarga® (regorafenib) tablets prescribing information, from Bayer HealthCare Pharmaceuticals, Inc. Copyright © 2013.¹²

Abbreviations: HFSR, hand-foot skin reaction; PPE, palmar-plantar erythrodysesthesia.

Table 2 Incidence of liver function test abnormalities for patients in the safety population who had liver function tests

Adverse event	Regorafenib (N=500)			Placebo (N=253)
	All grades (%)	Grade 3 (%)	Grade 4 (%)	All grades (%)	Grade 3 (%)	Grade 4 (%)
Hyperbilirubinemia	45	10	3	17	5	3
Increased AST	65	5	1	46	4	1
Increased ALT	45	5	1	30	3	<1

Note: Data taken from Stivarga® (regorafenib) tablets prescribing information, from Bayer HealthCare Pharmaceuticals, Inc. Copyright © 2013.¹²

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Figure 3 Time course of treatment-emergent adverse events in the CORRECT trial.

Note: Shown is the incidence of adverse events (AEs) over eight 4-week treatment cycles (one treatment cycle was 3 weeks of regorafenib 160 mg [or matching placebo] orally once daily and 1 week off treatment).

Table 3 Guidelines for modifying the regorafenib dose

Interrupt	• NCI CTCAE grade 2 HFSR/PPE that is recurrent or does not improve within 7 days despite dose reduction; interrupt therapy for a minimum of 7 days for grade 3 HFSR
	• Symptomatic grade 2 hypertension
	• Any NCI CTCAE grade 3 or 4 AE
Reduce to 120 mg	• The first occurrence of grade 2 HFSR of any duration
	• After recovery of any grade 3 or 4 AE
	• Grade 3 AST/ALT elevation; only resume if the potential benefit outweighs the risk of hepatotoxicity
Reduce to 80 mg	• Recurrence of grade 2 HFSR at the 120 mg dose
	• After recovery of any grade 3 or 4 AE at the 120 mg dose (except hepatotoxicity)
Discontinue permanently	• Failure to tolerate 80 mg dose
	• Any occurrence of AST/ALT >20 × ULN
	• Any occurrence of AST/ALT >3 × ULN with concurrent bilirubin >2 × ULN
	• Recurrence of AST/ALT >5 × ULN despite dose reduction to 120 mg
	• Any grade 4 adverse reaction; only resume if the potential benefit outweighs the risks

Note: Recommended regorafenib dose modifications taken from Stivarga® (regorafenib) tablets prescribing information, from Bayer HealthCare Pharmaceuticals Inc.¹²

Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AS, aspartate aminotransferase; CTCAE, Common Terminology Criteria for Adverse Events; HFSR, hand-foot skin reaction; NCI, National Cancer Institute; PPE, palmar-plantar erythrodysesthesia; ULN, upper limit of normal.

Table 4 Management of regorafenib-related liver function abnormalities: grading of abnormalitiesa

Serum level on LFT	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
ALT/AST	>ULN to 3 × ULN	>3 to 5 × ULN	>5 to 20 × ULN	>20 × ULN	NA
Bilirubinb	>ULN to 1.5 × ULN	>1.5 to 3.0 × ULN	>3 to 10 × ULN	>10 × ULN	NA

Notes:

a Grading by the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03.2010)

b exception: patients with Gilbert’s syndrome who develop elevated transaminases should be managed as per the outlined recommendations for the respective observed elevation of ALT and/or AST.

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; LFT, liver function test; NA, not applicable; ULN, upper limit of normal.

Table 5 Management of regorafenib-related liver function abnormalities: dose-modification guidelines

Gradea	ALT and/or AST elevations	Occurrence	Recommended measures
≤Grade 2	≤5 × ULN	Any occurrence	• Continue treatment
			• Monitor liver function weekly until transaminases return to <3 × ULN (grade 1) or baseline
≥Grade 2 with concurrent bilirubin >2 × ULN	>3 × ULN	Any occurrenceb	• Discontinue treatment permanently
			• Monitor liver function weekly until resolution or return to baseline
Grade 3	>5 × to ≤20 × ULN	First occurrence	• Interrupt treatment
			• Monitor transaminases weekly until levels return to <3 × ULN or baseline
			• Patients may restart treatment if the potential risk outweighs the risk of liver toxicity
			• To restart treatment, reduce dose by 1 tablet (40 mg) and monitor liver function weekly for at least 4 weeks
		Recurrence	• Discontinue treatment permanently
Grade 4	>20 × ULN	Any occurrence	• Discontinue treatment permanently

Notes:

a Grading by the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03.2010)

b exception: patients with Gilbert’s syndrome who develop elevated transaminases should be managed as per the outlined recommendations for the respective observed elevation of ALT and/or AST.

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal.

GrotheyAVan CutsemESobreroACORRECT Study GroupRegorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trialLancet2013381986330331223177514

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Stivarga® (regorafenib) tablets, for oral use [prescribing information]Wayne, NJBayer HealthCare Pharmaceuticals Inc2013 Available from: http://labeling.bayerhealthcare.com/html/products/pi/Stivarga_PI.pdfAccessed November 1, 2013

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