WARNING: HEPATOTOXICITY

Transcription

1 Version NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) Colon Cancer Overall management of Colon Cancer from diagnosis through recurrence is described in the NCCN Guidelines f Colon Cancer. Visit NCCN.g to view the complete list of treatment options and the complete library of NCCN Guidelines. Indication Stivarga (regafenib) is indicated f the treatment of patients with metastatic colectal cancer (CRC) who have been previously treated with fluopyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-vegf therapy, and, if KRAS wild type, an anti-egfr therapy. Imptant Safety Infmation WARNING: HEPATOTOXICITY Severe and sometimes fatal hepatotoxicity has been observed in clinical trials. Monit hepatic function pri to and during treatment. Interrupt and then reduce discontinue STIVARGA f hepatotoxicity as manifested by elevated liver function tests hepatocellular necrosis, depending upon severity and persistence. Please see additional Imptant Safety Infmation on page 6, as well as accompanying full Prescribing Infmation,

2 Patient appropriate f intensive therapy 2 CONTINUUM OF CARE - CHEMOTHERAPY FOR ADVANCED OR METASTATIC DISEASE: 1 (PAGE 1 of 9) Initial Therapy FOLFOX 3 CapeOX 4 FOLFOX 3 + bevacizumab 5,6 CapeOX 4 + bevacizumab 5,6 Therapy After First Progression FOLFIRI 10 FOLFIRI 10 + bevacizumab 5,6 FOLFIRI 10 + ziv-aflibercept 11 Irinotecan 10 Irinotecan 10 + bevacizumab 5,6 Irinotecan 10 + ziv-aflibercept 11 FOLFIRI 10 + (cetuximab panitumumab) 6,12-15 (KRAS/NRAS WT gene only) 8 (Cetuximab panitumumab) 6,12-15 (KRAS/NRAS WT gene only) 8 + irinotecan 10 Therapy After Second Progression (Cetuximab panitumumab) 6,12-15 (KRAS/NRAS WT gene only) 8 + irinotecan; 10 f patients not able to tolerate combination, consider single agent (cetuximab panitumumab) 6,12-15 (KRAS/NRAS WT gene only) 8 Regafenib 16 Regafenib 16 Best supptive care 17 Therapy After Third Progression Regafenib (if not given previously) Best supptive care 17 FOLFOX 3 + cetuximab panitumumab 6,7 (KRAS/NRAS WT gene only) 8,9 Additional options on COL-C 2 of 9 through COL-C 3 of 9 F patients not appropriate f intensive therapy, see COL-C 4 of 9 FOLFIRI 10 FOLFIRI 10 + bevacizumab 5,6 FOLFIRI 10 + ziv-aflibercept 11 Irinotecan 10 Irinotecan 10 + bevacizumab 5,6 Irinotecan 10 + ziv-aflibercept 11 Regafenib 16 Best supptive care 17 See footnotes on COL-C 5 of 9 Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/03/14 National Comprehensive Cancer Netwk, Inc. 2014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. COL-C 1 OF 9 Visit NCCN.g to view the complete list of treatment options and the complete library of NCCN Guidelines. Please see additional Imptant Safety Infmation on page 6, as well as accompanying full Prescribing Infmation,

3 Patient appropriate f intensive therapy 2 CONTINUUM OF CARE - CHEMOTHERAPY FOR ADVANCED OR METASTATIC DISEASE: 1 (PAGE 2 of 9) Initial Therapy Therapy After First Progression Therapy After Second Progression Therapy After Third Progression FOLFIRI 10 FOLFIRI 10 + bevacizumab 5,6 FOLFIRI 10 + cetuximab panitumumab 6,7 (KRAS/NRAS WT gene only) 8,9 FOLFOX 3 CapeOX 4 FOLFOX 3 + bevacizumab 5,6 CapeOX 4 + bevacizumab 5,6 (Cetuximab panitumumab) 6,12-15 (KRAS/NRAS WT gene only) 8 + irinotecan; 10 f patients not able to tolerate combination, consider single agent (cetuximab panitumumab) 6,12-15 (KRAS/NRAS WT gene only) 8 FOLFOX 3 CapeOX 4 FOLFOX 3 + bevacizumab 5,6 CapeOX 4 + bevacizumab 5,6 (Cetuximab panitumumab) 6,12-15 (KRAS/NRAS WT gene only) 8 + irinotecan; 10 f patients not able to tolerate combination, consider single agent (cetuximab panitumumab) 6,12-15 (KRAS/NRAS WT gene only) 8 Regafenib 16 FOLFOX 3 CapeOX 4 Regafenib 16 Best supptive care 17 Regafenib (if not given previously) Best supptive care 17 Additional options on COL-C 1 of 9 through COL-C 3 of 9 F patients not appropriate f intensive therapy, see COL-C 4 of 9 See footnotes on COL-C 5 of 9 Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/03/14 National Comprehensive Cancer Netwk, Inc. 2014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. COL-C 2 OF 9 Visit NCCN.g to view the complete list of treatment options and the complete library of NCCN Guidelines. Please see additional Imptant Safety Infmation on page 6, as well as accompanying full Prescribing Infmation,

4 CONTINUUM OF CARE - CHEMOTHERAPY FOR ADVANCED OR METASTATIC DISEASE: 1 (PAGE 4 of 9) Initial Therapy Therapy After First Progression Patient not appropriate f intensive therapy 2 Infusional 5-FU + leucovin Capecitabine ± bevacizumab Cetuximab (KRAS/NRAS WT gene only) 8,9 (categy 2B) Panitumumab (KRAS/NRAS WT gene only) 8,9 (categy 2B) Improvement in functional status No improvement in functional status Consider initial therapy as COL-C 1 of 9 through COL-C 3 of 9 21 Best supptive care See NCCN Guidelines f Palliative Care See footnotes on COL-C 5 of 9 Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/03/14 National Comprehensive Cancer Netwk, Inc. 2014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. COL-C 4 OF 9 Visit NCCN.g to view the complete list of treatment options and the complete library of NCCN Guidelines. Please see additional Imptant Safety Infmation on page 6, as well as accompanying full Prescribing Infmation,

5 CHEMOTHERAPY FOR ADVANCED OR METASTATIC DISEASE (PAGE 5 of 9) 1 F chemotherapy references, see Chemotherapy Regimens and References (COL-C 6-9). 2 PET-CT should not be used to monit progress of therapy. CT with contrast MRI is recommended. 3 Discontinuation of oxaliplatin should be strongly considered from FOLFOX CapeOX after 3 4 months of therapy ( sooner if significant neurotoxicity develops grade 2) with other drugs maintained (fluopyrimidine + bevacizumab) until time of tum progression. Oxaliplatin may be reintroduced if it was discontinued previously f neurotoxicity rather than disease progression. Tournigand C, Cervantes A, Figer A, et al. OPTIMOX1: A randomized study of FOLFOX4 FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colectal cancer - A GERCOR Study. J Clin Oncol 2006;24: There are no data to suppt the routine use of Ca/Mg infusion to prevent oxaliplatin-related neurotoxicity and therefe it should not be done. 4 The majity of safety and efficacy data f this regimen have been developed in Europe, where a capecitabine starting dose of 1000 mg/m 2 twice daily f 14 days, repeated every 21 days, is standard. Evidence suggests that Nth American patients may experience greater toxicity with capecitabine (as well as with other fluopyrimidines) than European patients, and may require a lower dose of capecitabine. The relative efficacy of CapeOx with lower starting doses of capecitabine has not been addressed in large-scale randomized trials. 5 There is an increased risk of stroke and other arterial events, especially in those aged 65 years. The use of bevacizumab may interfere with wound healing. 6 Combination therapy involving cytotoxics, anti-egfrs, and anti-vegfs is not recommended. Hecht JR, Mitchell E, Chidiac T, et al. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone f metastatic colectal cancer. J Clin Oncol 2009;27: Tol J, Koopman M, Cats A, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colectal cancer. N Engl J Med 2009;360(6): If cetuximab panitumumab is used as initial therapy, then neither cetuximab n panitumumab should be used in second subsequent lines of therapy. 8 See Principles of Pathologic Review (COL-A 4 of 5) - KRAS, NRAS, and BRAF Mutation Testing. 9 There are insufficient data to guide the use of anti-egfr therapy in the first-line setting with active chemotherapy based on BRAF V600E mutation status. 10 Irinotecan should be used with caution and with decreased doses in patients with Gilbert s disease elevated serum bilirubin. There is a commercially available test f UGT1A1. Guidelines f use in clinical practice have not been established. 11 There are no data to suggest activity of FOLFIRI-ziv-aflibercept in a patient who has progressed on FOLFIRI-bevacizumab, vice versa. Ziv-aflibercept has only shown activity when given in conjunction with FOLFIRI in FOLFIRI-naïve patients. 12 Cetuximab is indicated in combination with irinotecan-based therapy as single-agent therapy f patients who cannot tolerate irinotecan. 13 EGFR testing has no demonstrated predictive value; therefe, routine EGFR testing is not recommended. No patient should be included excluded from cetuximab panitumumab therapy on the basis of EGFR test results. 14 There are no data, n is there a compelling rationale, to suppt the use of panitumumab after clinical failure on cetuximab, the use of cetuximab after clinical failure on panitumumab. As such, the use of one of these agents after therapeutic failure on the other is not recommended. 15 Patients with a V600E BRAF mutation appear to have a poer prognosis. Limited available data suggest lack of antitum activity from anti-egfr monoclonal antibodies in the presence of a V600E mutation when used after a patient has progressed on first-line therapy. 16 Regafenib is a treatment option f patients who have progressed through all available regimens (eg, KRAS/NRAS mutant KRAS/NRAS WT with previous exposure to anti-egfr inhibit.) 17 Single-agent combination therapy with capecitabine, mitomycin, gemcitabine has not been shown to be effective in this setting. 18 Infusional 5-FU is preferred. 19 Patients with diminished creatinine clearance may require dose modification of capecitabine. 20 A treatment option f patients not able to tolerate oxaliplatin irinotecan. 21 The use of single-agent capecitabine as a salvage therapy after failure on a fluopyrimidine-containing regimen has been shown to be ineffective; therefe, this is not recommended. Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/03/14 National Comprehensive Cancer Netwk, Inc. 2014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. COL-C 5 OF 9 Visit NCCN.g to view the complete list of treatment options and the complete library of NCCN Guidelines. Please see additional Imptant Safety Infmation on page 6, as well as accompanying full Prescribing Infmation,

6 editial summarizes trials that assessed EGFR inhibits in combination with various chemotherapy agents. 553 These data are also discussed here. The Role of KRAS, NRAS, and BRAF Status The recept f EGFR has been repted to be overexpressed in 49% to 82% of colectal tums EGFR testing of colectal tum cells has no proven predictive value in determining likelihood of response to either cetuximab panitumumab. Data from the BOND study indicated that the intensity of immunohistochemical staining of EGFR in colectal tum cells did not crelate with the response rate to cetuximab. 412 A similar conclusion was drawn with respect to panitumumab. 558 Therefe, routine EGFR testing is not recommended, and no patient should be either considered f metastic excluded from colectal cetuximab cancer. panitumumab therapy based on EGFR test results. Me recent evidence shows mutations in KRAS outside exon 2 and mutations in NRAS are also predictive f a lack of benefit to cetuximab and panitumumab (see NRAS and Other KRAS Mutations, below). 565,566 The panel therefe strongly recommends KRAS/NRAS genotyping of tum tissue (either primary tum metastasis) in all patients with Cetuximab and panitumumab are monoclonal antibodies directed against EGFR that inhibit its downstream signaling pathways, but EGFR status as assessed using immunohistochemistry is not predictive of treatment efficacy. 412,559 Furtherme, cetuximab and panitumumab are only effective in approximately 10% to 20% of patients with colectal cancer. 412,439,559 The RAS/RAF/MAPK pathway is downstream of EGFR; mutations in components of this pathway are being studied in search of predictive markers f efficacy of these therapies. Rather, this early establishment of KRAS/NRAS status is appropriate to plan f the treatment continuum, so that the infmation may be obtained in a non-time-sensitive manner and the patient and provider can discuss the implications of a KRAS/NRAS mutation, if present, while other treatment A sizable body of literature has shown that tums with a mutation in codon of exon 2 of the KRAS options gene still are essentially exist. insensitive to cetuximab panitumumab therapy (see KRAS Exon 2 Mutations, below). 406,438,485,546, Me recent evidence shows mutations in KRAS outside of exon 2 and mutations in NRAS are also predictive f a lack of benefit to cetuximab and panitumumab (see NRAS and Other KRAS Mutations, below). 565,566 The panel therefe strongly recommends KRAS/NRAS genotyping of tum tissue (either primary tum metastasis) in all patients with metastatic colectal cancer. Patients with known KRAS NRAS mutations should not be treated with either cetuximab panitumumab, either alone in combination with other anticancer agents, because they have virtually no chance of benefit and the exposure to toxicity and expense cannot be justified. It is implied throughout the guidelines that NCCN recommendations involving cetuximab panitumumab relate only to patients with disease characterized by KRAS/NRAS wild-type genes. Although BRAF genotyping can be considered f patients with tums characterized by the wild-type KRAS/NRAS, this testing is currently optional and not a necessary part of decision-making regarding use of anti-egfr agents (see BRAF V600E Mutations, below). The panel strongly recommends genotyping of tum tissue (either primary tum metastasis) in all patients with metastatic colectal cancer f RAS (KRAS exon 2 and non-exon 2; NRAS) and BRAF at diagnosis of stage IV disease. The recommendation f KRAS/NRAS testing, at this point, is not meant to indicate a preference regarding regimen selection in the first-line setting. Rather, this early establishment of KRAS/NRAS status is appropriate to plan f the treatment continuum, so that the infmation may be obtained in a nontime-sensitive manner and the patient and provider can discuss the implications of a KRAS/NRAS mutation, if present, while other treatment options still exist. Note that because anti-egfr agents have no role in the management of stage I, II, III disease, KRAS/NRAS genotyping of colectal cancers at these earlier stages is not recommended. KRAS mutations are early events in colectal cancer fmation, and therefe a very tight crelation exists between mutation status in the primary tum and the metastases F this reason, KRAS/NRAS genotyping can be perfmed on archived specimens of either the Version , 10/03/14 National Comprehensive Cancer Netwk, Inc. 2014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-36 Visit NCCN.g to view the complete list of treatment options and the complete library of NCCN Guidelines. Please see additional Imptant Safety Infmation on page 6, as well as accompanying full Prescribing Infmation,

7 Imptant Safety Infmation from Bayer HealthCare Pharmaceuticals, Inc. WARNING: HEPATOTOXICITY Severe and sometimes fatal hepatotoxicity has been observed in clinical trials. Monit hepatic function pri to and during treatment. Interrupt and then reduce discontinue STIVARGA f hepatotoxicity as manifested by elevated liver function tests hepatocellular necrosis, depending upon severity and persistence. Hepatotoxicity: Severe drug-induced liver injury with fatal outcome occurred in 0.3% of 1200 STIVARGA-treated patients across all clinical trials. In metastatic colectal cancer (mcrc), fatal hepatic failure occurred in 1.6% of patients in the STIVARGA arm and 0.4% of patients in the placebo arm; all the patients with hepatic failure had metastatic disease in the liver. Liver Function Moniting: Obtain liver function tests (ALT, AST, and bilirubin) befe initiation of STIVARGA and monit at least every 2 weeks during the first 2 months of treatment. Thereafter, monit monthly me frequently as clinically indicated. Monit liver function tests weekly in patients experiencing elevated liver function tests until improvement to less than 3 times the upper limit of nmal (ULN) baseline values. Temparily hold and then reduce permanently discontinue STIVARGA, depending on the severity and persistence of hepatotoxicity as manifested by elevated liver function tests hepatocellular necrosis. Hemrhage: STIVARGA caused an increased incidence of hemrhage. The overall incidence (Grades 1-5) was 21% with STIVARGA compared to 8% with placebo in mcrc. Fatal hemrhage occurred in 4 of 632 (0.6%) STIVARGA-treated patients and involved the respiraty, gastrointestinal, genitourinary tracts. Permanently discontinue STIVARGA in patients with severe life-threatening hemrhage and monit INR levels me frequently in patients receiving warfarin. Dermatological Toxicity: STIVARGA caused an increased incidence of hand-foot skin reaction (HFSR) (also known as palmar-plantar erythrodysesthesia [PPE]) and severe rash, frequently requiring dose modification. The overall incidence of HFSR was increased with STIVARGA compared to placebo in mcrc (45% vs 7%). The incidence of Grade 3 HFSR (17% vs 0%), Grade 3 rash (6% vs <1%), serious adverse reactions of erythema multifme (0.2% vs 0%), and Stevens-Johnson syndrome (0.2% vs 0%) was higher in STIVARGA-treated patients. Toxic epidermal necrolysis occurred in 0.17% of 1200 STIVARGA-treated patients across all clinical trials. Withhold STIVARGA, reduce the dose, permanently discontinue depending on the severity and persistence of dermatologic toxicity. Hypertension: STIVARGA caused an increased incidence of hypertension (30% with STIVARGA vs 8% with placebo in mcrc). Hypertensive crisis occurred in 0.25% of 1200 STIVARGA-treated patients across all clinical trials. Do not initiate STIVARGA until blood pressure is adequately controlled. Monit blood pressure weekly f the first 6 weeks of treatment and then every cycle, me frequently, as clinically indicated. Temparily permanently withhold STIVARGA f severe uncontrolled hypertension. Cardiac Ischemia and Infarction: STIVARGA increased the incidence of myocardial ischemia and infarction (1.2% with STIVARGA vs 0.4% with placebo). Withhold STIVARGA in patients who develop new acute cardiac ischemia infarction, and resume only after resolution of acute cardiac ischemic events if the potential benefits outweigh the risks of further cardiac ischemia. Reversible Posteri Leukoencephalopathy Syndrome (RPLS): RPLS occurred in 1 of 1200 STIVARGA-treated patients across all clinical trials. Perfm an evaluation f RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, altered mental function. Confirm the diagnosis of RPLS with MRI and discontinue STIVARGA in patients who develop RPLS. Gastrointestinal Perfation Fistula: Gastrointestinal perfation fistula occurred in 0.6% of 1200 patients treated with STIVARGA across all clinical trials; this included 4 fatal events. Permanently discontinue STIVARGA in patients who develop gastrointestinal perfation fistula. Wound Healing Complications: Treatment with STIVARGA should be stopped at least 2 weeks pri to scheduled surgery. Resuming treatment after surgery should be based on clinical judgment of adequate wound healing. STIVARGA should be discontinued in patients with wound dehiscence. Embryo-Fetal Toxicity: STIVARGA can cause fetal harm when administered to a pregnant woman. Use effective contraception during treatment and up to 2 months after completion of therapy. If this drug is used during pregnancy, if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Nursing Mothers: Because many drugs are excreted in human milk and because of the potential f serious adverse reactions in nursing infants from STIVARGA, a decision should be made whether to discontinue nursing discontinue the drug, taking into account the imptance of the drug to the mother. Most Frequently Observed Adverse Drug Reactions in mcrc ( 30%): The most frequently observed adverse drug reactions ( 30%) in STIVARGA-treated patients vs placebo-treated patients in mcrc, respectively, were: asthenia/fatigue (64% vs 46%), decreased appetite and food intake (47% vs 28%), HFSR/PPE (45% vs 7%), diarrhea (43% vs 17%), mucositis (33% vs 5%), weight loss (32% vs 10%), infection (31% vs 17%), hypertension (30% vs 8%), and dysphonia (30% vs 6%). Visit NCCN.g to view the complete list of treatment options and the complete library of NCCN Guidelines. Please see additional Imptant Safety Infmation on page 6, as well as accompanying full Prescribing Infmation,

8 Indication Stivarga (regafenib) is indicated f the treatment of patients with metastatic colectal cancer (CRC) who have been previously treated with fluopyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-vegf therapy, and, if KRAS wild type, an anti-egfr therapy. Imptant Safety Infmation WARNING: HEPATOTOXICITY Severe and sometimes fatal hepatotoxicity has been observed in clinical trials. Monit hepatic function pri to and during treatment. Interrupt and then reduce discontinue STIVARGA f hepatotoxicity as manifested by elevated liver function tests hepatocellular necrosis, depending upon severity and persistence. Please see additional Imptant Safety Infmation on page 6, as well as accompanying full Prescribing Infmation, The National Comprehensive Cancer Netwk (NCCN ) appreciates that suppting companies recognize NCCN s need f autonomy in the development of the content of NCCN resources. All NCCN Guidelines are produced completely independently. NCCN Guidelines are not intended to promote any specific therapeutic modality. The distribution of this flash card is suppted by Bayer HealthCare Pharmaceuticals, Inc National Comprehensive Cancer Netwk GL-N PP-990-US-1481