Written by: Jeff Engle, PharmD, MS
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Description: This PQI will discuss effective management of adverse effects of sorafenib in the treatment of hepatocellular carcinoma and discuss data supporting the sequencing of patients to second-line therapy with regorafenib for increased survival benefit.

Background: Hepatocellular carcinoma (HCC) is associated with a high mortality rate and historically the treatment options have been limited. Prior to 2018, sorafenib was the only Food and Drug Administration approved targeted therapy for the initial treatment of unresectable HCC in patients diagnosed with late stage or metastatic disease.7 Second-line treatment options, though growing in number, have limited and at times conflicting survival data; and all factors of options should be considered.14, 18 A retrospective study of the RESORCE trial ascertained median time from start of sorafenib to death in patients receiving sequential therapy to regorafenib.  Exploratory analysis revealed time from sorafenib initiation to death as 26 months for regorafenib patients vs. 19.2 months for placebo patients.16

PQI Process: Upon receipt of a prescription for sorafenib:

  • Obtain CBC with differential, metabolic panel including magnesium and phosphorus, liver function tests, lipase and amylase prior to starting therapy and then monthly until labs have stabilized
  • Consider obtaining thyroid stimulating hormone level at baseline, every 4 weeks for 4 months, and then every 2-3 months thereafter
  • Monitor blood pressure at baseline and weekly during the first 6 weeks of sorafenib, and then monitor blood pressure, utilizing clinic appointments and treatment any developing hypertension as needed
  • Treatment associated hypertension and dermatologic toxicity are managed with dose interruptions and reductions.8 Grade 1 dermatologic toxicity may not require dosage adjustments (see table 3 for dose reductions due to toxicity)
  • Consider proactively discussing 2nd line treatment options following progression or intolerance

If regorafenib is considered for 2nd line tyrosine kinase inhibitor transitioning

  • Ensure recovery from sorafenib mediated adverse effects and that patient did not permanently discontinue sorafenib due to toxicity or inability to tolerate doses
    • RESORCE trial required that patients be able to tolerate at least 400 mg a day of sorafenib for 20 days of the last 28 days prior to withdrawal to be eligible
  • Determine Child-Pugh Class status and make appropriate recommendation for therapy
  • If underlying hypertension exists or developed while on sorafenib, ensure appropriate blood pressure control prior to starting regorafenib
  • Refer to Regorafenib (Stivarga®) In the Treatment of Hepatocellular Carcinoma PQI for managing adverse effects

Patient Centered Activities:

Counseling for sorafenib

  • Provide patient Oral Chemotherapy Education (OCE) sheet
  • Counsel patient on the signs and symptoms of hand-foot syndrome and other dermatologic side effects
  • Counsel on appropriate management of chemotherapy induced diarrhea
  • Counsel on measuring blood pressure weekly at home (first 6 weeks) and instruct to report blood pressures > 140/90 mmHg
  • Dose adjustments for baseline hepatic and renal dysfunction have been recommended based on a phase I pharmacokinetic study and are included in Table 1 and 215

Counseling for regorafenib

 

Supplemental Information:

Table 1: Dose Adjustments for Baseline Hepatic Dysfunction15*

Degree of Hepatic ImpairmentCriteriaSorafenib Dose
MildBilirubin >1 to ≤1.5 times ULN and/or AST >ULN400 mg twice daily
ModerateBilirubin >1.5 to ≤3 times ULN; any AST200 mg twice daily
SevereAlbumin <2.5 g/dL with any bilirubin/AST200 mg once daily
Bilirubin >3 to 10 x ULN with any ASTNo tolerable dose identified

*Reference used differs slightly from sorafenib prescribing information reference

 

Table 2: Dose Adjustments for Baseline Renal Dysfunction15

Baseline Creatinine ClearanceSorafenib Dose
40-59 mL/min400 mg twice daily
20-39 mL/min200 mg twice daily
< 20 mL/minUnable to define dose
Hemodialysis200 mg once daily

 

Table 3: Dose Reduction Levels for Adverse Effects*

Dose ReductionSorafenib Dose
Starting400 mg twice daily
1200 mg twice daily
2200 mg once daily or 400 mg every other day
3Discontinue

 

Patient Assistance

Sorafenib patients can utilize the REACH support program while on therapy

  • Nurse counselors are available for answering questions and providing patient education including Patient Starter Kits
  • Service counselors are available to discuss patient access services including co-pay assistance

References:

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019 Jan;69(1):7-34.
  2. Cronin KA, Lake AJ, Scott S, et al. Annual report to the nation on the status of cancer, part I: National cancer statistics. Cancer. 2018 Jul 1;124(13):2785-2800.
  3. Morgan TR, Mandayam S, Jamal MM. Alcohol and hepatocellular carcinoma. Gastroenterology. 2004; 127: S87–96.
  4. El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012;142:1264–73.e1.
  5. Marrero JA, Kulik LM, Sirlin CB, et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases. Hepatology. 2018 Aug;68(2):723-750.
  6. National Comprehensive Cancer Network. Hepatobiliary cancers version 1.2019. https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf. Accessed February 10, 2019.
  7. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378-390.
  8. Nexavar (sorafenib) [prescribing information]. Wayne, NJ: Bayer Healthcare Pharmaceuticals Inc; October 2010.
  9. Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib (RESORCE): a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389:56-66.
  10. El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMat 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389:2492-2502.
  11. Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018;19(7):940-952.
  12. Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379:54-63.
  13. Zhu AX, Kang YK, Yen CJ, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019 Feb;20(2):282-296.
  14. Merck Provides Update on KEYNOTE-240, a Phase 3 Study of KEYTRUDA® (pembrolizumab) in Previously Treated Patients with Advanced Hepatocellular Carcinoma. Merck. Published February 19, 2019. https://bit.ly/2SQ6J45. Accessed March 18, 2019.
  15. Miller AA, Murry DJ, Owzar K, et al. Phase I and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301. J Clin Oncol. 2009 Apr 10;27(11):1800-5.
  16. https://www.ncoda.org/chemotherapy-induced-diarrhea/
  17. https://www.ncoda.org/regorafenib-in-the-treatment-of-hepatocellular-carcinoma/
  18. Finn RS et. Al Outcomes of sequential treatment with sorafenib followed by regorafenib for HCC. J Hepatol.2018 Aug;69(2):353-358. doi: 10.1016/j.jhep.2018.04.010.
Important notice: NCODA has developed this Positive Quality Intervention platform. This platform represents a brief summary of medication uses and therapy options derived from information provided by the drug manufacturer and other resources. This platform is intended as an educational aid and does not provide individual medical advice and does not substitute for the advice of a qualified healthcare professional.  This platform does not cover all existing information related to the possible uses, directions, doses, precautions, warning, interactions, adverse effects, or risks associated with the medication discussed in the platform and is not intended as a substitute for the advice of a qualified healthcare professional. The materials contained in this platform are for informational purposes only and do not constitute or imply endorsement, recommendation, or favoring of this medication by NCODA, which assumes no liability for and does not ensure the accuracy of the information presented.  NCODA does not make any representations with respect to the medications whatsoever, and any and all decisions, with respect to such medications, are at the sole risk of the individual consuming the medication. All decisions related to taking this medication should be made with the guidance and under the direction of a qualified healthcare professional.

 

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Written by: Bryan J. Brinda, PharmD
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Description: This PQI will discuss proper patient selection and management of adverse events related to the administration of oral gilteritinib pharmacotherapy in patients with relapsed/refractory AML that have an FMS-like tyrosine kinase 3 (FLT3) mutation as detected by an  FDA-approved test. Optimal patient identification, dosing, and follow-up are essential to help patients benefit fully while taking this medication.

Background: Gilteritinib is a tyrosine kinase inhibitor that has demonstrated activity in patients with relapsed/refractory (R/R) AML who have mutations in the internal tandem duplication (ITD) and/or tyrosine kinase domain (TKD) of FLT3 (found in 30% of AML population). This represents a treatment paradigm shift as the first oral monotherapy option for this particular subset of FLT3- mutated AML patients who, if interested in further treatment, would traditionally utilize IV salvage chemotherapy. Clinicians should be aware of the need for molecular testing and identifying therapy options with the highest level of evidence. In the final analysis of the ADMIRAL study, Overall Survival (OS) was reported as 9.3 months for patients receiving gilteritinib versus 5.6 months for those receiving salvage chemotherapy (Hazard Ratio = 0.64 (95% CI 0.49, 0.83), P=0.0004). The rate of complete response (CR/CRh) was reported at 22.6%. The median time to first response was 2 months and transfusion-independence was observed in 34.5% of patients, representing a potential improvement in quality of life. Gilteritinib is actively being studied in other AML settings including front-line therapy with induction chemotherapy, maintenance therapy after transplant, and in combination with hypomethylators.

PQI Process: Upon receipt of new prescription for gilteritinib:

  • Verify genetic testing is complete with positive FLT3 mutation and appropriate prior lines of therapy
  • Ensure that the correct dose is prescribed (3 x 40 mg oral tablets [120 mg total]) by mouth daily
  • Verify that baseline blood counts, chemistries, as well as creatine phosphokinase (CPK) have been assessed prior to initiation of gilteritinib. Schedule these labs for every week for the first month, every other week for the second month, and once monthly thereafter for the duration of therapy
  • Ensure ECG results obtained prior to initiation of gilteritinib as well as appointments scheduled to receive follow-up ECGs on days 8 and 15 of the first cycle and consider for the next two subsequent cycles
  • Monitor for any signs/symptoms of pancreatitis, PRES, differentiation syndrome
    • Fever, dyspnea, hypoxia, pulmonary infiltrates, pleural effusions, edema
  • Call office at first sign of fever (temperature >100.4F)
  • Consider the use of antidiarrheals
  • Important: Upon refill, check and clarify dosing, quantity, and instructions to the patient (number of tablets per dose, etc.)

Patient Centered Activities:

  • Provide Oncology Chemotherapy Education (OCE) sheet
  • Ensure patient knows the appropriate drug dose and schedule (3 x 40 mg oral tablets [120 mg total] once daily continuously)
  • Ensure patient knows that the drug may be taken without regard to meals and that the tablets should not be broken or crushed
  • Patients should take their dose as soon as possible if missed on the same day if at least 12 hours before next scheduled dose followed by a return to normal dosing schedule. Patient should not take two doses within 12 hours.
  • Counsel female patients of childbearing age to use effective contraception during treatment and for at least six months after the last dose of gilteritinib; male patients should utilize contraception during treatment and for at least 4 months after the last dose of gilteritinib
  • Dosage modifications as described in Table in Supplemental Information

 

References:

  1. XOSPATA® (gilteritinib) [package insert].
  2. Perl AE, Altman JK, Cortes J, et al. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicenter, first-in-human, open-label, phase 1-2 study. Lancet Oncology. 2017;18(8):1061-1075.
  3. Usuki K, Sakura T, Kobayashi Y, et al. Clinical profile of gilteritinib in Japanese patients with relapsed/refractory acute myeloid leukemia: an open-label phase 1 study. Cancer Science. 2018;109(10):3235-3244.
  4. Perl AE, Cortes JE, Strickland SA, et al. An open-label, randomized phase III study of gilteritinib versus salvage chemotherapy in relapsed or refractory FLT3 mutation- positive acute myeloid leukemia. Journal of Clinical Oncology. DOI: 10.1200/JCO.2017.35.15_suppl.TPS7067.

Supplemental Information

Dose Modifications

Adverse EventRecommended Action
·  Differentiation Syndrome· Systemic steroids until resolved for 3 days (interrupt gilteritinib if signs remain >48H)· Resume when symptoms improve to Grade 2
·  Posterior reversible encephalopathy syndrome (PRES)· Discontinue gilteritinib
·  QTc interval > 500 msec· Interrupt gilteritinib and resume at reduced dose of 80 mg (2 x 40 mg tablets) daily whenQTc interval returns to within 30 msec of baseline or ≤480 msec
·  QTc interval increased by > 30 msec on ECG on day 8 of cycle 1· Confirm with ECG on day 9· If confirmed, consider gilteritinib dose reduction to 80 mg (2 x 40 mg tablets) daily
·  Pancreatitis· Interrupt gilteritinib until pancreatitis is resolved and resume at a reduced dose of 80 mg (2 x 40 mg tablets) daily
·  Other grade 3 or higher toxicity (related to treatment)· Interrupt gilteritinib until toxicity resolves or improves to grade 1 and reduce dose to 80 mg (2 x 40 mg tablets) daily

 

Co-Pay Assistance

  • Patients with commercial paying insurance are eligible for co-pay support
    • Patients pay as little as $0 per prescription
    • Enrollment is for a 12 month period and the program benefit covers up to a maximum of $25,000 per calendar year
    • Contact XOSPATA® support solutions (1-844-632-9272) OR your preferred network specialty pharmacy to determine eligibility and enrollment

Common adverse events (all grade >30%):

  • Transaminase increase (51%)
  • Fatigue/malaise (44%)
  • Fever (41%)
  • Mucositis (41%)
  • Edema (40%)
  • Rash (36%)
  • Diarrhea (35%)
  • Dyspnea (35%)
  • Nausea (30%)

Rare and serious adverse events:

  • Electrocardiogram QT prolonged (9%)
  • Hypersensitivity (8%)
  • Pancreatitis (5%)
  • Cardiac Failure (4%)
  • Pericardial Effusion (4%)
  • Differentiation syndrome (3%) [Boxed Warning]
  • Posterior reversible encephalopathy syndrome (1%)

*AE reported from 319 gilteritinib patients across 3 clinical trials

Important notice: NCODA has developed this Positive Quality Intervention platform. This platform represents a brief summary of medication uses and therapy options derived from information provided by the drug manufacturer and other resources. This platform is intended as an educational aid and does not provide individual medical advice and does not substitute for the advice of a qualified healthcare professional. This platform does not cover all existing information related to the possible uses, directions, doses, precautions, warning, interactions, adverse effects, or risks associated with the medication discussed in the platform and is not intended as a substitute for the advice of a qualified healthcare professional. The materials contained in this platform are for informational purposes only and do not constitute or imply endorsement, recommendation, or favoring of this medication by NCODA, which assumes no liability for and does not ensure the accuracy of the information presented. NCODA does not make any representations with respect to the medications whatsoever, and any and all decisions, with respect to such medications, are at the sole risk of the individual consuming the medication. All decisions related to taking this medication should be made with the guidance and under the direction of a qualified healthcare professional.
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