17

January

Sorafenib for the Treatment of Hepatocellular Carcinoma and Transition to Second-line Regorafenib

Written by: Jeff Engle, PharmD, MS
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This PQI will discuss effective management of adverse effects of sorafenib (Nexavar) 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 patients18.

PQI Process:

Upon receipt of a prescription for sorafenib:

  • Consider obtaining 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 400mg a day of sorafenib for 20 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 or if underlying hypertension exists, ensure appropriate blood pressure control prior to starting regorafenib
  • Refer to Regorafenib in the treatment of Hepatocellular Carcinoma PQI for managing adverse effects17

Patient Centered Activities:

Counseling for Sorafenib

  • Provide patient Oral Chemotherapy Education Sheet (oralchemoedsheets.com)
  • Counsel patient on the signs and symptoms of hand-foot syndrome and other dermatologic side effects as well as management strategies below
    • Refer to Hand-Foot Syndrome PQI on NCODA Website
  • Counsel on appropriate management of chemotherapy induced diarrhea
    • Refer to Chemotherapy Induced Diarrhea PQI for more information16
  • Counsel on measuring blood pressure weekly at home for the first 6 weeks and instruct to report blood pressures > 140/90
  • 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 2.15

Counseling for Regorafenib

  • Provide patient Oral Chemotherapy Education Sheet (oralchemoedsheets.com)
  • Utilize principles contained within PQI on Regorafenib in HCC
  • Counsel patient on the signs and symptoms of hand-foot syndrome and other dermatologic side effects as well as management strategies below
    • Refer to Hand-Foot Syndrome PQI on NCODA Website

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

*see full prescribing information for more detailed dose interruption and modification strategies listed by indication and AE

Patient Assistance

Sorafenib patients can utilize the REACH support program while on therapy

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.

 

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