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The following information helps you to find FDA Alerts and Pharmacist’s Applications to Practice quickly and easily. In cooperation with the Food and Drug Administration (FDA), and as a service to our members, HOPA periodically distributes information about newly approved therapies for cancer patients from FDA’s Office of Oncology Drug Products Director, Dr. Richard Pazdur to inform oncologists and professionals in oncology-related fields in a timely manner. Links to product labels will take you to relevant clinical information on the indication, contraindications, dosing, and safety. In sending this information, HOPA does not endorse any product or therapy and does not take any position on the safety or efficacy of the product or therapy described.

Along with HOPA’s Publications Committee, members also review new drug updates and provide analysis and research on the application of these new drugs or indications. Pharmacist’s Applications to Practice, or PAP, are listed after drugs that include the additional analysis. If you are interested in helping the Publications Committee with creating a Pharmacist's Application to Practice, please contact Jeff Price at jprice@hoparx.org.

You can also find additional information on FDA Alerts and Updates by listening to FDA Drug Safety Podcasts.


May 10, 2019–Ramucirumab (CYRAMZA®) approved as a single agent for hepatocellular carcinoma (HCC) in patients who have an alpha fetoprotein (AFP) of ≥ 400 ng/mL and have been previously treated with sorafenib (with Pharmacist's Applications to Practice)

April 24, 2015–Ramucirumab (CYRAMZA®, Eli Lilly and Company) for use in combination with FOLFIRI for the treatment of patients with metastatic colorectal cancer (mCRC) whose disease has progressed on a first line bevacizumab-, oxaliplatin- and fluoropyrimidine-containing regimen

May 10, 2019, with PAP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125477s029lbl.pdf

On May 10, 2019, the Food and Drug Administration approved ramucirumab (CYRAMZA®, Eli Lilly and Company) as a single agent for hepatocellular carcinoma (HCC) in patients who have an alpha fetoprotein (AFP) of ≥ 400 ng/mL and have been previously treated with sorafenib.

Approval was based on REACH‑2 (NCT02435433), a multinational, randomized, double-blind, placebo-controlled, multicenter study in 292 patients with advanced HCC with AFP ≥ 400 ng/mL who had disease progression on or after sorafenib or who were intolerant. Patients were randomized (2:1) to receive ramucirumab 8 mg/kg plus best supportive care (BSC) or placebo plus BSC every 2 weeks as an intravenous infusion until disease progression or unacceptable toxicity.

The trial’s primary endpoint was overall survival (OS). The estimated median OS was 8.5 months (7.0, 10.6) for patients receiving ramucirumab and 7.3 months (5.4, 9.1) for those receiving placebo (HR 0.71; 95% CI: 0.53, 0.95; p=0.020).

The most common adverse reactions observed in patients with HCC receiving single-agent ramucirumab (≥ 15% and ≥ 2% higher incidence than placebo) were fatigue, peripheral edema, hypertension, abdominal pain, decreased appetite, proteinuria, nausea, and ascites. The most common laboratory abnormalities (≥ 30% and a ≥ 2% higher incidence than placebo) were hypoalbuminemia, hyponatremia, and thrombocytopenia.

The recommended ramucirumab dose is 8 mg/kg administered intravenously every 2 weeks.

View full prescribing information for CYRAMZA.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.

 

Pharmacist’s Applications to Practice

Ramucirumab for the Treatment of Advanced Hepatocellular Carcinoma

Author: Matthew Arango, PharmD BCOP
Specialty Practice Pharmacist—Gastrointestinal Oncology
The Ohio State University James Comprehensive Cancer Center
Columbus, OH

What is the potential role for ramucirumab in the treatment of advanced hepatocellular carcinoma (HCC)?

  • Ramucirumab is approved by the U.S. Food and Drug Administration (FDA) for the treatment of HCC in patients who have an alpha fetoprotein (AFP) ≥400 ng/mL and have been previously treated with sorafenib.1 Patients with advanced HCC (i.e., those who have metastatic disease or are no longer candidates for locoregional therapy) have an average life expectancy of approximately 8 months without treatment. Historically, sorafenib has been the only agent shown to improve survival in this patient population, but within the past 2 years multiple additional agents have been shown to have benefit in either the first- or second-line settings.2
  • Ramucirumab is an inhibitor of vascular endothelial growth factor receptor-2 (VEGFR2). VEGFR2 inhibition results in decreased proliferation and migration of human endothelial cells as well as inhibition of angiogenesis.1 Ramucirumab is the only intravenous (IV) inhibitor of angiogenesis approved in this setting following treatment with sorafenib.
    • Other agents approved for the treatment of HCC after sorafenib include the oral multikinase inhibitors regorafenib and cabozantinib and the IV immune checkpoint inhibitors nivolumab and pembrolizumab.2
  • No second-line HCC treatments have been compared head to head in a large randomized trial, but ramucirumab and oral multikinase inhibitors have similar reductions in hazard of death across individual trials compared to placebo.3-5
    • In patients with AFP <400 ng/mL, ramucirumab did not appear to improve outcomes compared to placebo.6 Subgroup analyses of patients treated with regorafenib and cabozantinib did not demonstrate a different treatment effect for patients with AFP <400 ng/mL or AFP ≥400 ng/mL.4,5
  • Regulatory approval for the new indication was based on data from the phase 3 multinational REACH-2 trial, which randomized patients with advanced HCC and AFP ≥400 ng/mL after treatment with sorafenib to either ramucirumab or placebo.3
    • Median overall survival was significantly improved in the ramucirumab group at 8.5 months versus 7.3 months (hazard ratio [HR] 0.71; 95% confidence interval [CI] 0.53–0.95]; p = .0199).
    • Progression-free survival and disease control rate were also improved with ramucirumab, but a significant difference was not shown in objective response rate or time to symptomatic deterioration compared to placebo.

What role can the pharmacist play in the management of patients on ramucirumab?

  • Ramucirumab for HCC is administered at a dose of 8 mg/kg IV over 60 minutes once every 14 days.1
    • There are no recommended dose adjustments for renal or hepatic dysfunction.
    • Dose reduction to 6 mg/kg (and additional reduction to 5 mg/kg) is recommended in cases of proteinuria with ≥2g protein/24 hours.
    • Of note, ramucirumab dosing is different for the non-small-cell lung cancer indication.
  • It is recommended that ramucirumab be infused through a protein-sparing 0.22 micron filter and that the IV line be flushed with 0.9% sodium chloride at the completion of the infusion.1
  • Patients should receive premedication with an IV histamine-1 receptor antagonist (e.g., diphenhydramine) prior to each treatment.
  • Monitor blood pressure, urine protein, and renal and hepatic function at regular intervals.1
  • In HCC patients, the most common treatment-related adverse events in the ramucirumab group were hypertension (17%), proteinuria (14%), fatigue (14%), nausea (12%), decreased appetite (11%), bleeding or hemorrhagic events (11%), hepatic injury or failure (8%), and infusion-related reactions (7%).3
    • With the additional safety data from REACH-2, the FDA removed the boxed warning that highlighted the risks of hemorrhage, gastrointestinal perforation, and impaired wound healing, though all have been reported in patients receiving ramucirumab, and caution should be exercised for patients at increased risk.1,3

Clinical Pearls

  • Ramucirumab is supplied as 100 mg/10 mL and 500 mg/50 mL vials (contains polysorbate 80). Store vials in the refrigerator in the original carton to protect from light until ready for use.1
  • In addition to AFP ≥400 ng/mL, patients were required to have Child-Pugh class A liver disease to be eligible for the REACH-2 trial. Patients with hepatic encephalopathy, prior liver transplant, uncontrolled hypertension, clinically meaningful ascites, or esophageal or gastric varices requiring endoscopic intervention were excluded.3
  • The manufacturer of ramucirumab offers investigation of insurance benefits, patient financial assistance, and treatment plan guides to aid patients and providers.7
  • Because no direct comparative studies between available second-line agents for treating advanced HCC after sorafenib have been conducted, consider toxicities and comorbidities to guide treatment.
    • Ramucirumab may be preferred to oral multikinase inhibitors for patients without prescription benefits, a history of hand-foot skin reaction with sorafenib, the inability to swallow, or a preference to simplify the home medication regimen.
    • Ramucirumab may be preferred to nivolumab or pembrolizumab for patients who are currently receiving immunosuppressive medications or who have a history of autoimmune conditions requiring systemic treatment.

References

  1. Cyramza (ramucirumab) [package insert]. Indianapolis, IN: Eli Lilly and Company; May 2019.
  2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Hepatobiliary Cancers, Version 3.2019 (August 1, 2019). Available at https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf. Accessed September 9, 2019.
  3. Zhu AX, Kand Y-K, Yen C-J, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20:282-296.
  4. Bruix J, Qin S, Granito A, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389:56-66.
  5. Abou-Alfa GK, Meyer T, Cheng A-L, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379:54-63.
  6. Zhu AX, Park JO, Ryoo B-K, et al. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2015;16:859-870.
  7. Lilly PatientOne program. Available at https://www.cyramza.com/financial-assistance/. Accessed September 9, 2019

April 24, 2015

http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125477s011lbl.pdf

On April 24, 2015, the U. S. Food and Drug Administration approved ramucirumab (CYRAMZA®, Eli Lilly and Company) for use in combination with FOLFIRI for the treatment of patients with metastatic colorectal cancer (mCRC) whose disease has progressed on a first line bevacizumab-, oxaliplatin- and fluoropyrimidine-containing regimen.  Ramucirumab is a recombinant human monoclonal IgG1 antibody that binds to the human vascular endothelial growth factor- receptor 2 (VEGF-R2), preventing the interaction of VEGF-R2 to its ligands.   

This approval is based on the results of a randomized, double-blind, multinational trial enrolling patients with mCRC that progressed during or within 6 months of discontinuation of bevacizumab-, oxaliplatin- and fluoropyrimidine-based combination chemotherapy.

The clinical trial accrued 1072 patients who were randomly allocated (1:1) to receive FOLFIRI plus placebo or FOLFIRI plus ramucirumab (N=536 per arm).  Treatment cycles on both arms were repeated every 2 weeks and ramucirumab was administered at a dose of 8 mg/kg by intravenous infusion every two weeks. Ramucirumab was continued until disease progression or unacceptable toxicity. 

The primary efficacy endpoint was overall survival (OS).  Treatment assignment was stratified by geographic region (North America vs. Europe vs. other regions), KRAS status (wild-type vs. mutant) and time to progression for the beginning of first-line treatment (< 6 months vs. greater than or equal to 6 months). 

The median age of the study population was 62 years, 57% were men, and 99% had an ECOG performance status of 0 or 1.  A statistically significant OS improvement was observed in patients receiving FOLFIRI plus ramucirumab compared to those receiving FOLFIRI plus placebo [HR 0.85 (95% CI: 0.73, 0.98), p=0.023, stratified log-rank test].  Median OS was 13.3 and 11.7 months for patients on the FOLFIRI plus ramucirumab and FOLFIRI plus placebo arms, respectively.  PFS was also significantly improved in patients who received ramucirumab in combination with FOLFIRI [HR 0.79 (95% CI: 0.70, 0.90), p<0.001]. Median PFS was 5.7 and 4.5 months, respectively.  

In general, the safety data was consistent with the known safety profile established in previously approved indications.  However, thyroid dysfunction (hypothyroidism) was reported in 2.6% of patients based on thyroid monitoring in patients with mCRC.

The recommended dose and schedule in patients receiving ramucirumab in combination with FOLFIRI after progression on a first-line bevacizumab containing regimen is 8 mg/kg administered every 2 weeks as a 60-minute IV infusion. 

Full prescribing information is available at:http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125477s011lbl.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

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