What is obinutuzumab?
Obinutuzumab is a humanized anti-CD20 monoclonal antibody.
How does obinutuzumab work?
The CD20 antigen is expressed on the surface of pre B- and mature B-lymphocytes. Obinutuzumab binds to a specific epitope of the CD20 molecule found on B cells. This activates complement-dependent cytotoxicity, antibody dependent cellular cytoxicity and phagocytosis, all leading to cell death.
What is this approved for?
Obinutuzumab is approved in combination with chlorambucil for treatment of chronic lymphocytic leukemia (CLL). It is also approved in combination with bendamustine followed by continued monotherapy for patients with follicular lymphoma (FL) who relapsed after, or are refractory to a rituximab containing regimen.
What is the basis for this approval?
Obinutuzumab was approved based on an improvement in progression-free survival (PFS) in a randomized, open-label, multicenter trial in patients with indolent NHL. The trial compared 396 patients with indolent NHL who were randomized to obinutuzumab plus bendamustine for 6 cycles followed by continued obinutuzumab monotherapy for up to 2 years versus 6 cycles of bendamustine. The independent review median PFS was 14.9 months in the bendamustine arm while the median PFS was not reached in the obinutuzumab plus bendamustine arm (HR 0.55, 95% CI 0.4-0.74; p = 0.00011). The investigator assessed median PFS was 14 months for bendamustine and 29 months for obinutuzumab plus bendamustine (HR 0.52, 95% CI 0.39-0.70; p < 0.0001) (J Clin Oncol 2015;33:18_suppl, LBA8502-LBA8502).
How do you administer this drug?
Administer as an IV infusion.
* The dosing for CLL is:
* Obinutuzumab 100 mg on day 1, 900 mg on day 2, 1,000 mg on day 8 and 15 of cycle 1
* Obintuzumab 1,000 mg on day 1 every 28 days for cycles 2-6
* The dosing for FL is:
* Obintuzumab 1,000 mg on day 1, 8, and 15 of cycle 1
* Obintuzumab 1,000 mg on day 1 every 28 days for cycles 2-6, then
* Obintuzumab 1,000 mg every 2 months for 2 years (monotherapy)
Are there any premedications needed?
To reduce risk of infusion reactions, premedicate patients with IV dexamethasone or methylprednisolone at least 1 hr prior to infusion, 650-1000 mg acetaminophen and an antihistamine (such as 50 mg diphenhydramine) at least 30 minutes prior to obinutuzumab infusion.
Patients who are at high risk of tumor lysis syndrome (TLS) should receive prophylaxis with allopurinol and adequate hydration along with monitoring of electrolytes and renal function.
What are the common side effects associated with obinutuzumab (> or = 10%)?
CLL: infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, nausea, and diarrhea.
FL: infusion reactions, neutropenia, nausea, fatigue, cough, diarrhea, constipation, pyrexia, thrombocytopenia, vomiting, upper respiratory tract infection, decreased appetite, arthralgia, sinusitis, anemia, asthenia, and urinary tract infection.
What are the uncommon side effects associated with obinutuzumab (less than 10%)?
CLL: anemia (4%), leukopenia (4%), diarrhea (2%), urinary tract infection (1%), pyrexia (<1%), cough (<1%), and nasopharyngitis (<1%).
FL: urinary tract infection (3%), upper respiratory tract infection (2%), pyrexia (1%), asthenia (1%), sinusitis (1%), and pain in extremity (1%).
Are there any important drug interactions I should be aware of?
No specific drug interactions have been identified with obintuzumab.
How do I adjust the dose in the setting of renal or hepatic insufficiency?
Based on population pharmacokinetic analysis, a baseline creatinine clearance (CrCl) > 30 mL/min does not affect the pharmacokinetics of obintuzumab. (CrCl < 30 mL/min have not been studied.) Obintuzumab has not been studied in patients with hepatic impairment, currently no recommendations for dose adjustment.
Practical tips
Hepatitis B virus (HBV) reactivation can occur and is associated with a risk of fulminant hepatitis, hepatic failure, and death. Pretreatment screening for HBV infection is recommended.
What should my patients know about obinutuzumab?
Patients should seek medical attention for:
* Symptoms of infusion reactions such as dizziness, nausea, chills, fever, vomiting, diarrhea, breathing problems, or chest pain.
* Symptoms of TLS such as nausea, vomiting, diarrhea, and lethargy
* Symptoms of infection including fever and cough.
* Changes in neurological function such as confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems
What else should I know about obinutuzumab?
Advise patients of the need for:
* Periodic monitoring of blood counts
* Avoid vaccinations with live viral vaccines
* Patients with a history of HBV infection should potentially be considered for prophylaxis of reactivation
What useful links are available regarding obinutuzumab?
* http://www.gazyva.com
* https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm488013.htm
Any ongoing clinical trials related to obinutuzumab?
Clinical trials involving obinutuzumab are being conducted in several settings including combinations of obinutuzumab and lenadidomide in CLL and FL, and obintuzumab and ibrutinib in CLL. More information can be found online at https://clinicaltrials.gov.
J. ANDREW SKIRVIN, PHARMD, BCOP, is Associate Clinical Professor, Northeastern University, School of Pharmacy, Boston, and RANDI KOWALCZYK, PHARMD, is at Northeastern University, School of Pharmacy, Boston.