In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
Indication
On November 1, 2013, obinutuzumab (Gazyva) was approved for use in combination with chlorambucil (Leukeran) in the treatment of previously untreated chronic lymphocytic leukemia (CLL).1,2 Approval was based on results of an open-label trial showing improved progression-free survival with the combination of obinutuzumab plus chlorambucil vs chlorambucil alone in patients with previously untreated CD20-positive CLL. The study also included a rituximab (Rituxan) plus chlorambucil group; comparative data for the two combination groups are not yet available.
In the trial, 356 patients with coexisting medical conditions or reduced renal function (creatinine clearance < 70 but ≥ 30 mL/min) were randomly assigned 2:1 to receive obinutuzumab at 1,000 mg on days 1, 8, and 15 of the first cycle and day 1 of five subsequent 28-day cycles plus oral chlorambucil at 0.5 mg/kg on day 1 and 15 of each cycle (n = 238) or chlorambucil alone (n = 118). After a very high incidence of infusion-related reactions during the first dose in obinutuzumab recipients, the first obinutuzumab dose was divided into 100 mg on day1 and 900 mg on day 2 of the first cycle for the last 45 study patients treated.
Patients received glucocorticoid, acetaminophen, and antihistamine premedication prior to initial obinutuzumab infusions and subsequently as needed. Patients with active infection, positive hepatitis B virus (HBV) serology (HBsAg- or anti-HBc–positive, patients positive for anti-HBc could be included if hepatitis B viral DNA was not detectable), positive hepatitis C serology, or immunization with live virus vaccine within the prior 28 days were excluded from the study.
Patients had a median age of 73 years, 60% were male, 95% were Caucasian, 68% had creatinine clearance < 70 mL/min, 76% had multiple coexisting medical conditions, and 22%, 42%, and 36% were Binet stage A, B, and C, respectively. In total, 81% of the combination group and 67% of the chlorambucil-alone group received all six cycles of treatment.
Median progression-free survival on independent review was 23.0 months in the combination arm vs 11.1 months in the chlorambucil-alone arm (hazard ratio = 0.16, P < .0001). The overall response rate was 75.9% vs 32.1%, with complete response in 27.8% vs 0.9%, and median duration of response was 15.2 vs 3.5 months.
How It Works
Obinutuzumab is a monoclonal antibody targeting the CD20 antigen expressed on the surface of pre B- and mature B-lymphocytes. After binding to CD20, obinutuzumab mediates B-cell lysis by engaging immune effector cells, directly activating intracellular death signaling pathways, and activating the complement cascade. Immune effector cell activities include antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis.
How It Is Given
Obinutuzumab is given via intravenous infusion at a dose of 100 mg on day 1 and 900 mg on day 2 of the first treatment cycle, and at 1,000 mg on day 8 and 15 of cycle 1 and day 1 of the subsequent five 28-day cycles.
Premedication with a glucocorticoid, acetaminophen, and antihistamine should be given before the first two doses. Thereafter, acetaminophen should be given before all doses, antihistamine premedication should be given to all patients with an infusion-related reaction ≥ grade1 during the prior infusion, and glucocorticoid premedication should be given to all patients with an infusion-related reaction ≥ grade 3 during the prior infusion or a lymphocyte count > 25 × 109/L.
Tumor lysis syndrome should be anticipated, and premedication with an antihyperuricemic beginning 12 to 24 hours before the start of therapy and adequate hydration for tumor lysis syndrome prophylaxis should be provided, particularly in patients with high tumor burden or high circulating absolute lymphocyte count (> 25 × 109/L). Electrolyte abnormalities should be corrected, supportive care provided, and renal function and fluid balance monitored.
Since hypotension may occur during infusion, withholding of antihypertensive treatment for 12 hours before and 1 hour after administration should be considered. Patients with neutropenia should receive antimicrobial prophylaxis throughout the treatment period, and antiviral and antifungal prophylaxis should be considered. Blood counts should be routinely monitored.
Safety Profile
The most common adverse events of any grade in the pivotal trial’s combination-group patients were infusion-related reactions (69% vs 0% in chlorambucil alone group), neutropenia (40% vs 18%), and thrombocytopenia (15% vs 7%). The most common grade 3 or 4 adverse events were infusion-related reactions (21% vs 0%), neutropenia (34% vs 16%), thrombocytopenia (11% vs 3%), and anemia (4% vs 5%). Infusion-related reaction symptoms included dyspnea, hypotension, nausea, vomiting, chills, flushing, and pyrexia.
The most common grade 3 or 4 hematologic abnormalities were neutropenia (46% vs 27%), lymphopenia (40% vs 2%), leukopenia (36% vs < 1%), and thrombocytopenia (14% vs 11%), and the most common grade 3 or 4 chemistry abnormalities were hyponatremia (8% vs 2%) and hyperkalemia (5% vs 2%).
The incidence of infection was similar in the two groups, with infection occurring in 38% of the combination group and grade 3 or 4 infection occurring in 9% (none fatal). Grade 3 or 4 tumor lysis syndrome occurred in 2% of the combination group and in 0% of the chlorambucil-alone group. Anti-obinutuzumab antibodies were detected in 13% of combination-group patients; the clinical significance of these antibodies is not known.
Obinutuzumab carries a boxed warning for HBV reactivation, which has resulted in fulminant hepatitis, hepatic failure, and death in some cases, and for progressive multifocal leukoencephalopathy, which has resulted in death. Obinutuzumab also has warnings/precautions for infusion-related reactions, tumor lysis syndrome, neutropenia, thrombocytopenia, and immunization.
Patients should be monitored for infection, platelet counts, and bleeding. Management of hemorrhage may require blood product support. Patients should not receive live virus vaccines prior to or during obinutuzumab treatment. ■
References
1. U.S. Food and Drug Administration: Gazyva (obinutuzumab). Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm373263.htm.
2. GAZYVATM (obinutuzumab) injection for intravenous infusion prescribing information. Genentech, Inc, November 2013. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2013/125486s000lbl.pdf.
