On November 16, 2017, obinutuzumab (Gazyva) was granted regular approval in combination with chemotherapy, followed by obinutuzumab monotherapy for patients achieving at least a partial remission, for the treatment of adult patients with previously untreated stage II bulky, III, or IV follicular lymphoma.^1,2 

Supporting Efficacy Data 

APPROVAL WAS BASED on findings in the open-label phase III GALLIUM trial in 1,385 patients with previously untreated non-Hodgkin lymphoma, including 1,202 patients with follicular lymphoma.^2,3 Patients were randomized to receive either obinutuzumab plus chemotherapy (n = 691; n = 601 with follicular lymphoma) or rituximab (Rituxan) plus chemotherapy (n = 694; n = 601 with follicular lymphoma), followed in responding patients by obinutuzumab or rituximab maintenance for up to 2 years. Of the patients with follicular lymphoma, 91% had stage III or IV disease, 44% had bulky disease, and 79% had at least intermediate-risk disease. Chemotherapy was stipulated at each study site and given at standard doses; among all patients with follicular lymphoma, chemotherapy consisted of bendamustine in 57%, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) in 33%, and CVP (cyclophosphamide, vincristine, and prednisone) in 10%. 

At a median follow-up of 38 months, median progression-free survival, assessed by independent review committee, was not reached in either group. Progression-free survival events had occurred in 18% of the obinutuzumab group vs 23% of the rituximab group, with an estimated hazard ratio of 0.72 (P = .0118). Overall response rates were 91% vs 88%, and complete remission rates were 28% and 27%, respectively. 

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. Due to its reduced fucose content, obinutuzumab induces greater antibody-dependent cellular cytotoxicity activity in human cancer cell lines compared with rituximab and also exhibits increased induction of direct cell death. Obinutuzumab binds to FcγRIII via purified proteins with greater affinity than rituximab; obinutuzumab and rituximab bind to overlapping epitopes on CD20 with similar affinity. 

How It Is Used 

FOR PATIENTS WITH previously untreated follicular lymphoma, obinutuzumab is administered with one of the following chemotherapy regimens: six 28-day cycles in combination with bendamustine; six 21-day cycles in combination with CHOP, followed by two additional 21-day cycles of obinutuzumab alone; or eight 21-day cycles in combination with CVP. Patients with a complete or partial response to the initial 6 or 8 cycles should continue on obinutuzumab at 1,000 mg as monotherapy for up to 2 years. 

Each dose of obinutuzumab is 1,000 mg administered intravenously as follows: during cycle 1—on days 1, 8, and 15; during cycles 2–6 or 2–8—on day 1; for monotherapy in those with a partial or complete response—every 2 months for up to 2 years. 

All patients should receive premedication for infusion-related reactions prior to obinutuzumab infusion. Product labeling provides detailed instructions for premedication and for management of infusion-related reactions. 

Patients with a high tumor burden, high circulating absolute lymphocyte counts (> 25 109/L), or renal impairment are considered at risk of tumor-lysis syndrome and should receive prophylaxis, including premedication with antihyperuricemics. Patients with grade 3 to 4 neutropenia lasting for more than 1 week should receive antimicrobial prophylaxis until resolution of neutropenia to grade 1 or 2; antiviral and antifungal prophylaxis should be considered. Treatment interruption should be considered for patients with infection, grade 3 or 4 cytopenia, or grade ≥ 2 nonhematologic toxicity. 

Safety Profile 

AMONG THE 1,385 patients evaluated for safety in the GALLIUM trial, the most common adverse events of any grade in the obinutuzumab group with an incidence ≥ 20% and ≥ 2% greater than in the rituximab group included infusion reactions (72% vs 60%), neutropenia (53% vs 47%), upper respiratory tract infection (50% vs 43%), cough (35% vs 28%), constipation (32% vs 29%), and diarrhea (30% vs 26%). Grade ≥ 3 adverse events occurred in 79% vs 72%; the most common adverse events with an incidence ≥ 5% and observed more frequently with obinutuzumab were neutropenia (49% vs 41%), febrile neutropenia, infusion reactions (12% vs 8%), and thrombocytopenia (7% vs 3%). 

Serious adverse events occurred in 50% vs 43% of patients. Fatal adverse events during treatment occurred in 3% vs 2%, with fatal infection occurring in 2% vs < 1%. Patients receiving bendamustine had a higher incidence of serious and fatal infection than recipients of CHOP or CVP. 

During the monotherapy period, common adverse events (≥ 10%) with an incidence ≥ 2% higher with obinutuzumab were upper respiratory tract infection (40%), cough (23%), musculoskeletal pain (20%), neutropenia (19%), and herpes virus infection (13%). 

Obinutuzumab carries a boxed warning for hepatitis B virus 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, hypersensitivity reaction, tumor-lysis syndrome, infections, neutropenia, thrombocytopenia, and immunization. Patients should not receive live virus vaccines prior to or during obinutuzumab treatment. The agent is contraindicated in patients with known hypersensitivity reactions to obinutuzumab or any of the excipients, including serum sickness with prior obinutuzumab use. In pregnancy, obinutuzumab is likely to cause fetal B-cell depletion. ■

REFERENCES 

1. U.S. Food and Drug Administration: FDA approves obinutuzumab for previously untreated follicular lymphoma. Available at www.fda.gov. Accessed December 12, 2017. 

2. Gazyva (obinutuzumab) injection for intravenous infusion prescribing information. Genentech, Inc, November 2017. Available at www.accessdata.fda.gov/ drugsatfda_docs/label/2017/125486s017s018lbl.pdf. Accessed December 12, 2017. 

3. Marcus R, Davies A, Ando K, et al: Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med 377:1331-1344, 2017.