Note: REQUIRES PRECERTIFICATION.*
Aetna considers obinutuzumab medically necessary for the followiing indications in persons without active hepatitis B infection:
Gazyva (obinutuzumab) therapy is not considered medically necessary for members who have experienced significant disease progression while on obinutuzumab.
Aetna considers obinutuzumab experimental and investigational for all other indications including the following (not an all-inclusive list):
Note: * Precertification of obinutuzumab (Gazyva) is required of all Aetna participating providers and members in applicable plan designs. For precertification of obinutuzumab, call (866) 503-0857, or fax (866) 267-3277.Background
Gazyva (obinutuzumab) is a monoclonal antibody that targets the CD20 antigen expressed on the surface of pre B‐ and mature B‐lymphocytes. Upon binding to CD20, obinutuzumab mediates B‐cell lysis through (1) engagement of immune effector cells, (2) by directly activating intracellular death signaling pathways and/or (3) activation of the complement cascade. The immune effector cell mechanisms include antibody‐dependent cellular cytotoxicity and antibody‐dependent cellular phagocytosis. Obinutuzumab in combination with chlorambucil, is indicated for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL).
Chronic lymphocytic leukemia (CLL) represents the most prevalent adult leukemia and the introduction of therapeutic antibodies has increased the number of available treatments. For both previously untreated symptomatic CLL and as salvage therapy, rituximab, a CD20 antibody, is currently widely used in combination-based strategies. Recent data suggest that the addition of rituximab to fludarabine with or without cyclophosphamide prolongs survival in younger patients with CLL. Other improved CD20 antibodies with promising clinical activity, include ofatumumab and obinutuzumab (GA-101). Alemtuzumab, a CD52 antibody, likewise has demonstrated benefit in both symptomatic, previously untreated CLL and in patients with relapsed disease. Also, recent efforts to combine currently applied therapeutic antibodies with other biologic and targeted therapies with efficacy in CLL offers the potential to move toward alternative non-chemotherapy-based treatment approaches (Jaglowski et al, 2010).
Laprevotte et al (2013) reported that rituximab combined with chemotherapy is a standard treatment for CLL. They investigated whether endogenous IL-8 affects rituximab or obinutuzumab (GA-101) B-leukemic depletion mediated by natural killers. Rituximab, and more significantly obinutuzmab, were effective in B-cell depletion and natural killer activation using whole peripheral blood lymphocytes from untreated CLL patients.
Obinutuzumab was approved on November 1, 2013 by the Food and Drug Administration (FDA) for use in combination with chlorambucil for previously untreated CLL (NCI, 2013). Obinutuzmab is a CD20-cytolytic antibody. The FDA labeling produced by Genentech (2013) lists a boxed warning stating that “hepatitis B Virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients receiving CD20-directed cytolytic antibodies, including GAZYVA. Screen all patients for HBV infection before treatment initiation. Monitor HBV positive patients during and after treatment with GAZYVA. Discontinue GAZYVA and concomitant medications in the event of HBV reactivation... Progressive Multifocal Leukoencephalopathy (PML) including fatal PML, can occur in patients receiving GAZYVA”.
Obinutuzumab is available as Gazyva in 1000mg/40mL single dose vials. Dosing and administration of obinutuzumab includes premedication with glucocorticoid, acetaminophen and anti-histamine. Obinutuzumab is to be diluted and administered as intravenous infusion and is not to be administered as an intravenous push or bolus. The recommended dose for 6 cycles (28 day cycles) for CLL/SLL is as follows: 100 mg on day 1 Cycle 1; 900 mg on day 2 Cycle 1; 1,000 mg on day 8 and 15 of Cycle 1; and 1,000 mg on day 1 of Cycles 2 through 6 (Genentech, 2013). Currently available data limits the use of Gazyva (obinutuzumab) to six cycles.
An FDA news release stated that "Gazyva’s approval for CLL is based on a study of 356 participants in a randomized open-label multi-center trial comparing Gazyva in combination with chlorambucil to chlorambucil alone in participants with previously untreated CLL...Participants receiving Gazyva in combination with chlorambucil demonstrated a significant improvement in progression free survival: an average of 23 months compared with 11.1 months with chlorambucil alone" (FDA, 2013).
National Comprehensive Cancer Network Drug and Biologics Compendium (NCCN, 2016) indicates obinutuzumab (Gazyva) for the following:
Gazyva has the following boxed warnings:
In an open-label, multi-center, phase Ib study, Radford et al (2013) examined the safety and activity of obinutuzumab plus chemotherapy in relapsed/refractory follicular lymphoma in 56 patients. Subjects received obinutuzumab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (G-CHOP; every 3 weeks for 6 to 8 cycles) or obinutuzumab plus fludarabine and cyclophosphamide (G-FC; every 4 weeks for 4 to 6 cycles). Patients were randomly assigned to either obinutuzumab 1,600 mg on days 1 and 8 of cycle 1 followed by 800 mg on day 1 of subsequent cycles or 400 mg for all doses. Treatment responders were eligible for obinutuzumab maintenance every 3 months for up to 2 years. Grade 1/2 infusion-related reactions (IRRs) were the most common treatment-related adverse event (AE) (all grades: G-CHOP, 68 %; G-FC, 82 %). Grade 3/4 IRRs were rare (7 %) and restricted to the first infusion. All patients received the planned obinutuzumab dose. Neutropenia was the most common treatment-related hematologic AE for G-CHOP (43 %) and G-FC (50 %). At the end of induction, a total of 96 % (27/28) of patients who received G-CHOP (complete response [CR], 39 % [11/28]) and 93 % (26/28) of patients who received G-FC (CR, 50 % [14 of 28]) achieved responses. The authors concluded that G-CHOP and G-FC had an acceptable safety profile with no new or unexpected AEs, but G-FC was associated with more AEs than G-CHOP. They stated that obinutuzumab plus chemotherapy resulted in 93 % to 96 % response rates, supporting phase III investigation.
Morschhauser et al (2013) noted that obinutuzumab was superior to rituximab in human diffuse large B-cell lymphoma (DLBCL) and mantle-cell lymphoma (MCL) xenograft models. In a phase I study by these researchers, obinutuzumab exhibited encouraging activity but no clear dose-response relationship, and few patients had aggressive histologies. In a randomized phase II study, these investigators examined the safety and effectiveness of 2 doses of obinutuzumab in patients with heavily pre-treated DBLCL and MCL. Patients were randomly assigned to receive 8 cycles of obinutuzumab either as a flat dose of 400 mg for all infusions (days 1 and 8 of cycle 1; day 1 of cycles 2 to 8) or 1,600 mg on days 1 and 8 of cycle 1 and 800 mg on day 1 of cycles 2 to 8. A total of 40 patients were enrolled: 21 patients in the 400/400-mg treatment arm (DLBCL, n = 10; MCL, n = 11) and 19 patients in the 1,600/800-mg arm (DLBCL, n = 15; MCL, n = 4). End-of-treatment response was 28 % (32 % and 24 % in the 1,600/800-mg and 400/400-mg study arms, respectively). Best overall response rates (ORRs) were 37 % in the 1,600/800-mg arm and 24 % in the 400/400-mg study arm (DLBCL, 8 [32 %] of 25 patients; MCL, 4 [27 %] of 15 patients). Five (20 %) of 25 rituximab-refractory patients exhibited treatment response, including 4 of 12 in the 1,600/800-mg group. The most common AEs were IRRs, which were manageable; 3 patients had grade 3/4 IRRs; grade 3/4 neutropenia was seen in only 1 patient. The authors concluded that obinutuzumab 1,600/800 mg achieved early steady-state concentration and clinical activity with an acceptable safety profile in relapsed/refractory DLBCL and MCL, supporting further exploration.
Cameron and McCormack (2014) stated that obinutuzumab is an intravenously administered, humanized and glyco-engineered, type II anti-CD20 monoclonal antibody for the treatment of B-cell malignancies. It is approved in the U.S. for use in combination with chlorambucil for the first-line treatment of CLL, and has been filed for approval in the EU in this indication. The antibody is based on GlycArt Biotechnology's (later Roche Glycart AG) proprietary GlycoMAb® technology, which uses glycol-engineered antibodies that specifically increase antibody-dependent cellular cytotoxicity and thereby increase immune-mediated target cell death. Obinutuzumab is a type II anti-CD20 antibody that induces enhanced direct cell death. The monoclonal antibody is in world-wide phase III development with Roche and its subsidiaries, Genentech and Chugai Pharmaceutical, as well as Biogen Idec, for DLBCL and non-Hodgkin's lymphoma (NHL) generally, and is also in phase III development in countries outside of the U.S. and EU for CLL.
An UpToDate review on “Treatment of relapsed or refractory diffuse large B cell lymphoma” (Freedman and Friedberg, 2014) states that “CLINICAL TRIALS -- Often there is no better therapy to offer a patient than enrollment onto a well-designed, scientifically valid, peer-reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (www.clinicaltrials.gov). Areas of active study include novel agents such as obinutuzumab, everolimus, PI3 kinase inhibitors, aurora A kinase inhibitors, and syk inhibitors”.
Furthermore, NCCN’s Drugs & Biologics Compendium (2014) does not list large B-cell lymphoma/DLBCL as a recommended indication of obinutuzumab.
In the phase II part of the phase I/II GAUGUIN study, Salles et al (2013) evaluated the safety and effectiveness of 2 different doses of obinutuzumab in patients with relapsed/refractory indolent NHL. Patients were randomly assigned to receive 8 cycles of obinutuzumab as a flat dose of 400 mg on days 1 and 8 of cycle 1 and also on day 1 of cycles 2 to 8 (400/400 mg) or 1,600 mg on days 1 and 8 of cycle 1 and 800 mg on day 1 of cycles 2 to 8 (1,600/800 mg). A total of 40 patients were enrolled, including 34 with follicular lymphoma; 38 of 40 patients had previously received rituximab and 22 of 40 were rituximab refractory. The ORR at the end of treatment was 55 % (95 % CI: 32 % to 76%) in the 1,600/800-mg group (9 % complete responders) and 17 % (95 % CI: 4 % to 41 %) in the 400/400-mg group (no complete responders). Five of 10 rituximab-refractory patients had an end-of-treatment response in the 1,600/800-mg group versus 1 of 12 in the 400/400-mg group. Median progression-free survival (PFS) was 11.9 months in the 1,600/800-mg group (range of 1.8 to 33.9+ months) and 6.0 months in the 400/400-mg group (range of 1.0 to 33.9+ months). The most common AEs were IRRs seen in 73 % of patients, but only 2 patients had grade 3 to 4 IRRs (both in the 1,600/800-mg group). No IRRs were considered serious, and no patients withdrew for IRRs. The authors concluded that the 1,600/800-mg dose schedule of obinutuzumab has encouraging activity with an acceptable safety profile in relapsed/refractory indolent NHL.
Owen and Stewart (2014) analyzed data for the use of obinutuzumab in the treatment of CD20(+) lympho-proliferative disorders with a focus on CLL. Targeted therapy against CD20 with the mAb rituximab led to significant improvements in survival for patients with B-cell NHL and is the current mainstay of treatment for CD20(+) malignancies. Despite this, many patients relapse or become refractory after rituximab-containing therapies, so efforts have been made to develop better anti-CD20 mAbs. Obinutuzumab recently demonstrated superiority over rituximab in the only published phase III study comparing the 2 antibodies. The authors concluded that the demonstration of superiority of obinutuzumab over rituximab in the CLL11 phase III study is potentially practice-changing. Obinutuzumab has also proven safe and effective in CD20(+) NHL in phase I/II studies and results of phase III studies in NHL are eagerly awaited.
Acute Lymphoblastic Leukemia and Burkitt Lymphoma:
Awasthi and colleagues (2015) noted that CD20 is expressed in approximately 100 % of children and adolescents with Burkitt lymphoma (BL) and 40 % with precursor B-cell acute lymphoblastic leukemia (pre-B-ALL). These researchers evaluated the anti-tumor activity of obinutuzumab versus rituximab against rituximab-resistant (Raji 4RH) and rituximab-sensitive (Raji) BL and pre-B-ALL (U698-M) cells in-vitro and in human BL or Pre-B-ALL xenografted mice. They demonstrated that obinutuzumab compared to rituximab significantly enhanced cell death against Raji 35.6 ± 3.1 % versus 25.1 ± 2.0 %, (p = 0.001), Raji4RH 19.7 ± 2.2 % versus 7.9 ± 1.5 % (p = 0.001) and U-698-M 47.3 ± 4.9% versus 23.2 ± 0.5 % (p = 0.001), respectively. Obinutuzumab versus rituximab also induced a significant increase in antibody-dependent cellular cytotoxicity (ADCC) with K562-IL15-41BBL expanded NK cells against Raji 73.8 ± 8.1 % versus 56.81 ± 4.6 % (p = 0.001), Raji-4RH 40.0 ± 1.6 % versus 0.5 ± 1.1 % (p = 0.001) and U-698-M 70.0 ± 1.6 % versus 45.5 ± 0.1 % (p = 0.001), respectively. Overall survival in tumor xenografted mice receiving 30 mg/kg of obinutuzumab was significantly increased when compared to those receiving 30 mg/kg of rituximab in BL; Raji (p = 0.05), Raji4RH (p = 0.02) and U698-M (p = 0.03), respectively. These pre-clinical data suggested that obinutuzumab is significantly superior to rituximab in inducing cell death, ADCC and against rituximab-sensitive/-resistant BL and pre-B-ALL xenografted mice. The authors concluded that taken together, these pre-clinical results provided evidence to suggest that future investigation of obinutuzumab is warranted in patients with relapsed/refractory CD20(+) BL and/or pre-B-ALL.
Follicular Lymphoma/Gastric MALT Lymphoma/Non-Gastric MALT Lymphoma/Splenic Marginal Zone Lymphoma:
On February 26, 2016, the UFDA approved Gazyva (obinutuzumab) plus bendamustine chemotherapy followed by Gazyva alone as a new treatment for people with follicular lymphoma who did not respond to a Rituxan (rituximab)-containing regimen, or whose follicular lymphoma returned after such treatment. The approval is based on results from the phase III GADOLIN study, which showed that, in people with follicular lymphoma whose disease progressed during or within 6 months of prior rituximab-based therapy, obinutuzumab plus bendamustine followed by obinutuzumab alone demonstrated a 52 % reduction (HR = 0.48, 95 % CI: 0.34 to 0.68, p < 0.0001) in the risk of disease worsening or death (PFS), compared to bendamustine alone, as assessed by an independent review committee (IRC). The supplemental Biologics License Application based on these data was granted Priority Review, a designation granted to medicines that the FDA has determined to have the potential to provide significant improvements in the treatment, prevention or diagnosis of a disease.
The recommended dose and schedule for the regimen are as follows:
National Comprehensive Cancer Network’s Drugs & Biologics Compendium (2016) recommends obinutuzumab as maintenance therapy for rituximab refractory disease in patients with follicular lymphoma, gastric MALT lymphoma, non-gastric MALT lymphoma, and splenic marginal zone lymphoma (all 2B recommendations).
|CPT Codes / HCPCS Codes / ICD-10 Codes|
|Information in the [brackets] below has been added for clarification purposes.  Codes requiring a 7th character are represented by "+":|
|Other CPT codes related to the CPB:|
|96413||Chemotherapy administration, intravenous infusion technique; up to 1 hour, single or initial substance/drug|
|+96415||each additional hour (List separately in addition to code for primary|
|HCPCS codes covered if selection criteria are met :|
|J9301||Injection, obinutuzumab, 10 mg|
|Other HCPCS codes related to the CPB:|
|J9310||Injection, rituximab, 100 mg|
|ICD-10 codes covered if selection criteria are met:|
|C82.00 - C82.99||Follicular lymphoma [rituximab refractory disease]|
|C83.00 - C83.09||Small cell B-cell lymphoma [splenic marginal zone lymphoma][rituximab refractory disease]|
|C88.4||Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue [MALT-lymphoma] [gastric/non-gastric MALT lymphoma] [rituximab refractory disease]|
|C91.10 - C91.12||Chronic lymphocytic leukemia of B-cell type [small lymphocytic lymphoma]|
|ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):|
|B16.0 - B16.9||Acute hepatitis B|
|B18.0 - B18.1||Chronic viral hepatitis B|
|C83.10 - C83.19||Mantle cell lymphoma|
|C83.30 - C83.39||Diffuse large B-cell lymphoma|
|C83.70 - C83.79||Burkitt lymphoma|
|C85.20 - C85.29||Mediastinal (thymic) large B-cell lymphoma|
|C91.00 - C91.02||Acute lymphoblastic leukemia [ALL]|