Coverage Policy Manual
Policy #: 2021019
Category: Pharmacy
Initiated: June 2021
Last Review: March 2022
  Obinutuzumab (e.g., Gazyva)

Description:
CD20 is a cell surface antigen expressed on pre-B and mature-B lymphocytes. More than 90% of malignant B-cells in non-Hodgkin lymphoma (NHL) express CD201,. CD20-directed cytolytic antibodies mediate cell lysis by (1) antibody-dependent cell-mediated cytotoxicity, (2) complement-dependent cytotoxicity, and (3) induction of intracellular death signaling pathways (apoptosis). All 3 CD20-directed cytolytic antibodies carry black box warnings for hepatitis B virus reactivation and progressive multifocal leukoencephalopathy.
 
Obinutuzumab is a monoclonal antibody which targets the CD20 antigen expressed on the surface of B-lymphocytes, both pre-B-lymphocytes and mature B-lymphocytes.  When obinutuzumab binds with the CD20 antigen it causes B-cell lysis and cell death likely through three ways.  First, it causes engagement of immune effector cells; second, it directly activates intracellular death signaling pathways; third, activation of the complement cascade.  Once engaged, the immune effector cells mechanisms of cell death include antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis.
 
Obinutuzumab has a black box warning concerning Hepatitis B virus reactivation and Progressive Multifocal Leukoencephalopathy.  Hepatitis B virus, (HBV) reactivation can in some cases result in fulminant hepatitis, hepatic failure and death. The development of Progressive Multifocal Leukoencephalopathy could result in death .
 
Regulatory
 
In 2013, obinutuzumab (e.g., Gazyva®) was approved by FDA through the breakthrough therapy designation process for treatment of patients with previously untreated CLL in combination with chlorambucil. In February 2016, the drug was approved, in combination with bendamustine followed by obinutuzumab monotherapy, for the treatment of patients with FL who relapsed or are refractory to a rituximab-containing regimen.
 
Coding
 
J9301     Injection, obinutuzumab, 10 mg

Policy/
Coverage:
Effective August 1, 2021, for members of plans that utilize an oncology benefits management program, Prior Approval is required for this service and is managed through the oncology benefits management program.
  
Effective January 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The use of obinutuzumab (e.g., Gazyv®) meets member benefit certificate primary coverage criteria that there be scientific effectiveness as indicated for the treatment of adults that meet the criteria indicated below:
 
Initiation of therapy
1. Must be >18 yrs.
2. Free from active infection.
3. Has not received a live vaccine within 28 days prior to starting treatment and live vaccines will not be administered during treatment.   
4. Individual has been screened for hepatitis B (HBV) infection (i.e. HBsAg and anti-HBc) prior to initiating therapy. If the individual has evidence of current or prior HBV infection, they will be monitored for HBV reactivation during treatment.    
5. Documented diagnosis of the following:   
A. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) for ANY ONE of the following:
      • Used in combination with bendamustine for first-line treatment in individuals with indications for treatment without del (17p)/TP53 mutation (NCCN 2A); OR  
      • Used in combination with chlorambucil for first-line treatment in individuals without del (17p)/TP53 mutation who have a significant comorbidity or individuals 65 years of age or older (NCCN 2A); OR   
      • Used in combination with acalabrutinib for first-line treatment in individuals without del (17p)/TP53 mutation (NCCN 1) or with del (17p)/TP53 (NCCN 2) with indications for treatment OR  
      • Used in combination with venetoclax for first-line treatment in individuals without del (17p)/TP53 mutation who are frail and have significant comorbidities or are 65 years of age and older (NCCN 1) or in combination with venetoclax for first-line treatment without del (17p)/TP53 mutation in younger patients without significant comorbidities (NCCN 2A) OR  
      • Used in combination with venetoclax for first-line treatment in individuals with del(17p)/TP53 mutation with indications for treatment (NCCN 2A); OR  
      • First-line therapy for CLL/SLL with del(17p)/TP53 as a single agent (NCCN 2A); OR   
      • Second-line and subsequent therapy as a single agent for CLL/SLL without del (17p)/TP53 mutation in individuals with indication for retreatment (NCCN 2A)  
B. B-Cell Lymphomas with diagnosis of ANY ONE of the following:
      • Follicular lymphoma (FL) (Grade 1-2) for ANY ONE of the following:
        • Used as first-line therapy for stage I, contiguous stage II, non-contiguous stage II, or for individuals with indications for treatment with stage III or stage IV disease in combination with bendamustine, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or CVP (cyclophosphamide, vincristine, prednisone) (NCCN 2A)
        • Used as subsequent therapy, if not previously used as first-line therapy, for refractory or progressive disease for ANY ONE of the following:  
          • Used in combination with bendamustine, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), or CVP (cyclophosphamide, vincristine, prednisone) (NCCN 2A)
          • Used as a single agent (NCCN 2A)
          • Used in combination with lenalidomide (NCCN 2A)
        • Used as a single agent for maintenance therapy and ANY ONE of the following:
          • Used as first-line consolidation therapy of extended dosing following chemoimmunotherapy (NCCN 2A)
          • Used as second-line consolidation therapy or extended dosing in individuals who are refractory to rituximab (NCCN 2A)
          • Used in individuals with histologic transformation to diffuse-large B-cell lymphoma with extensive follicular lymphoma who achieve a complete response to chemoimmunotherapy (NCCN 2A)
        • Used as a substitute for rituximab in individuals experiencing rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. (NCCN 2A)
      • Gastric MALT Lymphoma or Non-Gastric MALT Lymphoma (Noncutaneous) for ANY ONE of the following indications:
        • Used as second-line and subsequent therapy for relapsed or progressive disease for patients with indications for treatment in combination with bendamustine (if not previously treated with bendamustine) (NCCN, 2A)
        • Used as a single agent for maintenance therapy, as second line consolidation or extended dosing, in rituximab refractory individuals treated with obinutuzumab and bendamustine for recurrent disease. (NCCN 2A)
        • Used as a substitute for rituximab in individuals with intolerance (including those experiencing severe hypersensitivity reactions requiring discontinuation of rituximab) or rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. (NCCN 2A)
      • Nodal Marginal Zone Lymphoma
        • First-line therapy for stage I, contiguous stage II, non-contiguous stage II, or stage III, IV disease in patients with indications for treatment in combination with bendamustine, as a component of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with obinutuzumab regimen, or as a component of CVP (cyclophosphamide, vincristine, and prednisone) with obinutuzumab regimen (NCCN 2A)
        • Second-line and subsequent therapy for refractory or progressive disease in patients with indications for treatment in combination with bendamustine (not recommended if previously treated with bendamustine) (NCCN 2A)
        • Used as a single agent for maintenance therapy, as second line consolidation or extended dosing, in rituximab refractory individuals treated with obinutuzumab and bendamustine for recurrent disease. (NCCN 2A)
        • Used as a substitute for rituximab in individuals with intolerance (including those experiencing severe hypersensitivity reactions requiring discontinuation of rituximab) or rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. (NCCN 2A)
      • Splenic Marginal Zone Lymphoma
        • Second-line therapy for disease recurrence following initial management of splenomegaly (if previously treated with rituximab) and subsequent therapy in patients with indications for treatment in combination with bendamustine (not recommended if previously treated with bendamustine) (NCCN 2A)
        • Used as a single agent for maintenance therapy, as second line consolidation or extended dosing, in rituximab refractory individuals treated with obinutuzumab and bendamustine for recurrent disease. (NCCN 2A)
        • Used as a substitute for rituximab in individuals with intolerance (including those experiencing severe hypersensitivity reactions requiring discontinuation of rituximab) or rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. (NCCN 2A)
      • Histologic Transformation of Nodal Marginal Zone Lymphoma to Diffuse Large B-Cell Lymphoma, Mantle Cell Lymphoma, Diffuse Large B-Cell Lymphoma, High Grade B-Cell Lymphomas with Translocations of MYC and BCL2 and/or BCL6 (Double/Triple Hit Lymphoma), High-Grade B-Cell Lymphomas NOS, Burkitt Lymphoma, AIDS Related B-Cell Lymphomas, Post-Transplant Lymphoproliferative Disorders, or Castleman’s Disease:
        • Used as a substitute for rituximab in individuals with intolerance (including those experiencing severe hypersensitivity reactions requiring discontinuation of rituximab) or rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. (NCCN 2A)  
 
Continuation of therapy
The use of obinutuzumab meets member benefit certificate primary coverage criteria that there be scientific effectiveness as indicated for continuation of treatment of adult patients that meet ALL of the criteria indicated below:
 
  1. The individual continues to meet initial approval criteria
  2. Disease response with treatment as defined by stabilization of disease of decrease in size of tumor or tumor spread.
  3. Absence of unacceptable toxicity from the drug, (ex. Severe neutropenia/febrile neutropenia, severe thrombocytopenia, severe infusion related reactions, hypersensitivity reactions including serum sickness, tumor lysis syndrome [TLS], serious bacterial, fungal, or viral infections, etc.)
  4. Has been evaluated for the presence of progressive multifocal leukoencephalopathy (PML) and has been found to be negative
  5. Additional requirements for diagnosis of ANY ONE of the following:
    • Maintenance treatment of B-cell lymphomas, length of therapy does not exceed two years.
    • Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma indication is NOT medical appropriate for renewal.
 
The use of this drug is covered if an FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting of specified criteria (See policy #2000030).
 
Dosage and Administration
 
Indication(s)          Dosage & Administration                                       
     Combination therapy:
                • 100 mg day 1, 900 mg day 2, then 1000 mg days 8 and 15 of cycle 1 (loading doses)
                • 1000 mg on day 1 of cycles 2-6  
CLL/SLL               Monotherapy:
                • 100 mg day 1, 900 mg day 2, then 1000 mg days 8 and 15 of cycle 1 (loading doses)  
                • 1000 mg on day 1 of cycles 2-8  
                                     -OR-
                • 100 mg day 1, 900 mg day 2, then 1000 mg day 3, 2000 mg day 8 and 15 of cycle 1 (loading doses)  
                • 2000 mg on day 1 of cycles 2-8   
(Cycles are 28 days unless otherwise noted)
 Initial Combination Therapy
                • 1000 mg days 1, 8, & 15 of cycle 1 (loading doses; given in combination with chemotherapy or lenalidomide  
B-Cell Lymphomas
          • In combination with lenalidomide:
                • 1000mg day 1 of cycles 2-6 in combination with bendamustine
                • 1000mg day 1 of cycles 2-9 (21-day cycle) in combo with CHOP, followed by 2 additional 21-day cycles of obinutuzumab alone.
                • 1000 mg day 1 of cycles 2-8 (21-day cycle) with CVP
          • In combination with lenalidomide:
                • 1000 mg day 1 of cycles 2-6  
(Cycles are 28 days unless otherwise noted)
 
Initial Monotherapy
                • 1000 mg once a week for 4 weeks on (days 1,8,15 & 22)
 
Maintenance therapy for use after initial combination therapy or monotherapy
                • 1000 mg every 2 months for up to 2 years as monotherapy
 
NOTE: When initial therapy is given in combination with lenalidomide the first year of maintenance therapy will be given with lenalidomide, followed by an additional year of monotherapy.  
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of obinutuzumab does not meet primary coverage criteria that there be scientific evidence of effectiveness for all other indications except those listed above.
 
For members with contracts without primary coverage criteria, the use of obinutuzumab is investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective Prior to January 2022    
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
The use of obinutuzumab (Gazyv®) meets member benefit certificate primary coverage criteria that there be scientific effectiveness as indicated for the treatment of adult patients that meet the criteria indicated below:
Initiation of therapy
  1. Must be >18 yrs.
  2. Free from active infection.
  3. Has not received a live vaccine within 28 days prior to starting treatment and live vaccines will not be administered during treatment.  
  4. Individual has been screened for hepatitis B (HBV) infection (i.e. HBsAg and anti-HBc) prior to initiating therapy.  If the individual has evidence of current or prior HBV infection, they will be monitored for HBV reactivation during treatment.   
  5. Documented diagnosis of the following:
A.  Chronic lymphocytic leukemia/Small Lymphocytic Lymphoma (CLL/SLL) if ANY ONE of the following:
      • Used in combination with bendamustine for first-line treatment in individuals without del (17p)/TP53 mutation (NCCN 2A); OR  
      • Used in combination with Ibrutinib (2b) or  chlorambucil for first-line treatment in individuals without del (17p)/TP53 mutation who have significant comorbidity or age > 65 yrs (NCCN 2A); OR  
      • Used in combination with acalabrutinib for first-line treatment in individuals with (unable to tolerate purine analogs) or without del (17p)/TP53 mutation (NCCN 1 (with indications), 2A all others); OR
      • Used in combination with venetoclax for first-line treatment without del (17p)/TP53 mutation in frail patients with significant comorbidities or age >65 and younger patients with or without significant comorbidities (NCCN 1) OR
      • Used in combination with venetoclax for first-line treatment with del(17p)/TP53 mutation with indications for treatment (NCCN 2A);  OR
      • First-line therapy for CLL/SLL with del(17p)/TP53 as a single agent (NCCN 2A); OR  
      • Second-line and subsequent therapy as a single agent for CLL/SLL without del (17p)/TP53 mutation in patients with indication for retreatment (NCCN 2A)
B.  B-Cell Lymphomas with diagnosis of ANY ONE of the following:
      • Follicular lymphoma (FL) (Grade 1-2) if ANY ONE of the following:
        • Used as first-line therapy for stage II non-contiguous, III or IV disease and used in combination with chemotherapy (e.g. bendamustine or CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or CVP (cyclophosphamide, vincristine, prednisone)
        • Used as subsequent therapy, if not previously used as first-line therapy, for refractory or have progressive disease for ANY ONE of the following:
            • Used in combination with chemotherapy (e.g. bendamustine or CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or CVP (cyclophosphamide, vincristine, prednisone)
            • Used as a single agent
            • Used in combination with lenalidomide
        • Used as a single agent for maintenance therapy and ANY ONE of the following:
            • Used as first-line consolidation therapy of extended dosing following chemoimmunotherapy
            • Used as second-line consolidation therapy or extended dosing in individuals who are refractory to rituximab
            • Used in individuals with histologic transformation to diffuse-large B-cell lymphoma with extensive follicular lymphoma who achieve a complete response to chemoimmunotherapy
        • Used as a substitute for rituximab in individuals experiencing rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis.
      •  MALT Lymphoma (Gastric or Non-Gastric or Marginal Zone Lymphoma (Splenic or Nodal) and ANY ONE of the following:
        • Used in combination with bendamustine and ANY ONE of the following:
            • Used as subsequent therapy, if not previously treated with bendamustine, for recurrent disease after prior treatment with rituximab (Splenic Marginal Zone Lymphoma only)
            • Used as subsequent therapy, if not previously treated with bendamustine, for recurrent or progressive disease (Gastric MALT Lymphoma)
            • Used as subsequent therapy, if not previously treated with bendamustine, for refractory or progressive disease (Non-Gastric MALT or Nodal Marginal Zone Lymphoma only)
        • Used as a single agent for maintenance therapy, as second line consolidation or extended dosing, in rituximab refractory individuals treated with obinutuzumab and bendamustine for recurrent disease.
        • Used as a substitute for rituximab in individuals experiencing rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis.  
      • Histologic Transformation of Nodal Marginal Zone Lymphoma to Diffuse Large B-Cell Lymphoma, Mantle Cell Lymphoma, Diffuse Large B-Cell Lymphoma, High Grade B-Cell Lymphomas, Burkitt Lymphoma, AIDS Related B Cell Lymphomas, Post-Transplant Lymphoproliferative Disorders, or Castleman’s Disease and the following:
        • Used as a substitute for rituximab in individuals experiencing rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis.   
 
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting of specified criteria
 
Continuation of therapy
The use of obinutuzumab (Gazyv®) meets member benefit certificate primary coverage criteria that there be scientific effectiveness as indicated for continuation of treatment of adult patients that meet ALL of the criteria indicated below:
    • The individual continues to meet initial approval criteria
    • Disease response with treatment as defined by stabilization of disease of decrease in size of tumor or tumor spread.
    • Absence of unacceptable toxicity from the drug, (ex. Severe neutropenia/febrile neutropenia, severe thrombocytopenia, severe infusion related reactions, hypersensitivity reactions including serum sickness, tumor lysis syndrome [TLS], serious bacterial, fungal, or viral infections, etc.)
    • Has been evaluated for the presence of progressive multifocal leukoencephalopathy (PML) and has been found to be negative
    • Additional requirements for diagnosis of ANY ONE of the following:
      • Maintenance treatment of B-cell lymphomas, length of therapy does not exceed two years.
      • Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma indication is NOT medical appropriate for renewal.
 
Dosage and Administration
Indication(s)          Dosage & Administration                                       
                                 Combination therapy:        
          • 100 mg day 1, 900 mg day 2, then 1000 mg days 8 and 15 of cycle 1 (loading doses)
          • 1000 mg on day 1 of cycles 2-6
CLL/SLL                   Monotherapy:
          • 100 mg day 1, 900 mg day 2, then 1000 mg days 8 and 15 of cycle 1 (loading doses)
          • 1000 mg on day 1 of cycles 2-8
                                     -OR-
          • 100 mg day 1, 900 mg day 2, then 1000 mg day 3, 2000 mg day 8 and 15 of cycle 1 (loading doses)
          • 2000 mg on day 1 of cycles 2-8  
(Cycles are 28 days unless otherwise noted)
 
 Initial Combination Therapy
          • 1000 mg days 1, 8, & 15 of cycle 1 (loading doses; given in combination with chemotherapy or lenalidomide
B-Cell Lymphomas
            • In combination with lenalidomide:
                  • 1000mg day 1 of cycles 2-6 in combination with bendamustine
                  • 1000mg day 1 of cycles 2-9 (21-day cycle) in combo with CHOP, followed by 2 additional 21-day cycles of obinutuzumab alone.
                  • 1000 mg day 1 of cycles 2-8 (21-day cycle) with CVP
            • In combination with lenalidomide:
                  • 1000 mg day 1 of cycles 2-6
  (Cycles are 28 days unless otherwise noted)
Initial Monotherapy
          • 1000 mg once a week for 4 weeks on (days 1,8,15 & 22)
Maintenance therapy for use after initial combination therapy or monotherapy
          • 1000 mg every 2 months for up to 2 years as monotherapy
          • NOTE: When initial therapy is given in combination with lenalidomide the first year of maintenance therapy will be given with lenalidomide, followed by an additional year of monotherapy.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of obinutuzumab does not meet primary coverage criteria that there be scientific evidence of effectiveness for all other indications except those listed above.
 
For members with contracts without primary coverage criteria, the use of obinutuzumab is investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.  

Rationale:
Chronic Lymphocytic Leukemia
 
First-Line Therapy for Previously Untreated Chronic Lymphocytic Leukemia
The FDA’s approval of obinutuzumab (also known as GA101) was based on an open-label, phase 3 RCT, CLL11.78, CLL11 was conducted at 155 centers in 24 countries. Adults (≥18 years of age) with previously untreated, CD20-positive CLL with coexisting medical conditions (eg, creatinine clearance, 70-30 mL/min) were enrolled. Patients were randomized 2:2:1 to obinutuzumab plus chlorambucil (n=238), rituximab plus chlorambucil (n=233), or chlorambucil monotherapy (n=118). The National Comprehensive Cancer Network does not currently recommend chlorambucil monotherapy for first-line treatment of CLL.  The primary end point was PFS. Only results comparing obinutuzumab combination therapy with chlorambucil monotherapy were considered by FDA for approval (Lee HZ, et al 2014). Median PFS by independent review was 23 months in the obinutuzumab group and 11 months in the chlorambucil group (HR=0.16; 95% CI, 0.11 to 0.24; p<0.001). Investigator-assessed PFS was similar. OS was increased in the obinutuzumab group deaths of 15.5% (37/238) of patients in the combination therapy arm compared with 28.8 compared with the chlorambucil group (HR for death, 0.41; 95% CI, 0.23 to 0.74; p=0.002), but OS data were not yet mature (medians had not been reached). The most common serious adverse event in CLL11 was infusion reaction (11%). A follow-up report by Goede et al (2015) confirmed the OS benefit for combination therapy (HR=0.47; 95% CI, 0.29 to 0.76; p=0.001), with % (34/118) in the chlorambucil monotherapy arm (Goede V, et al., 2015)
 
Second-Line Therapy for Relapsed or Refractory Chronic Lymphocytic Leukemia
Cartron et al (2014) published results of the open-label, phase 1/2 GAUGIN study of obinutuzumab monotherapy for relapsed or refractory CLL.  Phase 1 (n=13) was a dose-finding study. Phase 2 (n=20) administered a fixed dose of obinutuzumab (1000 mg IV) for 8 cycles total. Twelve (65%) patients received all doses. At median follow-up of 29 months, best overall response was 30% (CR=5%; PR=25%). Median PFS was 10.7 months.
 
Follicular Lymphoma
 
First-Line Therapy for Previously Untreated Follicular Lymphoma
Marcus et al (2017) published a randomized study (GALLIUM trial) comparing obinutuzumab-based with rituximab-based chemotherapy as first-line treatment for FL.  Between 2011 and 2014, 1202 patients were randomized to the treatment groups. The estimated 3-year PFS rate was 80% for obinutuzumab and 73.3% for rituximab (HR=0.66; 95% CI, 0.51 to 0.85; p=0.001); the 3-year OS rates were 94% and 92.1% (HR=0.75; 95% CI, 0.49 to 1.17; p=0.21) for obinutuzumab and rituximab, respectively. The response rate for obinutuzumab was 88.5% and 86.9% for rituximab (95% CI, -2.1 to 5.5; p =.33), and grade 3, 4, and 5 adverse events occurred in 74.6% and 67.8% of the 2 groups, respectively. Trial limitation included nonrandomized assignment of chemotherapy agents.
 
Second-Line Therapy for Relapsed or Refractory Follicular Lymphoma
Obinutuzumab has been approved for use in combination with bendamustine for treatment of patients with FL who relapsed after, or who are refractory to, a rituximab-containing regimen. The pivotal phase 3 trial (GADOLIN) was an open-label multicenter study of 321 patients randomized to bendamustine alone (n=166) or obinutuzumab plus bendamustine for 6 cycles. Following initial treatment, patients in the combination therapy arm who did not have disease progression continued receiving obinutuzumab monotherapy for 2 years. PFS, determined by an independent review committee, was reached at a median of 13.8 months in the bendamustine arm and not reached within a median of 21 months in the obinutuzumab plus bendamustine arm (HR=0.48; 95% CI, 0.34 to 0.68; p<0.001). Median OS had not been reached in either arm at 24 months. More recent results from GADOLIN were published in 2018 and confirmed the PFS benefit shown in the primary analysis (Cheson BD et al. 2018).   At a median follow-up of 31.8 months, PFS events had occurred in 115 patients in the obinutuzumab plus bendamustine arm (56.4%) and 146 in the monotherapy arm (69.9%). Median PFS was significantly longer in the combination arm (25.8 months; 95% CI, 19.5 to 41.1 months) than in the bendamustine monotherapy arm (14.1 months; 95% CI, 12.6 to 16.0 months), with a HR for progression or death of 0.57 (95% CI, 0.44 to 0.73; P <.001). There was also an OS benefit demonstrated in the combination treatment arm: 25.5% of patients in the combination arm and 34.9% in the monotherapy arm died (HR, 0.67; 95% CI, 0.47 to 0.96; P =.03).
 
Morschhauser et al (2019) published a single-arm, phase 2 study of obinutuzumab plus lenalidomide in 89 patients with relapsed or refractory FL previously treated with at least one rituximab-containing regimen.  Patients received induction treatment with lenalidomide plus obinutuzumab, followed by 1-year maintenance with lenalidomide plus obinutuzumab, and 1-year maintenance with obinutuzumab. The primary endpoint was overall response; PFS and OS were secondary endpoints. The primary endpoint was met with an overall response rate of 79% (38% achieved a complete response). At 2 years, PFS was 65% (95% CI 54% to 74%) and OS was 87% (95% CI 78% to 93%). Median PFS and OS were not reached. This regimen is not FDA approved for the treatment of relapsed or refractory FL, and RCTs are needed to establish the efficacy and safety of obinutuzumab plus lenalidomide compared to current treatments.
 
Second-Line Therapy for Relapsed or Refractory Non-Hodgkin Lymphoma
The 2016 publication of the phase 3 trial (GADOLIN) described above for relapsed or refractory FL assessed 396 patients with NHL (Sehn LH, et al. 2016). The trial was stopped after a preplanned interim analysis. About 81% of patients had FL, 12% had marginal zone lymphoma, 7% had small lymphocytic leukemia, and 1 patient had Waldenström macroglobulinemia. Median follow-up was 21.9 months. As in the subgroup with FL (included in the FDA label), median PFS was not reached at the time of follow-up in the chemoimmunotherapy induction and obinutuzumab maintenance arm. In the bendamustine monotherapy arm, median PFS was 14.9 months (HR=0.55; 95% CI, 0.40 to 0.74; p<0.001). Thus, PFS was significantly longer with obinutuzumab combined with bendamustine.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2022. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:
J9301Injection, obinutuzumab, 10 mg

References: Cartron G, de Guibert S, Dilhuydy MS, et al.(2014) Obinutuzumab (GA101) in relapsed/refractory chronic lymphocytic leukemia: final data from the phase 1/2 GAUGUIN study. Blood. Oct 02 2014; 124(14): 2196-202. PMID 25143487

Cheson BD, Chua N, Mayer J, et al.(2018) Overall Survival Benefit in Patients With Rituximab-Refractory Indolent Non-Hodgkin Lymphoma Who Received Obinutuzumab Plus Bendamustine Induction and Obinutuzumab Maintenance in the GADOLIN Study. J Clin Oncol. Aug 01 2018; 36(22): 2259-2266. PMID 29584548.

Gazyva® (obinutuzumab) [package insert]. South San Francisco, CA: Genentech, Inc, 2021.

Goede V, Fischer K, Engelke A, et al.(2015) Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia. Jul 2015; 29(7): 1602-4. PMID 25634683.

Goede V, Fischer K, Engelke A, et al.(2015) Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia. Jul 2015; 29(7): 1602-4. PMID 25634683.

Lee HZ, Miller BW, Kwitkowski VE, et al.(2014) U.S. Food and drug administration approval: obinutuzumab in combination with chlorambucil for the treatment of previously untreated chronic lymphocytic leukemia. Clin Cancer Res. Aug 01 2014; 20(15): 3902-7. PMID 24824310.

Marcus R, Davies A, Ando K, et al.(2017) Obinutuzumab for the First-Line Treatment of Follicular Lymphoma. N Engl J Med. Oct 05 2017; 377(14): 1331-1344. PMID 28976863

Morschhauser F, Le Gouill S, Feugier P, et al.(2019) Obinutuzumab combined with lenalidomide for relapsed or refractory follicular B-cell lymphoma (GALEN): a multicentre, single-arm, phase 2 study. Lancet Haematol. Aug 2019; 6(8): e429-e437. PMID 31296423.

National Comprehensive Cancer Network (NCCN).(2021) NCCN Drugs and Biologics Compendium. Obinutuzumab. NCCN.org/DrugCompendium. Accessed 8/19/2021.

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