| Coverage Policy Manual | |
| Policy #: | 2021019 |
| Category: | Pharmacy |
| Initiated: | June 2021 |
| Last Review: | March 2024 |
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| Obinutuzumab (e.g., Gazyva) | |
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| 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 CD20. 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). 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, it causes an 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 Status
In 2013, obinutuzumab (e.g., Gazyva®) was approved by FDA through the breakthrough therapy designation process for treatment of individuals with previously untreated Chronic Lymphocytic Leukemia (CLL) in combination with chlorambucil. In February 2016, the drug was approved, in combination with bendamustine followed by obinutuzumab monotherapy, for the treatment of individuals with Follicular Lymphoma (FL) who relapsed or are refractory to a rituximab-containing regimen.
In November 2017 FDA has approved an expanded coverage of obinutuzumab to initial treatment of FL.
In January 2019 obinutuzumab was approved in a new combination with ibrutinib for treatment-naïve individuals with CLL.
In March 2024 obinutuzumab was approved in a new combination with zanubrutinib for relapsed or refractory follicular lymphoma after two or more lines of systemic therapy.
Coding
See CPT/HCPCS Code section below.
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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 March 27, 2024
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
For FDA labeled indications, all products must be dosed in accordance with the FDA label unless otherwise specified.
For off-label indications, authorizations will not exceed 2000 mg during a 28-day cycle OR maximum recommended doses as outlined in dosage and administration section.
Obinutuzumab (e.g., Gazyva) meets member benefit certificate primary coverage criteria that there be scientific effectiveness in improving health outcomes as indicated for the treatment of adults that meet when ALL the following criteria are met:
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
CONTINUED APPROVAL for up to 12 months:
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
Dosing per FDA Guidelines
The recommended dosage for chronic lymphocytic leukemia is 100 mg on day 1 and 900 mg on day 2 of Cycle 1, 1,000 mg on day 8 and 15 of Cycle 1, and 1,000 on day 1 of Cycles 2-6.
The recommended dosage for follicular lymphoma is 1,000 mg on day 1, 8, and 15 of Cycle 1, 1,000 mg on day 1 of Cycles 2-6 or Cycles 2-8, and then 1,000 mg every 2 months for up to 2 years.
Obinutuzumab is available as 1,000 mg/40 mL (25 mg/mL) single-dose vial.
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
Obinutuzumab (e.g., Gazyva), for any indication or circusmstance not described above, does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, the use of obinutuzumab, for any indication or circumstance not described above is investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective March 2023 to March 26, 2024
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
The use of obinutuzumab meets member benefit certificate primary coverage criteria that there be scientific effectiveness in improving health outcomes as indicated for the treatment of adults that meet the criteria indicated below:
Initiation of therapy
Continuation of therapy
The use of obinutuzumab meets member benefit certificate primary coverage criteria that there be scientific effectiveness in improving health outcomes as indicated for continuation of treatment of adult patients that meet ALL of the criteria indicated below:
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
Dosing per FDA Guidelines
The recommended dosage for chronic lymphocytic leukemia is 100 mg on day 1 and 900 mg on day 2 of Cycle 1, 1,000 mg on day 8 and 15 of Cycle 1, and 1.000 on day 1 of Cycles 2-6.
The recommended dosage for follicular lymphoma is 1,000 mg on day 1, 8, and 15 of Cycle 1, 1,000 mg on day 1 of Cycles 2-6 or Cycles 2-8, and then 1,000 mg every 2 months for up to 2 years.
Obinutuzumab is available as 1,000 mg/40 mL (25 mg/mL) single-dose vial.
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 in improving health outcomes for any indication or circumstance other than 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 January 2022 to February 2023
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:
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:
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
CLL/SLL Monotherapy:
-OR-
B-Cell Lymphomas
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
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:
Dosage and Administration
Indication(s) Dosage & Administration
Combination therapy:
CLL/SLL Monotherapy:
-OR-
B-Cell Lymphomas
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.
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| 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. In June 2023, Townsend et al have published final results from the GALLIUM study. After a median 7.9 (range, 0.0-9.8) years of follow-up, PFS remained improved with obinutuzumab- versus rituximab-based immunochemotherapy, with 7-year PFS rates of 63.4% versus 55.7% (P = 0.006). Time-to-next antilymphoma treatment was also improved (74.1% versus 65.4% of patients had not started their next antilymphoma treatment at 7 y; P = 0.001). Overall survival was similar between the arms (88.5% versus 87.2%; P = 0.36). Irrespective of the treatment received, PFS and OS were higher in patients with a complete molecular response (CMR) versus those with no CMR (P < 0.001). Serious adverse events were reported in 48.9% and 43.4% of patients in the obinutuzumab and rituximab arms, respectively; there was no difference in the rate of fatal adverse events (4.4% and 4.5%, respectively). No new safety signals were reported.
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.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2023. No new literature was identified that would prompt a change in the coverage statement.
2024 Update
Follicular lymphoma coverage was updated based on final results from GALLIUM study and new FDA approval of obinutuzumab and zanubrutinib combination studied in ROSEWOOD trial.
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| CPT/HCPCS: | |
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| 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. National Comprehensive Cancer Network Compendium®. Obinutuzumab. Last accessed 03/01/2021 https://www.nccn.org/professionals/drug_compendium/content/. National Comprehensive Cancer Network. Be-Cell Lymphomas (Version 2.2021). Last accessed 03/01/2021 https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf. National Comprehensive Cancer Network. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (Version 2.2021). Last accessed 03/01/2021 https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf. Sehn LH, Chua N, Mayer J, et al.(2016) Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol. Aug 2016; 17(8): 1081-1093. PMID 27345636. |
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Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2024 American Medical Association. |
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