Medical Policy

 

Subject: Obinutuzumab (Gazyva®)
Document #: DRUG.00062 Publish Date:    12/27/2017
Status: Revised Last Review Date:    11/02/2017

Description/Scope

This document addresses the indications and criteria for the use of obinutuzumab (Gazyva, Genentech, South San Francisco, CA).  Obinutuzumab is a humanized monoclonal antibody of the IgG1 subclass that targets the CD20 antigen expressed on the cell surface of pre B- and mature B-lymphocytes.  Once obinutuzumab binds to the targeted cell, various pathways are triggered resulting in the lysis of the B-cells.

Note: Please see the following related documents for additional information:

Position Statement

Medically Necessary:

  1. Obinutuzumab is considered medically necessary when either of the following criteria is met:
    1. As first-line treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma, without del (17p) mutation, when used in combination with chlorambucil; or
    2. As a single agent for the treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma without del (17p) mutation.
  2. Obinutuzumab is considered medically necessary as a treatment of follicular lymphoma when used as a component of one of the following combination chemotherapy regimens and as monotherapy, for up to 24 months or until disease progression, following the listed combination therapy regimens:
    1. Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP regimen); or
    2. Cyclophosphamide, vincristine, and prednisone (CVP regimen); or
    3. Bendamustine.

Investigational and Not Medically Necessary:

Obinutuzumab is considered investigational and not medically necessary when the above criteria are not met and for all other indications, including but not limited to diffuse large B-cell lymphoma and mantle-cell lymphoma.

Rationale

The addition of rituximab, a monoclonal anti-CD20 antibody, to chemotherapy regimens (e.g., cyclophosphamide and fludarabine) has been shown to improve the survival of physically fit individuals with CLL compared to chemotherapy alone.  However, randomized trials of rituximab have not demonstrated a similar survival advantage in individuals with significant co-morbidities.  The combination of rituximab and chlorambucil has been investigated as an alternative option in this population.  Obinutuzumab, known as GA101, also targets the CD20 antigen and has been investigated in the same population.  Rituximab kills CLL cells primarily by means of complement-dependent cellular toxicity after binding to CD20.  In contrast, obinutuzumab induces cell death primarily by antibody-dependent cytotoxicity; this difference in mechanism of action could translate into increased efficacy (Salles, 2013).

In November 2013, the U.S. Food and Drug Administration (FDA) approved Gazyva (obinutuzumab) as the first drug with breakthrough therapy designation.  Obinutuzumab received FDA approval in combination with chlorambucil as a treatment of individuals with previously untreated chronic lymphocytic leukemia (CLL).  The basis of this approval was a pivotal randomized, multicenter, open-label, phase III trial which consisted of three arms: Arm 1 (active control arm) received chlorambucil alone (Clb); Arm 2 received obinutuzumab in combination with Clb (G-Clb); and those on Arm 3 were treated with rituximab in combination with Clb (R-Clb) (Goede, 2014a).  All enrolled participants had clinically meaningful burden of coexisting conditions as represented by scores of 6 or higher on the Cumulative Illness Rating Scale (CIRS) (range 0-56) or a creatinine clearance of 30 to 69 ml per minute.  The primary endpoint of the study was progression-free survival (PFS).  Enrollment included a total of 781 participants, with 118 in Arm 1 (Clb), 333 in Arm 2 (G-Clb) and 330 in Arm 3 (R-Clb).  The median age was 73 years, the median creatinine clearance was 62 ml/minute and the median baseline CIRS score was 8.  The authors reported:

Significant improvement in the median PFS was observed with G-Clb or R-Clb, as compared with Clb alone (26.7 months with G-Clb vs. 11.1 months with Clb alone; hazard ratio for progression or death, 0.18; 95% confidence interval [CI], 0.13 to 0.24; P<0.001; and 16.3 months with R-Clb vs. 11.1 months with Clb alone; hazard ratio, 0.44; 95% CI, 0.34 to 0.57; P<0.001).

At 3 months, complete responses (CR) were significantly improved in the antibody groups (G-Clb [20.7%], R-Clb [7.0%]) compared to no cases of CR noted in the Clb alone cohort.  Adverse events were more frequent in the G-Clb and R-Clb groups compared to Clb alone with the most frequent serious adverse events reported as infections, infusion-related reactions and neoplasms.  Grade 3 or 4 infusion-related reactions occurred during the first infusion of obinutuzumab in 20% of the participants, but there were no deaths associated with the reactions.  Death due to adverse events was lowest in the G-Clb group (4%) compared to R-Clb (6%) and Clb alone (9%).  The investigators noted the addition of antibodies to Clb increased the efficacy and the toxicity of the treatment.  Longer follow-up is needed to determine if the improved disease-free survival (DFS) and higher response rate with G-Clb compared to R-Clb will result in improved overall survival benefit.  Data from this pivotal trial resulted in the FDA approval for obinutuzumab treatment as first-line treatment of individuals with CLL (Goede, 2014).

The National Comprehensive Cancer Network® (NCCN®) Clinical Practice Guidelines (CPG) for CLL/SLL (2017) considers “CLL and SLL as different manifestations of the same disease and are managed in much the same way.”  In CLL, significant numbers of abnormal lymphocytes are found in the bone marrow while in SLL, the lymphocytes are found primarily in the lymph nodes.  The NCCN notes obinutuzumab in combination with chlorambucil is indicated as first-line therapy for individuals with stage II-IV CLL/small lymphocytic lymphoma (SLL), especially those who are considered ‘frail’ as a result of advanced age or comorbidities (Ladyzynski, 2014; Shah, 2014).  Based on a subset analysis of the pivotal clinical trial, the NCCN CPGs for CLL/SLL (V1.2018) had given a Category 3 recommendation for the treatment of CLL/SLL with del (17P) disease with obinutuzumab and chlorambucil in the first-line setting, due to a lack evidence of a clinical benefit in this subpopulation.  However, based on consensus, and lack of other treatment options, this recommendation has been changed to a Category 2A for obinutuzumab as monotherapy in the first-line setting for the treatment of CLL/SLL with del (17P).

The NCCN also gives obinutuzumab a Category 2A recommendation for single-agent treatment of relapsed/refractory CLL/SLL with the exception of del (17p) disease.  This recommendation is based on the GAUGUIN study, a Phase I and II dose-finding clinical trial that included 33 participants, of which 26 completed the study (Cartron, 2014).  A total of 62% (8) of 13 participants achieved a partial response (PR) in phase I and 15% (3) of 20 in phase II, while none achieved a CR.  Overall response rate (ORR) was 30% with a median PFS of 10.7 months and a duration of response of 8.9 months.  The NCCN also cites the results of the CLL11 study which were published only in abstract form and not listed in the National Library of Medicine’s PubMed database (Goede, 2014b).  This report included 30 subjects who received chlorambucil alone as initial treatment and developed progressive disease and were placed on combined obinutuzumab-chlorambucil therapy.  Clinical response was reported in 87% of subjects with a partial response in 77%, complete response in 7%, and no response in 3%.  Despite the lack of more robust evidence of efficacy of obinutuzumab in individuals with refractory or relapsed CLL, the NCCN consensus position was that in this difficult-to-treat population this therapy provides significant clinical benefits where no other options exist.

On February 26, 2016 the FDA granted Gazyva (obinutuzumab) an additional approval for use in combination with bendamustine followed by obinutuzumab monotherapy for the treatment of individuals with follicular lymphoma (FL) who relapse after, or are refractory to, a rituximab-containing regimen.  This approval was based on results of an open-label, multicenter RCT demonstrating improvement in PFS in 321 subjects with follicular lymphoma with no response to or who have progressed during or within 6 months of a rituximab-containing regimen (GADOLIN Study). The trial compared 6 cycles of bendamustine therapy alone (n=166) vs. 6 cycles of obinutuzumab plus bendamustine combination therapy followed by continued obinutuzumab monotherapy (n=155) for up to 2 years.  Subjects had received a median of 2 prior therapies (range 1-10).  The independent review-assessed median PFS was 13.8 months in the bendamustine arm while the median PFS was not reached in the obinutuzumab plus bendamustine arm (hazard ratio [HR]=0.48, log-rank test p<0.0001).  This trial also enrolled 46 subjects with marginal zone lymphoma and 28 subjects with small lymphocytic lymphoma who were included in the safety analysis.  The most common adverse reactions (greater than or equal to 10%) in the safety population treated with obinutuzumab plus bendamustine followed by obinutuzumab monotherapy were infusion reactions, neutropenia, nausea, fatigue, cough, diarrhea, constipation, pyrexia, thrombocytopenia, vomiting, upper respiratory tract infection, decreased appetite, arthralgia, sinusitis, anemia, asthenia and urinary tract infection.  Serious adverse reactions were reported in 38% of subjects treated with obinutuzumab plus bendamustine followed by obinutuzumab monotherapy.  The most common serious adverse reactions (greater than 2%) were febrile neutropenia, neutropenia, infusion related reactions, sepsis, pneumonia and pyrexia (Sehn, 2016).

Sehn and colleagues (2015) reported on the results of a randomized controlled trial (RCT) comparing obinutuzumab to rituximab in 149 subjects with relapsed CD20+ indolent follicular lymphoma.  Subjects were randomly assigned in a 1:1 fashion to four once-per-week infusions of either obinutuzumab (1000 mg, n=74) or rituximab (375 mg/m2, n=75).  Subjects without evidence of disease progression after induction therapy received obinutuzumab or rituximab maintenance therapy every 2 months for up to 2 years (n=70 in each arm).  The final analysis included 37 obinutuzumab subjects and 35 rituximab subjects (48.3% of the original study population).  Following induction, blinded independent review reported that obinutuzumab subjects had a higher ORR than rituximab subjects (44.6% vs. 26.7%, p=0.01), but no significant differences in complete response (CR) rates (p=0.34).  Independent reviewer-assessed best overall response (BOR) was higher in obinutuzumab subjects vs. rituximab subjects (63.5% vs. 49.3%, p=0.04); however, there were no significant differences in CR rates (p=0.07).  This study also included a small population of 26 subjects with non-follicular B-cell lymphoma who also were randomized to receive obinutuzumab or rituximab.  In this group the median follow-up was 32 months, with no differences between groups noted for progression-free survival (HR=1.44).  Both follicular and non-follicular subjects together comprise the safety population.  Only infusion reactions (74% vs. 51%) and cough (24% vs. 9%) were significantly more frequent adverse events in the obinutuzumab group (p=0.003 and p=0.013, respectively).  The authors concluded that these findings warrant further investigation in a phase III trial.

The NCCN CPGs for B-cell Lymphomas (V3.2017) include 2A recommendations for the use of obinutuzumab maintenance for multiple types of refractory NHLs (gastric MALT lymphoma, nodal marginal zone lymphoma, nongastric MALT lymphoma, primary cutaneous B-Cell lymphoma and splenic marginal zone lymphoma), as well as 2A recommendation for its use a component of any of the following combination regiments for the aforementioned types of NHL: (1) cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP regimen), (2) Cyclophosphamide, vincristine, and prednisone (CVP regimen) or (3) Bendamustine.  The rationale cited for the above 2A indications is from an interim analysis (n=1202) of an open-label, randomized (1:1) phase III trial comparing the efficacy and safety of rituximab to obinutuzumab as both induction and maintenance therapy in indolent NHLs. Although participants with untreated follicular lymphoma and marginal lymphoma were enrolled, only data for follicular lymphoma was presented.  Participants received CHOP, CVP or bendamustine in combination with either rituximab or obinutuzumab.  After a median follow-up of 34.5 months, the relative risk reduction for progression or death was 34% (HR=0.66; 95% CI, 0.51, 0.85; p=0.001.  Grade 3-5 adverse events were higher in the obinutuzumab arm (74.6%) relative to the rituximab arm (67.8%) (Marcus, 2017).

The NCCN CPGs for B-Cell lymphomas (V5.2017) also include a 2A recommendation for the use of obinutuzumab as a single agent for the treatment of primary cutaneous marginal zone/follicle center lymphoma for extensive or refractory generalized cutaneous disease.  There is no rationale provided for this recommendation.

There are ongoing trials investigating the use of obinutuzumab as a single agent and in combination with other agents to treat other types of cancer, such as diffuse large B-cell lymphoma and mantle-cell lymphoma.  However, at this time, the published data consists of early results from phase I and phase II trials that are primarily dose-finding studies.

Background/Overview

In 2017, an estimated 20,000 individuals with CLL will be diagnosed. CLL and SLL are different manifestations of the same disease and are managed similarly (NCCN, 2017).  The American Cancer Society (ACS, 2017) indicates approximately one-third of all new cases of leukemia are CLL, and mainly affect older adults. 

In 2017, an estimated 72,000 new cases of non-Hodgkin lymphoma will be diagnosed (National Cancer Institute, 2017).  Follicular lymphoma is a type of B-cell, non-Hodgkin lymphoma and accounts for about 1 in 5 cases of lymphoma in the United States.  Generally, it presents as a lymphatic malignancy with a slow-growing, or indolent, disease course.  Although highly treatable, follicular lymphoma is difficult to cure and may develop into a more aggressive type of lymphoma, known as diffuse large B-cell lymphoma (ACS, 2017).

Obinutuzumab is a humanized monoclonal antibody that targets the CD20 antigen on the cell surface of pre B- and mature B-lymphocytes.  After binding to CD20, obinutuzumab facilitates the B-cell depletion and cell death by various mechanisms which include:

  1. Engagement of immune effector cells;
  2. By directly activating the intracellular death signaling pathways; and/or
  3. Activation of the complement cascade. 

Antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis are types of immune effector cell mechanisms (Product Information Label, 2016).

Adverse Events and Warnings

Black box warnings from the FDA Product Information Label (2016) include the following information and recommendations:

Additional Warnings from the FDA Product Information Label (2016) include:

Definitions

Complete response (CR): The disappearance of all signs of cancer as a result of treatment; also called complete remission; does not indicate the cancer has been cured.

Disease-free survival (DFS): In cancer, the length of time after primary treatment for a cancer ends that the individual survives without any signs or symptoms of that cancer. In a clinical trial, measuring the disease-free survival is one way to see how well a new treatment works.

Line of therapy:

Monoclonal antibody: A protein developed in the laboratory that can locate and bind to specific substances in the body and on the surface of cancer cells.

Partial response (PR): A decrease in the size of a tumor, or in the amount of cancer in the body, resulting from treatment; also called partial remission.

Progression-free survival (PFS): The length of time during and after treatment that an individual lives but does not get worse (usually measured by the size of a tumor or amount of cancer in the body).

Refractory disease: Illness or disease that does not respond to treatment.

Relapsed disease: The worsening of an oncologic disease after a period of improvement or remission.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

HCPCS

 

J9301

Injection, obinutuzumab, 10 mg [Gazyva]

 

 

ICD-10 Diagnosis

 

 

C82.00-C82.99

Follicular lymphoma

 

C83.00-C83.09

Small cell B-cell lymphoma

 

C91.10-C91.12

Chronic lymphocytic leukemia of B-cell type

 

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

References

Peer Reviewed Publications:

  1. Byrd JC, Flynn JM, Kipps TJ, et al. Randomized phase 2 study of obinutuzumab monotherapy in symptomatic, previously untreated chronic lymphocytic leukemia. Blood. 2016;127(1):79-86.
  2. Cartron G, de Guibert S, Dilhuydy MS, et al. Obinutuzumab (GA101) in relapsed/refractory chronic lymphocytic leukemia: final data from the phase 1/2 GAUGUIN study. Blood. 2014; 124(14):2196-2202.
  3. Cheson BD, Trask PC, Gribben JG, et al. Health-related quality of life and symptoms in patients with rituximab-refractory indolent non-Hodgkin lymphoma treated in the phase III GADOLIN study with obinutuzumab plus bendamustine versus bendamustine alone. Ann Hematol. 2017; 96(2):253-259.
  4. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014; 370(12):1101-1110.
  5. Ladyzynski P, Molik M Foltynski P. A network meta-analysis of progression free survival and overall survival in first-line treatment of chronic lymphocytic leukemia. Cancer Treat Rev. 2015; 41(2):77-93.
  6. Marcus R, Davies A, Ando K, et al. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med. 2017; 377(14):1331-1344.
  7. Morschhauser FA, Cartron G, Thieblemont C, et al. Obinutuzumab (GA101) monotherapy in relapsed/refractory diffuse large b-cell lymphoma or mantle-cell lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013; 31(23):2912-2919.
  8. Patz M, Isaeva P, Forcob N, et al. Comparison of the in vitro effects of the anti-CD20 antibodies rituximab and GA101 on chronic lymphocytic leukaemia cells. Br J Haematol. 2011; 152(3):295-306.
  9. Radford J, Davies A, Cartron G, et al. Obinutuzumab (GA101) plus CHOP or FC in relapsed/refractory follicular lymphoma: results of the GAUDI study (BO21000). Blood. 2013; 122(7):1137-1143.
  10. Salles GA, Morschhauser F, Solal-Céligny P, et al. Obinutuzumab (GA101) in patients with relapsed/refractory indolent non-Hodgkin lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013; 31(23):2920-2926.
  11. Sehn LH, Assouline SE, Stewart DA, et al. A phase 1 study of obinutuzumab induction followed by 2 years of maintenance in patients with relapsed CD20-positive B-cell malignancies. Blood. 2012; 119(22):5118-5125.
  12. Sehn, Chua, Mayer, et al. 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. 2016 Aug;17(8):1081-1093.
  13. Sehn LH, Goy A, Offner FC, et al. Randomized phase II trial comparing obinutuzumab (GA101) with Rituximab in patients With relapsed CD20+ indolent B-cell non-Hodgkin lymphoma: final analysis of the GAUSS study. J Clin Oncol. 2015; 33(30):3467-3474.
  14. Shah A. Obinutuzumab: a novel anti-CD20 monoclonal antibody for previously untreated chronic lymphocytic leukemia. Ann Pharmacother. 2014; 48(10):1356-1361.
  15. Siegel R, Ma J, Zou Z, and Jemal A. Cancer Statistics. 2015. CA Cancer J Clin. 2015; 65(1):5-29.
  16. Städler N, Shang A, Bosch F, et al. A systematic review and network meta-analysis to evaluate the comparative efficacy of interventions for unfit patients with chronic lymphocytic leukemia. Adv Ther. 2016;33(10):1814-1830.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Bauer K, Rancea M, Roloff V, et al. Rituximab, ofatumumab and other monoclonal anti-CD20 antibodies for chronic lymphocytic leukaemia. Cochrane Database Syst Rev. 2012;(11):CD008079.
  2. Gazyva [Product Information]. South San Francisco, CA. Genentech, Inc.; February 01, 2016. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125486s013lbl.pdf. Accessed on September 25, 2017.
  3. National Comprehensive Cancer Network®. NCCN Drugs & Biologic Compendium® (electronic version). For additional information visit the NCCN website: http://www.nccn.org. Accessed on September 25, 2017.
  4. NCCN Clinical Practice Guidelines in Oncology®. © 2017 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on September 25, 2017.
    • B-Cell Lymphomas (V5.2017). September 28, 2017.
    • Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (V1.2018). September 08, 2017.
  5. Obinutuzumab. In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated August 15, 2017. Available at: http://www.micromedexsolutions.com. Accessed on September 25, 2017
  6. Obinutuzumab Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised April 06, 2016. Accessed on September 25, 2017.
Websites for Additional Information
  1. American Cancer Society (ACS). Non-Hodgkin Lymphoma: Follicular Lymphoma. Available at: https://www.cancer.org/cancer/non-hodgkin-lymphoma/about/types-of-non-hodgkin-lymphoma.html. Accessed on September 25, 2017.
  2. American Cancer Society (ACS). Leukemia: Chronic Lymphocytic. Available at: http://www.cancer.org/cancer/leukemia-chroniclymphocyticcll/detailedguide/leukemia-chronic-lymphocytic-key-statistics. Accessed on September 25, 2017.
  3. National Cancer Institute (NCI). Available at: https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq.  Accessed on September 25 2017.
    • Adult Non-Hodgkin’s Lymphoma Treatment (PDQ). Last modified September 25, 2017.
Index

Chronic Lymphocytic Leukemia
Gazyva
Monoclonal Antibody

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History

Status

Date

Action

Revised

11/02/2017

Medical Policy & Technology Assessment Committee (MPTAC) review.

Revised

11/01/2017

Hematology/Oncology Subcommittee review. Clarified MN criteria for monotherapy for follicular lymphoma. Updated header language from “Current Effective Date” to “Publish Date.” Updated Rationale, Background/Overview and References sections.

Revised

05/04/2017

MPTAC review.

Revised

05/03/2017

Hematology/Oncology Subcommittee review. Added additional regimens for follicular lymphoma and without del (17/p) CLL/SLL to the MN criteria. Updated formatting in the criteria. Updated Rationale, Background/Overview and References sections.

Revised

05/05/2016

MPTAC review.

Revised

05/04/2016

Hematology/Oncology Subcommittee review. Added new MN position statement for treatment of relapsed/refractory CLL/SLL and follicular lymphoma, with criteria. Updated Rationale and Reference sections. Updated Coding section and removed ICD-9 codes.

Revised

05/07/2015

MPTAC review.

Revised

05/06/2015

Hematology/Oncology Subcommittee review. Added single agent and relapsed/refractory to Investigational and Not Medically Necessary Statement.  Updated Description/Scope, Rationale, Background, Definitions and References sections.

 

01/01/2015

Updated Coding section with 01/01/2015 HCPCS changes; removed C9021 deleted 12/31/2014.

New

05/15/2014

MPTAC review.

New

05/14/2014

Hematology/Oncology Subcommittee review. Initial document development.