Medical Policy

Policy Num:       02.001.061
Policy Name:     Gazyva^®  (obinutuzumab)
Policy ID:          [ 02.001.061 ] [ Ac / L / M+ / P+ ]  [ 0.00.00 ]

Last Review:  October 24, 2024
Next Review:  October 20, 2025

Related Policies:

05.001.016 Uses of Monoclonal Antibodies for the Treatment of Non- Hodgkin Lymphoma  (05.001.016)
8.01.50 Radioimmunotherapy in the Treatment of Non-Hodgkin Lymphoma

 Gazyva^®  (obinutuzumab)

SUMMARY

Gazyva (obinutuzumab) is an antineoplastic agent, anti-CD20 monoclonal antibody.

For individuals who have NHL who receive obinutuzumab alone or combined with chemotherapy, the evidence includes RCTs. Relevant outcomes are overall survival, change in disease status, quality of life, and treatment-related morbidity. Obinutuzumab was approved by the Food and Drug Administration for the treatment of FL in patients who have relapsed or are refractory to a rituximab-containing regimen; the drug was also approved for use in combination with chlorambucil for previously untreated CLL in combination with bendamustine. These indications are based on positive results in phase 3 trials that compared combination therapy with monotherapy. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

OBJECTIVE

The objective of this evidence review is to evaluate whether the use of monoclonal antibodies ( Obinutuzumab/Gazyva)  for the treatment of non-Hodgkin lymphoma improves net health outcomes.

POLICY STATEMENTS

Obinutuzumab

Intravenous obinutuzumab (Gazyva) may be considered medically necessary to treat patients with NHL for the following FDA labeled indications:

Follicular lymphoma (FL):

· In combination with chemotherapy followed by obinutuzumab monotherapy in patients achieving at least a partial remission, is indicated for the treatment of adult patients with previously untreated stage II bulky, III or IV FL.

· In combination with bendamustine followed by obinutuzumab monotherapy, for the treatment of patients with FL who relapsed after, or are refractory to, a rituximab-containing regimen.

Chronic lymphocytic leukemia (CLL):

· In combination with chlorambucil, for the treatment of patients with previously untreated CLL.

Obinutuzumab (Gazyva) is considered investigational for relapsed or refractory CLL.

CLL is considered to be identical (ie, one disease with different manifestations) to the mature (peripheral) B cell neoplasm small lymphocytic lymphoma (SLL), one of the indolent non-Hodgkin lymphomas. The term CLL is used when the disease manifests primarily in the bone marrow and blood while the term SLL is used when involvement is primarily nodal.

"Follicular Lymphoma (grade 1-2)

- First-line therapy for stage I, contiguous stage II, non-contiguous stage II disease, or for patients with indications for treatment with stage III or IV disease  preferred in combination with bendamustine, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CVP (cyclophosphamide, vincristine, and prednisone) regimens in combination with lenalidomide. Second-line and subsequent therapy (if not previously given) for no response, relapsed, or progressive disease in patients with indications for treatment preferred* in combination with bendamustine, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CVP (cyclophosphamide, vincristine, and prednisone) regimen as a single agent or in combination with lenalidomide
*obinutuzumab is preferred in rituximab refractory patients, which includes disease progressing on or within 6 months of prior rituximab therapy. Single-agent maintenance therapy  preferred as optional first-line consolidation or extended dosing following chemoimmunotherapy preferred as optional second-line consolidation or extended dosing for rituximab-refractory disease"
 

"Gastric MALT Lymphoma

-Second-line and subsequent therapy for relapsed, refractory, or progressive disease in patients with indications for treatment preferred in combination with bendamustine (not recommended if previously
treated with bendamustine) as a component of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with obinutuzumab regimen as a component of CVP (cyclophosphamide, vincristine, and prednisone with obinutuzumab regimen in combination with lenalidomide"

"Nongastric MALT Lymphoma (Noncutaneous)

-Second-line and subsequent therapy for relapsed, refractory, or progressive disease in patients with indications for treatment preferred in combination with bendamustine (not recommended if previously
treated with bendamustine) as a component of CHOP (cyclophosphamide, doxorubicin, vincristine, and
prednisone) with obinutuzumab regimen as a component of CVP (cyclophosphamide, vincristine, and prednisone) with obinutuzumab regimen in combination with lenalidomide"

"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 (preferred) as a component of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with obinutuzumab regimen as a component of CVP (cyclophosphamide, vincristine, and prednisone) with obinutuzumab regimen"

"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  preferred in combination with bendamustine (not recommended if previously treated with bendamustine)
as a component of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with obinutuzumab regimen as a component of CVP (cyclophosphamide, vincristine, and prednisone) with
obinutuzumab regimen in combination with lenalidomide"

"Mantle Cell Lymphoma

-Used as a substitute* for rituximab in patients with intolerance (including those experiencing severe hypersensitivity reactions requiring discontinuation of rituximab) as well as rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis"

"Diffuse Large B-Cell Lymphoma

-Used as a substitute* for rituximab in patients with intolerance (including those experiencing severe hypersensitivity reactions requiring discontinuation of rituximab) as well as rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis "

"Histologic Transformation of Indolent Lymphomas to Diffuse Large B-Cell Lymphoma

-Used as a substitute* for rituximab in patients with intolerance (including those experiencing severe hypersensitivity reactions requiring discontinuation of rituximab) as well as rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis "

"High-Grade B-Cell Lymphomas

-Used as a substitute* for rituximab in patients with intolerance (including those experiencing severe hypersensitivity reactions requiring discontinuation of rituximab) as well as rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis "

"Burkitt Lymphoma

-Used as a substitute* for rituximab in patients with intolerance (including those experiencing severe hypersensitivity reactions requiring discontinuation of rituximab) as well as rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis "

"AIDS-Related B-Cell Lymphomas

-Used as a substitute* for rituximab in patients with intolerance (including those experiencing severe hypersensitivity reactions requiring discontinuation of rituximab) as well as rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis"

"Post-Transplant Lymphoproliferative Disorders

-Used as a substitute* for rituximab in patients with intolerance (including those experiencing severe hypersensitivity reactions requiring discontinuation of rituximab) as well as rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis,vesiculobullous dermatitis, and toxic epidermal necrolysis"

"Castleman Disease

-Used as a substitute* for rituximab in patients with intolerance (including those experiencing severe hypersensitivity reactions requiring discontinuation of rituximab) as well as rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis "

"Hairy Cell Leukemia

-Consider in combination with vemurafenib as initial therapy for patients with indications for treatment who are unable to tolerate purine analogs including frail patients and those with active infection (useful in certain circumstances)"

"Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

-First-line therapy for CLL/SLL without del(17p)/TP53 mutation in patients who have indications for treatment  in combination with acalabrutinib (preferred) in combination with ibrutinib* *recommended only in patients ≥65 years of age and younger patients with significant comorbidities (creatinine clearance <70 mL/min) "

POLICY GUIDELINES

Off-Label Uses: Compendia recommended indications

Small Lymphocytic Lymphoma (SLL). CLL is considered to be identical (ie, one disease with different manifestations) to the mature (peripheral) B cell neoplasm small lymphocytic lymphoma (SLL), one of the indolent non-Hodgkin lymphomas. The term CLL is used when the disease manifests primarily in the bone marrow and blood while the term SLL is used when involvement is primarily nodal.

a. First-line therapy in patients without del(11)q or del(17p)/TP53
b. First-line therapy in patients with del(11)q or del(17p)/TP53 when used in combination with chlorambucil
c. Patients unable to tolerate purine analogs as a single agent or in combination with chlorambucil
d. Patients with relapsed or refractory disease

Gastric MALT lymphoma in patients who relapsed after, or are refractory to, a rituximabcontaining regimen
Nongastric MALT lymphoma in patients who relapsed after, or are refractory to, a rituximab-containing regimen

• Used as maintenance therapy, as second-line, consoloidation or exteded dosing, in rituximab refractory patients treated with obinutuzumab and bendamustine for recurrent disease OR
• Used in combination with bendamustine as second-line or greater therapy for refractory (recurrent for Gastric Malt and Splenic MZL) or progressive disease; OR
• Used as a substitute for rituximab in patient experiencing a rare complication such as mucocutaneous reactions including paraneoplastic pemhigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis and toxic epiderma necrolysis.

Histologic Transformation of Marginal Zone Lymphoma to Diffuse Large B-Cell Lymphoma, Mantle Cell Lymphoma, Burkitt Lyphoma, AIDS Related B Cell Lymphomas, Post-Transplant Lymhoproliferative Disordes, or Castleman's disease.

• Used as a substitute for rituximab in patients experiencing rare complicationss such as mucocutaneous reactions including paraneoplastic pemhigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis and toxic epiderma necrolysis.

Splenic marginal zone lymphoma in patients who relapsed after, or are refractory to, a rituximab-containing regimen

Gazyva carries a US BOXED WRNING regarding hepatitis B virus (HBV) reactivation and progressive multifocal leukoencephalopathy (PML). Patients must be screened for HBV and HCV infection before treatment initiation. Positive patients must be monitored during and after Gazyva treatment. In the event of HBV reactivation, discontinue Gazyva and concomitant medications (1). Patient has not received a live vaccine in the preceding 28 days.

Patients presenting with new onset or changes to pre-existing neurologic manifestations should be evaluated for the diagnosis of PML. Evaluation of Progressive multifocal leukoencephalopathy a US BOXED WARNING, is due to JC virus infection, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue Gazyva therapy and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML (1).

Infusion Reactions: Premedicate patients with glucocorticoid, acetaminophen, and anti-histamine. Monitor patients closely during infusions. Infusion Reactions: Interrupt or discontinue infusion for reactions.

BENEFIT APPLICATION

BlueCard/National Account Issues

State or federal mandates regarding off-label uses of drugs approved by FDA may supersede this policy.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

BACKGROUND

C20-Directed Cytolytic Antibodies

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.[1] 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 three CD20-directed cytolytic antibodies carry black box warnings for hepatitis B virus reactivation and progressive multifocal leukoencephalopathy

Obinutuzumab (Gazyva) is a humanized monoclonal antibody produced in Chinese hamster ovary cell culture. In addition to the cytolytic mechanisms described earlier, obinutuzumab induces antibody-dependent cellular phagocytosis.

Dosing: Adult

Note: Premedication with acetaminophen, an antihistamine, and a glucocorticoid (dexamethasone or methylprednisolone) 30 to 60 minutes prior to treatment may be necessary (see Administration). Antihyperuricemic prophylaxis and adequate hydration are recommended for patients at high risk for tumor lysis syndrome. Antimicrobial, antiviral, and antifungal prophylaxis may be considered in certain patients.

Chronic lymphocytic leukemia (previously untreated; in combination with chlorambucil [Goede 2014]): IV:

Cycle 1: 100 mg on day 1, followed by 900 mg on day 2, followed by 1 g weekly for 2 doses (days 8 and 15); treatment cycle is 28 days.

Cycles 2 through 6: 1 g on day 1 every 28 days for 5 doses.

Missed doses: Administer the missed dose as soon as possible; adjust dosing schedule to maintain the time schedule between doses. In some cases, patients who do not complete the day 1 cycle 1 dose may proceed to the day 2 cycle 1 treatment (if appropriate).

Chronic lymphocytic leukemia (previously untreated, as a single agent [off label; Byrd 2016]): IV:

Cycle 1: 100 mg on day 1, followed by 900 mg on day 2, followed by 1 g weekly for 2 doses (days 8 and 15); treatment cycle is 21 days.

Cycles 2 through 8: 1 g on day 1 every 21 days for 7 doses.

Chronic lymphocytic leukemia (previously untreated, in combination with ibrutinib [off-label combination; Moreno 2019]): IV:

Cycle 1: 100 mg on day 1, followed by 900 mg on day 2, followed by 1 g weekly for 2 doses (days 8 and 15); treatment cycle is 28 days.

Cycles 2 through 6: 1 g on day 1 every 28 days for 5 doses (continue ibrutinib until disease progression or unacceptable toxicity).

Chronic lymphocytic leukemia (previously untreated patients with coexisting conditions, in combination with venetoclax [off-label combination; Fischer 2019]): IV:

Cycle 1: 100 mg on day 1, followed by 900 mg on day 2 (or 1 g on day 1), followed by 1 g weekly for 2 doses (days 8 and 15); treatment cycle is 28 days (venetoclax is initiated on day 22 of cycle 1).

Cycles 2 through 6: 1 g on day 1 every 28 days for 5 doses (continue venetoclax until the end of cycle 12).

Follicular lymphoma (previously untreated; Marcus 2017): IV: Note: Patients with complete response or partial response to the initial 6 or 8 cycles of combination therapy (with either bendamustine or cyclophosphamide, doxorubicin, vincristine, prednisone [CHOP] or cyclophosphamide, vincristine, and prednisone [CVP]) should continue on obinutuzumab as monotherapy for up to 2 years.

Cycle 1 (either in combination with bendamustine or with CHOP or CVP chemotherapy): 1 g weekly for 3 doses on day 1, day 8, and day 15; treatment cycle is either 21 or 28 days (depending on combination therapy).

Cycles 2 through 6 (in combination with bendamustine): 1 g on day 1 every 28 days for 5 doses.

Cycles 2 through 8 (in combination with CHOP): 1 g on day 1 every 21 days for 5 combination therapy doses (in combination with CHOP in cycles 2 through 6), followed by 1 g on day 1 every 21 days for 2 doses (as monotherapy) in cycles 7 and 8.

Cycles 2 through 8 (in combination with CVP): 1 g on day 1 every 21 days for 7 doses.

Obinutuzumab monotherapy: 1 g once every 2 months for up to 2 years beginning ~2 months after the last induction phase obinutuzumab dose.

Missed doses: Administer the missed dose as soon as possible; adjust dosing schedule accordingly to maintain the time interval between chemotherapy cycles. During obinutuzumab monotherapy, maintain the original dosing schedule for subsequent doses.

Follicular lymphoma (relapsed/refractory; Cheson 2018; Sehn 2016): IV: Note: Patients with stable disease, complete response, or partial response after 6 cycles of combination therapy (with bendamustine) should continue on obinutuzumab as monotherapy for up to 2 years.

Cycle 1 (in combination with bendamustine): 1 g weekly for 3 doses on day 1, day 8, and day 15; treatment cycle is 28 days.

Cycles 2 through 6 (in combination with bendamustine): 1 g on day 1 every 28 days for 5 doses.

Obinutuzumab monotherapy: 1 g once every 2 months for up to 2 years beginning ~2 months after the last induction phase obinutuzumab dose.

Missed doses: Administer the missed dose as soon as possible; adjust dosing schedule accordingly to maintain the time interval between chemotherapy cycles. During obinutuzumab monotherapy, maintain the original dosing schedule for subsequent doses.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [preservative free]:

Gazyva: 1000 mg/40 mL (40 mL)

REGULATORY STATUS

In 2013, obinutuzumab (Gazyva™; Genentech) 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.^6,

RATIONALE

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

OBINUTUZUMAB (GAZYVA)

The purpose of obinutuzumab alone orcombined with chemotherapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with NHL.

The question addressed in this evidence review is: Do on-label and off-label uses of monoclonal antibodies for the treatment of NHL improve the net health outcome?

The following PICOs were used to select literature to inform this review.

Patients

The relevant population of interest is individuals with NHL

Interventions

The therapy being considered is obinutuzumab alone or combined with chemotherapy. Patients with NL are actively managed by oncologists, radiation oncologists, and hematologists in an inpatient or outpatient clinical setting.

Comparators

The following therapy is currently being used to treat NHL: standard chemotherapy regimens. .Patients with FL are actively managed by oncologists, radiation oncologists, and hematologists in an inpatient or outpatient clinical setting.

Outcomes

The general outcomes of interest are OS, change in disease status, quality of life, and treatment-related mobility. Interval follow-up of 1 to 12 years is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles :

·         To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

·         In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

·         To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

·         Studies with duplicative or overlapping populations were excluded.

Chronic Lymphocytic Leukemia

First-Line Therapy for Previously Untreated CLL

The FDA’s approval of obinutuzumab (also known as GA101) was based on an open-label, phase 3 RCT, CLL11.[74] 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.[75] The primary end point was PFS. Only results comparing obinutuzumab combination therapy with chlorambucil monotherapy were considered by FDA for approval.[76] 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 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 deaths of 15.5% (37/238) of patients in the combination therapy arm compared with 28.8% (34/118) in the chlorambucil monotherapy arm.[77]

Second-Line Therapy for Relapsed or Refractory CLL

Cartron et al (2014) published results of the open-label, phase 1/2 GAUGIN study of obinutuzumab monotherapy for relapsed or refractory CLL.[78] 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.

Section Summary: Obinutuzumab (Gazyva)

A phase 3 RCT showed substantially improved PFS in patients with previously untreated CLL who received obinutuzumab compared with those who received chlorambucil alone or rituximab plus chlorambucil. Preliminary analysis of OS has shown increased survival with obinutuzumab compared with chlorambucil monotherapy, but not compared with rituximab combination therapy. Randomized trials are needed to show improved survival outcomes compared with current treatment regimens.

Additional data are needed to establish the efficacy and safety of obinutuzumab for relapsed/refractory CLL.

Summary of Evidence

For individuals who have NHL who receive obinutuzumab alone or combined with chemotherapy, the evidence includes RCTs. Relevant outcomes are overall survival, change in disease status, quality of life, and treatment-related morbidity. Obinutuzumab was approved by the Food and Drug Administration for use in combination with chlorambucil for previously untreated CLL in combination with bendamustine. These indications are based on positive results in phase 3 trials that compared combination therapy with monotherapy. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 1 

Follicular Lymphoma

First-Line Therapy for Previously Untreated FL

Marcus et al (2017) published a randomized study (GALLIUM trial) comparing obinutuzumab-based with rituximab-based chemotherapy as firstline treatment for FL.[72] 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=0.33), 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 FL

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.[6] 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.

Second-Line Therapy for Relapsed or Refractory NHL

The 2016 publication of the phase 3 trial (GADOLIN) described above for relapsed or refractory FL assessed 396 patients with NHL.[73] 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.

Section Summary: Obinutuzumab (Gazyva)

A phase 3 RCT showed improved PFS in patients with FL who relapsed after, or were refractory to, a rituximab-containing regimen. 

Summary of Evidence

For individuals who have NHL who receive obinutuzumab alone or combined with chemotherapy, the evidence includes RCTs. Relevant outcomes are overall survival, change in disease status, quality of life, and treatment-related morbidity. Obinutuzumab was approved by the Food and Drug Administration for the treatment of FL in patients who have relapsed or are refractory to a rituximab-containing regimen. These indications are based on positive results in phase 3 trials that compared combination therapy with monotherapy. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 2

Individuals:• in combination with bendamustine followed by GAZYVA monotherapy, for the treatment of patients with follicular lymphoma (FL) who relapsed after a rituximab-containing regimen. Interventions of interest are:Obinutuzumab alone or combined with chemotherapy    Comparators of interest are:Standard chemotherapy regimens    Relevant outcomes include:Overall survivalProgression-free survivalResponse rates Quality of life. 

Section Summary: Obinutuzumab (Gazyva)

A phase 3 RCT showed improved PFS in patients with FL who relapsed after, or were refractory to, a rituximab-containing regimen. 

Summary of Evidence

For individuals who have NHL who receive obinutuzumab alone or combined with chemotherapy, the evidence includes RCTs. Relevant outcomes are overall survival, change in disease status, quality of life, and treatment-related morbidity. Obinutuzumab was approved by the Food and Drug Administration for the treatment of FL in patients who have relapsed or are refractory to a rituximab-containing regimen. These indications are based on positive results in phase 3 trials that compared combination therapy with monotherapy. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 3 

Individuals:in combination with bendamustine followed by GAZYVA monotherapy, for the treatment of patients with follicular lymphoma (FL) who are refractory to, a rituximab-containing regimen.    Interventions of interest are:Obinutuzumab alone or combined with chemotherapy    Comparators of interest are:Standard chemotherapy regimens    Relevant outcomes include:Overall survivalProgression-free survivalResponse rates Quality of lifE

Population Reference No. 4 

Follicular Lymphoma (grade 1-2)

First-line therapy for stage I, contiguous stage II, non-contiguous stage II disease, or for patients with indications for treatment with stage III or IV disease preferred in combination with bendamustine, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CVP (cyclophosphamide, vincristine, and prednisone) regimens in combination with lenalidomide

Second-line and subsequent therapy (if not previously given) for no response, relapsed, or progressive disease in patients with indications for treatment preferred* in combination with bendamustine, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CVP (cyclophosphamide, vincristine, and prednisone) regimen as a single agent or in combination with lenalidomide *obinutuzumab is preferred in rituximab refractory patients, which includes disease progressing on or within 6 months of prior rituximab therapy

Single-agent maintenance therapy preferred as optional first-line consolidation or extended dosing following chemoimmunotherapy preferred as optional second-line consolidation or extended dosing for rituximab-refractory disease

Used as a substitute* for rituximab in patients with intolerance (including those experiencing severe hypersensitivity reactions requiring discontinuation of rituximab) as well as rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis *Re-challenge with the same anti-CD20 monoclonal antibody is not recommended and it is unclear if the use of an alternative anti-CD20 monoclonal antibody poses the same risk of recurrence

Population Reference No. 5

Gastric MALT Lymphoma

Second-line and subsequent therapy for relapsed, refractory, or progressive disease in patients with indications for treatment preferred in combination with bendamustine (not recommended if previously treated with bendamustine) as a component of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with obinutuzumab regimen as a component of CVP (cyclophosphamide, vincristine, and prednisone with obinutuzumab regimen in combination with lenalidomide

Preferred maintenance therapy as second-line consolidation or extended dosing in rituximab-refractory patients treated with obinutuzumab and bendamustine regimen for recurrent disease

Used as a substitute* for rituximab in patients with intolerance (including those experiencing severe hypersensitivity reactions requiring discontinuation of rituximab) as well as rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis *Re-challenge with the same anti-CD20 monoclonal antibody is not recommended and it is unclear if the use of an alternative anti-CD20 monoclonal antibody poses the same risk of recurrence

Population Reference No. 6

Nongastric MALT Lymphoma (Noncutaneous)

Second-line and subsequent therapy for relapsed, refractory, or progressive disease in patients with indications for treatment preferred in combination with bendamustine (not recommended if previously treated with bendamustine) as a component of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with obinutuzumab regimen as a component of CVP (cyclophosphamide, vincristine, and prednisone) with obinutuzumab regimen in combination with lenalidomide

Preferred maintenance therapy as second-line consolidation or extended dosing in rituximab refractory patients treated with obinutuzumab and bendamustine regimen for recurrent disease

Used as a substitute* for rituximab in patients with intolerance (including those experiencing severe hypersensitivity reactions requiring discontinuation of rituximab) as well as rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis *Re-challenge with the same anti-CD20 monoclonal antibody is not recommended and it is unclear if the use of an alternative anti-CD20 monoclonal antibody poses the same risk of recurrence

Population Reference No. 7 

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 (preferred) as a component of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with obinutuzumab regimen as a component of CVP (cyclophosphamide, vincristine, and prednisone) with obinutuzumab regimen

Second-line and subsequent therapy for relapsed, refractory, or progressive disease in patients with indications for treatment preferred in combination with bendamustine (not recommended if previously treated with bendamustine) as a component of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with obinutuzumab regimen as a component of CVP (cyclophosphamide, vincristine, and prednisone) with obinutuzumab regimen in combination with lenalidomide

Preferred maintenance therapy as second-line consolidation or extended dosing in rituximab refractory patients treated with obinutuzumab and bendamustine regimen for recurrent disease

Used as a substitute* for rituximab in patients with intolerance (including those experiencing severe hypersensitivity reactions requiring discontinuation of rituximab) as well as rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis *Re-challenge with the same anti-CD20 monoclonal antibody is not recommended and it is unclear if the use of an alternative anti-CD20 monoclonal antibody poses the same risk of recurrence

Population Reference No. 8 

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 preferred in combination with bendamustine (not recommended if previously treated with bendamustine) as a component of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with obinutuzumab regimen as a component of CVP (cyclophosphamide, vincristine, and prednisone) with obinutuzumab regimen in combination with lenalidomide

Preferred maintenance therapy as second-line consolidation or extended dosing in rituximab refractory patients treated with obinutuzumab and bendamustine regimen for recurrent disease

Used as a substitute* for rituximab in patients with intolerance (including those experiencing severe hypersensitivity reactions requiring discontinuation of rituximab) as well as rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis *Re-challenge with the same anti-CD20 monoclonal antibody is not recommended and it is unclear if the use of an alternative anti-CD20 monoclonal antibody poses the same risk of recurrence

Population Reference No. 9 

Mantle Cell Lymphoma

Used as a substitute* for rituximab in patients with intolerance (including those experiencing severe hypersensitivity reactions requiring discontinuation of rituximab) as well as rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis *Re-challenge with the same anti-CD20 monoclonal antibody is not recommended and it is unclear if the use of an alternative anti-CD20 monoclonal antibody poses the same risk of recurrence

Population Reference No. 10 

Diffuse Large B-Cell Lymphoma

Used as a substitute* for rituximab in patients with intolerance (including those experiencing severe hypersensitivity reactions requiring discontinuation of rituximab) as well as rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis *Re-challenge with the same anti-CD20 monoclonal antibody is not recommended and it is unclear if the use of an alternative anti-CD20 monoclonal antibody poses the same risk of recurrence

Population Reference No. 11 Policy Statement

Histologic Transformation of Indolent Lymphomas to Diffuse Large B-Cell Lymphoma

Used as a substitute* for rituximab in patients with intolerance (including those experiencing severe hypersensitivity reactions requiring discontinuation of rituximab) as well as rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis *Re-challenge with the same anti-CD20 monoclonal antibody is not recommended and it is unclear if the use of an alternative anti-CD20 monoclonal antibody poses the same risk of recurrence

Population Reference No. 12 

High-Grade B-Cell Lymphomas

Used as a substitute* for rituximab in patients with intolerance (including those experiencing severe hypersensitivity reactions requiring discontinuation of rituximab) as well as rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis *Re-challenge with the same anti-CD20 monoclonal antibody is not recommended and it is unclear if the use of an alternative anti-CD20 monoclonal antibody poses the same risk of recurrence

Population Reference No. 13 

Burkitt Lymphoma

Used as a substitute* for rituximab in patients with intolerance (including those experiencing severe hypersensitivity reactions requiring discontinuation of rituximab) as well as rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis *Re-challenge with the same anti-CD20 monoclonal antibody is not recommended and it is unclear if the use of an alternative anti-CD20 monoclonal antibody poses the same risk of recurrence

Population Reference No. 14 

AIDS-Related B-Cell Lymphomas

Used as a substitute* for rituximab in patients with intolerance (including those experiencing severe hypersensitivity reactions requiring discontinuation of rituximab) as well as rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis *Re-challenge with the same anti-CD20 monoclonal antibody is not recommended and it is unclear if the use of an alternative anti-CD20 monoclonal antibody poses the same risk of recurrence

Population Reference No. 15 

Post-Transplant Lymphoproliferative Disorders

Used as a substitute* for rituximab in patients with intolerance (including those experiencing severe hypersensitivity reactions requiring discontinuation of rituximab) as well as rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis *Re-challenge with the same anti-CD20 monoclonal antibody is not recommended and it is unclear if the use of an alternative anti-CD20 monoclonal antibody poses the same risk of recurrence

Population Reference No. 16

Castleman Disease

Used as a substitute* for rituximab in patients with intolerance (including those experiencing severe hypersensitivity reactions requiring discontinuation of rituximab) as well as rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis *Re-challenge with the same anti-CD20 monoclonal antibody is not recommended and it is unclear if the use of an alternative anti-CD20 monoclonal antibody poses the same risk of recurrence

Population Reference No. 17 

Hairy Cell Leukemia

Consider in combination with vemurafenib as initial therapy for patients with indications for treatment who are unable to tolerate purine analogs including frail patients and those with active infection (useful in certain circumstances)

Population Reference No. 18 

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

First-line therapy for CLL/SLL without del(17p)/TP53 mutation in patients who have indications for treatment in combination with acalabrutinib (preferred) in combination with ibrutinib* *recommended only in patients ≥65 years of age and younger patients with significant comorbidities (creatinine clearance <70 mL/min)

First-line therapy for CLL/SLL without del(17p)/TP53 mutation in patients who have indications for treatment in combination with venetoclax (preferred) in combination with bendamustine (not recommended for frail patients) as a single agent* in combination with chlorambucil* in combination with high-dose methylprednisolone (HDMP) *recommended only in patients ≥65 years of age and younger patients with significant comorbidities (creatinine clearance <70 mL/min)

Subsequent therapy (if not given as first-line) for relapsed or refractory disease after prior Bruton Tyrosine Kinase inhibitor- and venetoclax-based regimens as a single agent or in combination with high-dose methylprednisolone (HDMP) for CLL/SLL without del(17p)/TP53 mutation in patients who have indications for treatment

Useful in certain circumstances in combination with venetoclax (if previously used as first-line therapy) for CLL/SLL without del(17p)/TP53 mutation as retreatment for relapse after a period of remission in patients who have indications for treatment

First-line therapy for CLL/SLL with del(17p)/TP53 in patients who have indications for treatment in combination with acalabrutinib or venetoclax (both preferred) as a single agent

SUPPLEMENTAL INFORMATION

Gazyva is a monoclonal antibody intended to be used for treatment of patients with previously untreated chronic lymphocytic leukemia (CLL) or for treatment of patients with follicular lymphoma who relapsed after, or are refractory to, a rituximab-containing regimen (FL). Gazyva works by helping certain cells in the immune system attack cancer cells. In particular, Gazyva targets the CD20 antigen expressed on the surface of the pre B- and mature B-lymphocytes (1). 

The decision to treat a patient with Gazyva® must be based on the
     following criteria:

1. It must be prescribed by a hematologist or oncologist.
2. Diagnosis of Chronic Lymphocytic Leukemia or follicular lymphoma
3. Used in adult population.

Admission of the patient to the hospital for the sole and only purpose of administering Gazyva® requires individual pre-authorization.

The request must include the following documentation: 

Insured's contract number.
Diagnostic code ICD-10.
Documentation of medical necessity.
Hepatitis B laboratory (antigen or antibody)
Pre-treatment
Diagnostic evidence
 Number of milligrams to be administered (per Cycle)

 If a patient, with the diagnosis approved for payment by this policy, is admitted
     to the hospital, and as part of the treatment the use of Gazyva® is required, Triple-S  will cover the treatment after the requirements above are met
     
Triple-S pays only the dose every 28 days of the medication

Triple-S will not consider for payment the use of Gazyva® under the following
circumstances:

    a. The patient has hypersensitivity to the product or any of its
    components.
    b. The patient is not older than 70 years.
    c. Patient does not meet any of the above criteria.

PRACTICE GUIDELINES AND POSITION STATEMENTS

National Comprehensive Cancer Network

The National Comprehensive Cancer Network (NCCN) has published multiple guidelines for the treatment of the various types of non-Hodgkin lymphoma. These include recommendations for the appropriate use of monoclonal antibody therapy (rituximab, ofatumumab and obinutuzumab alone or in combination with chemotherapy for treatment of NHL.^{81,82,83,84,77,}.

U.S. Preventive Services Task Force Recommendations

Not applicable.

MEDICARE NATIONAL COVERAGE

There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.

REFERENCES

1. ICD10 Code for CLL; ICD10Data.com. Available at http://www.icd10data.com/Search.aspx?search=Chronic leukemia. Accessed January 27, 2015.

2. Gazyva (obinutuzumab) [prescribing information]. South San Francisco, CA: Genentech Inc; December 2014.

3. 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. [PubMed 22438256]

4. Lexicomp®, Uptodate data base. Obinutuzumab Drug Information; Available at: http://www.uptodate.com/contents/obinutuzumab-druginformation?source=search_result&search=Gazyva&selectedTitle=1~16 #F22473720. Accessed January 27, 2015.

5. Gazyva; Available at: http://www.gazyva.com/about/cll-therapy. Accessed January 26, 2015.

6. CLL; National Cancer Insitute. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/CLL/Patient/page1. Accessed January 26, 2015.

CODES

APPLICABLE MODIFIERS

POLICY HISTORY