Medical Policies - Prescription Drugs
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Medical policies are a set of written guidelines that support current standards of practice. They are based on current peer-reviewed scientific literature. A requested therapy must be proven effective for the relevant diagnosis or procedure. For drug therapy, the proposed dose, frequency and duration of therapy must be consistent with recommendations in at least one authoritative source. This medical policy is supported by FDA-approved labeling and nationally recognized authoritative references. These references include, but are not limited to: MCG care guidelines, DrugDex (IIb level of evidence or higher), NCCN Guidelines (IIb level of evidence or higher), NCCN Compendia (IIb level of evidence or higher), professional society guidelines, and CMS coverage policy.
When the requested chemotherapeutic agent is being utilized in a regimen in combination with other chemotherapeutic agents, the entire regimen (including dose, frequency, and duration) must be consistent with recommendations in at least one authoritative source, including but not limited to FDA labeling and nationally recognized compendia or clinical guidelines such as National Comprehensive Cancer Network (NCCN) and CMS coverage policy. HCSC may require a provider to submit documentation from nationally recognized compendia, clinical guidelines, or active Phase III clinical trials supporting the requested regimen.
Obinutuzumab (Gazyva™) may be considered medically necessary in combination with bendamustine followed by obinutuzumab monotherapy, for the treatment of patients with follicular lymphoma who relapsed after or are refractory to a rituximab-containing regimen.
Obinutuzumab (Gazyva™) may be considered medically necessary for the treatment of previously untreated B-chronic lymphocytic leukemia (B-CLL) when used in combination with chlorambucil.
Obinutuzumab (Gazyva™) is considered experimental, investigational and/or unproven for all other indications, including, but not limited to:
• Relapsed or refractory chronic lymphocytic leukemia (CLL),
• Rheumatoid arthritis, and
• Systemic lupus erythematosus.
B-cell chronic lymphocytic leukemia (B-CLL), also known as chronic lymphoid leukemia (CLL), is the most common type of leukemia (a type of cancer of the white blood cells) in adults. CLL affects B-cell lymphocytes, which originate in the bone marrow, develop in the lymph nodes, and normally fight infection by producing antibodies.
In CLL, B-cells grow in an uncontrolled manner and accumulate in the bone marrow and blood, where they crowd out healthy blood cells. CLL is a stage of small lymphocytic lymphoma (SLL), a type of B-cell lymphoma, which presents primarily in the lymph nodes CLL and SLL are considered the same underlying disease, just with different appearances.
CLL is a disease of adults. Most (>75%) people newly diagnosed with CLL are over the age of 50, and the majority are men. However, in rare cases, it can occur in teenagers and occasionally in children. Some of these may relate to an inherited predisposition.
Most people are diagnosed without symptoms as the result of a routine blood test that returns a high white blood cell count, but, as it advances, CLL results in swollen lymph nodes, spleen, and liver, and eventually anemia and infections.
Follicular lymphoma is a type of non-Hodgkin lymphoma (NHL). It develops when the body makes abnormal B-cell lymphocytes. Like CLL, follicular lymphoma cells build up in lymph nodes. The most common symptom is a painless swelling in the neck, armpit or groin.
C20 directed or CD20 is a cell surface antigen expressed on pre-B and mature B-cell 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).
The U.S. Food and Drug Administration (FDA) issued a black box warning for obinutuzumab (Gazyva™) for hepatitis B virus (HBV) reactivation and progressive multifocal leukoencephalopathy (PML). (2) For HBV reactivation, in some cases administration of this CD20-directed cytolytic antibody may result in fulminant hepatitis, hepatic failure, and death. For PML, the administration of this CD20-directed cytolytic antibody may result in death.
Obinutuzumab (Gazyva™) is a humanized monoclonal antibody produced in Chinese hamster ovary cell culture. In addition to the cytolytic mechanisms described above, obinutuzumab induces antibody-dependent cellular phagocytosis (the engulfing of microorganisms or other cells and foreign particles by phagocytes).
In November 2013, obinutuzumab (Gazyva™; Genentech) was approved by the 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 follicular lymphoma who relapsed or are refractory to a rituximab-containing regimen. (2)
This medical policy was created in March 2017 and based on the U.S. Food and Drug Administration (FDA) approved label for obinutuzumab (Gazyva™). A recent search of the MedLine database was performed through February 13, 2017. The following is a summary of key literature.
Relapsed or Refractory Follicular Lymphoma
Gazyva™ has been FDA approved for use in combination with bendamustine for treatment of patients with follicular lymphoma who relapsed after, or who are refractory to, a rituximab-containing regimen. (2) The pivotal phase 3 trial (GADOLIN) was an open-label multicenter trial of 321 patients randomized to receive either 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. Progression-free survival (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 (PFS hazard ratio [HR]=0.48; 95% confidence interval [CI], 0.34 to 0.68; p<0.001). Median overall survival (OS) had not been reached in either arm at a median of 24 months of observation time.
Relapsed or Refractory non-Hodgkin Lymphoma (NHL)
The 2016 publication of the phase 3 trial (GADOLIN) described above for relapsed or refractory follicular lymphoma contained 396 patients with NHL. (3) The trial was stopped after a preplanned interim analysis. About 81% of patients had follicular lymphoma, 12% had marginal zone lymphoma, 7% had small lymphocytic leukemia (SLL), and 1 patient had Waldenström macroglobulinemia (WM). Median follow-up was 21.9 months. As in the subgroup with follicular lymphoma (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).
Chronic Lymphocytic Leukemia
Previously Untreated Chronic Lymphocytic Lymphoma (CLL)
The FDA approval of obinutuzumab (also known as GA101) was based on 1 open-label, phase 3 randomized clinical trial (RCT), CLL-11. (4) CLL-11 was conducted at 155 centers in 24 countries. Adults (≥18 years of age) with previously untreated, CD20-positive CLL with coexisting medical conditions (e.g., creatinine clearance, 70-30 mL/min) were enrolled. Patients were randomized 2:2:1 to receive obinutuzumab plus chlorambucil (n=238), rituximab plus chlorambucil (n=233), or chlorambucil monotherapy (n=118). The National Comprehensive Cancer Network (NCCN) does not currently recommend chlorambucil monotherapy for first-line treatment of CLL. (5) The primary end point was PFS. Only results comparing obinutuzumab combination therapy with chlorambucil monotherapy were considered by the FDA for approval. (6) 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. (6) 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 CLL-11 was infusion reaction (11%). A 2015 follow-up report 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 to 28.8% (34/118) in the chlorambucil monotherapy arm. (7)
Relapsed or Refractory CLL
Cartron et al. (2014) published results of the open-label, phase 1/2 GAUGUIN study of obinutuzumab monotherapy for relapsed/refractory CLL. (8) Phase 1 (n=13) was a dose-finding study. Phase 2 (n=20) administered a fixed dose of obinutuzumab (1000 mg intravenously) 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: Follicular Lymphoma and CLL
A phase 3 RCT showed improved PFS in patients with follicular lymphoma who relapsed after, or were refractory to, a rituximab-containing regimen. A phase 3 RCT showed substantially improved PFS in patients with previously untreated CLL who received obinutuzumab compared with those who received chlorambucil or rituximab plus chlorambucil. Preliminary analysis of OS showed increased survival with obinutuzumab compared with chlorambucil monotherapy, but not compared with rituximab combination therapy. A small phase 1/2 study of obinutuzumab monotherapy in relapsed or refractory CLL provided insufficient evidence to determine whether net health outcome is improved. Randomized trials are needed to show improved survival outcomes compared with current treatment regimens. Small phase 1 and 2 studies have compared 2 doses of obinutuzumab in relapsed or refractory indolent and aggressive NHL, as monotherapy and in combination regimens. More data are needed to establish the efficacy and safety of obinutuzumab for relapsed/refractory CLL.
Ongoing and Unpublished Clinical Trials: B-cell Neoplasms
Some currently unpublished trials that might influence this review are listed in Table 1.
Table 1. Summary of Key Trials
A Phase III, Multicenter, Open-label Randomized Trial Comparing the Efficacy of GA101 (RO5072759) in Combination with CHOP (G-CHOP) Versus Rituximab and CHOP (R-CHOP) in Previously Untreated Patients with CD20-positive Diffuse Large B-cell Lymphoma (DLBCL)
Randomized Phase III Study Using a PET-driven Strategy and Comparing GA101 OR Rituximab Associated to a Chemotherapy Delivered Every 14 Days (ACVBP or CHOP) in DLBCL CD20+ Lymphoma Untreated Patients from 18 to 60 Presenting With 1 or More Adverse Prognostic Factors of the Age-adjusted IPI
Multicentre, Phase III, Open Label, Randomized Study in Previously Untreated Patients with Advanced Indolent Non-Hodgkin's Lymphoma Evaluating the Benefit of GA101 (RO5072759) + Chemotherapy Compared to Rituximab + Chemotherapy Followed by GA101 or Rituximab Maintenance Therapy in Responders
NCT: National Clinical Trial;
a: Denotes industry-sponsored or cosponsored trial.
Practice Guidelines and Position Statements: B-cell Neoplasms
National Comprehensive Cancer Network (NCCN)
NCCN guidelines (v.1.2017) recommend obinutuzumab for the following indications (all category 2A) for CLL and SLL only (see Table 2). (5)
Table 2. NCCN Guidelines on Treatment Regimens Including Obinutuzumab for CLL and SLL Without del(17p)/TP53 Mutation (5)
CLL and SLL
Frail with significant comorbidity
First line, with chlorambucil
Age ≥65 y
First line, with chlorambucil
Relapsed/refractory, with significant comorbidity or age ≥65 y
Relapsed/refractory, without significant comorbidity
NCCN: National Comprehensive Cancer Network;
CLL: chronic lymphocytic lymphoma;
SLL: small lymphocytic lymphoma;
In rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), B-cell depletion therapy using rituximab results in variable clinical responses between patients, which likely relates to variable B-cell depletion in the presence of immune defects. (9) Outcomes in clinical trials with other type I anti-CD20 monoclonal antibodies, such as ocrelizumab and ofatumumab. Obinutuzumab is a type II monoclonal antibody, with a greater capacity for B-cell depletion, being considered for clinical trials. The authors concluded further study is warranted to determine if Gazyva™ would provide advantages to overcome disease-related immune defects in autoimmune diseases, such as RA or SLE.
Summary of Evidence
For individuals who have non-Hodgkin lymphoma (NHL) who receive obinutuzumab alone or combined with chemotherapy, the evidence includes randomized controlled trials (RCTs). Relevant outcomes are overall survival, disease-free survival, change in disease status, and quality of life. Obinutuzumab was approved by the U.S. Food and Drug Administration for the treatment of follicular lymphoma in patients who have relapsed or are refractory to a rituximab-containing regimen and for use in combination with chlorambucil for previously untreated chronic lymphocytic lymphoma (CLL) in combination with bendamustine. These indications are based on positive results in phase 3 trials that compared combination therapy to monotherapy. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
For individuals who have autoimmune disease, there is no scientific evidence nor published outcomes using obinutuzumab to treat disease-related immune defects, such as rheumatoid arthritis or systemic lupus erythematosus. The evidence is insufficient to determine that the technology results in a meaningful improvement in the net health outcome.
Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.
Disclaimer for coding information on Medical Policies
Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.
The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.
Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.
The following codes may be applicable to this Medical policy and may not be all inclusive.
ICD-9 Diagnosis Codes
Refer to the ICD-9-CM manual
ICD-9 Procedure Codes
Refer to the ICD-9-CM manual
ICD-10 Diagnosis Codes
Refer to the ICD-10-CM manual
ICD-10 Procedure Codes
Refer to the ICD-10-CM manual
The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.
The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.
A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.
1. Disease Education for non-Hodgkin lymphoma – Product information (2017). San Francisco, California: Genentech. Available at: <http://www.gene.com> (accessed on February 13, 2017).
2. FDA – Gazyva™ (obinutuzumab). U.S. Food and Drug Administration – Center for Devices and Radiologic Health. Available at <http://www.fda.gov> (accessed on February 13, 2017).
3. Sehn LH, Chua N, Mayer J, et al. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomized, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol. Aug 2016; 17(8):1081-93. PMID 27345636
4. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. Mar 20 2014; 370(12):1101-10. PMID 24401022
5. NCCN – Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (Version 1.2017). National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Available at <https://www.nccn.org> (accessed on February 13, 2017.
6. Lee HZ, Miller BW, Kwitkowski VE, et al. U.S. Food and Drug Administration approval: obinutuzumab in combination with chlorambucil for the treatment of previously untreated chronic lymphocytic leukemia. Clin Cancer Res. May 13 2014. PMID 24824310
7. Goede V, Fischer K, Engelke A, et al. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia. Jul 2015; 29(7):1602-4. PMID 25634683
8. 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. Oct 2 2014; 124(14):2196-202. PMID 25143487
9. Reddy V, Dahal LN, Cragg MS, et al. Optimizing B-cell depletion in autoimmune disease: is obinutuzumab the answer? Drug Discov Today. Aug 2016; 21(8):1330-8. PMID 27343722
10. Uses of Monoclonal Antibodies for the Treatment of Non-Hodgkin Lymphoma. Chicago, Illinois. Blue Cross Blue Shield Association Medical Policy Reference Manual (2016 November) Medicine 2.03.05.
|6/15/2018||Reviewed. No changes.|
|7/15/2017||New medical document. Coverage states, “Obinutuzumab (Gazyva™) may be considered medically necessary in combination with bendamustine followed by obinutuzumab monotherapy, for the treatment of patients with follicular lymphoma who relapsed after or are refractory to a rituximab-containing regimen. Obinutuzumab (Gazyva™) may be considered medically necessary for the treatment of previously untreated B-chronic lymphocytic leukemia (B-CLL) when used in combination with chlorambucil. Obinutuzumab (Gazyva™) is considered experimental, investigational and/or unproven for all other indications, including, but not limited to: • Relapsed or refractory chronic lymphocytic leukemia (CLL), • Rheumatoid arthritis, and • Systemic lupus erythematosus.”|
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