Medical Policy

 

Subject: Atezolizumab (Tecentriq®)
Document #: DRUG.00088 Publish Date:    12/27/2017
Status: Revised Last Review Date:    05/04/2017

Description/Scope

This document addresses the use of atezolizumab (Tecentriq) (Genentech, San Francisco, CA), an anti-programmed death ligand 1 (PD-L1) monoclonal antibody approved by the U.S. Food and Drug Administration (FDA) for treatment of locally advanced or metastatic urothelial carcinoma and metastatic non-small cell lung cancer (NSCLC) under specific circumstances.

Note: Please see these documents for related topics:

Position Statement

Medically Necessary:

The use of atezolizumab is considered medically necessary for the treatment of locally advanced or metastatic urothelial carcinoma when the following criteria are met:

  1. Disease has progressed during or following platinum-containing chemotherapy (for example, cisplatin); or
  2. Disease has progressed within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy; and
  3. Individual has a current Eastern Cooperative Oncology Group (ECOG) performance status of 0-2; and
  4. Individual has not received treatment with another PD-1 or PD-L1 agent (for example, nivolumab or pembrolizumab); and
  5. Individual is not receiving therapy for an autoimmune disease or chronic condition requiring treatment with a systemic immunosuppressant.

The use of atezolizumab is considered medically necessary for first-line treatment of locally advanced or metastatic urothelial carcinoma when the following criteria are met:

  1. Individual is ineligible for cisplatin treatment, defined as having one or more of the following risk factors for cisplatin toxicity:
    1. ECOG performance status 2;
    2. Glomerular filtration rate less than 60 mL/min;
    3. Hearing loss (measured at audiometry) of 25 dB at two contiguous frequencies;
    4. Grade 2 or greater peripheral neuropathy; and
  2. Individual has a current ECOG performance status of 0-2; and
  3. Individual has not received treatment with another PD-1 or PD-L1 agent (for example, nivolumab or pembrolizumab); and
  4. Individual is not receiving therapy for an autoimmune disease or chronic condition requiring treatment with a systemic immunosuppressant.

The use of atezolizumab is considered medically necessary for the treatment of metastatic non-small cell lung cancer when the following criteria are met:

  1. Disease has progressed during or following platinum-containing chemotherapy (for example, cisplatin); and
  2. When anaplastic lymphoma kinase (ALK) or epidermal growth factor receptor (EGFR) genomic tumor aberrations are present, must have demonstrated disease progression on U.S. Food and Drug Administration approved therapy; and
  3. Individual has a current ECOG performance status of 0-2; and
  4. Individual has not received treatment with another PD-1or PD-L1 agent (for example, nivolumab or pembrolizumab); and
  5. Individual is not receiving therapy for an autoimmune disease or chronic condition requiring treatment with a systemic immunosuppressant.

Investigational and Not Medically Necessary:

The use of atezolizumab is considered investigational and not medically necessary when the above criteria are not met and for all other uses, including but not limited to:

Rationale

Urothelial Carcinoma

On May 18, 2016, the FDA approved atezolizumab for the treatment of individuals with locally advanced or metastatic urothelial cancer who had disease progression during or following platinum-containing chemotherapy or whose disease progressed within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. Subsequently, on April 17, 2017 the FDA approved atezolizumab for the treatment of individuals with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy. The indications were approved under an accelerated process based on tumor response rate and durability of response. The FDA stated that continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials.

A phase I study (Powles, 2014) provided the initial evidence of the safety and efficacy of atezolizumab for the treatment of metastatic bladder cancer. Results of the phase I study were expanded into a multicenter, single-arm, phase II trial (NCT02108652) of individuals at least 18 years of age with inoperable locally advanced or metastatic urothelial carcinoma whose disease had progressed after previous platinum-based chemotherapy (Rosenberg, 2016). Key inclusion criteria were ECOG performance status of 0 or 1, measurable disease defined by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), adequate hematological and end-organ function, and no autoimmune disease, active infections or corticosteroid use. Treatment consisted of intravenous atezolizumab (1200 mg every 3 weeks). The primary endpoint of the study was objective response rate based on both the independent review facility-assessed objective response rate and the investigator-assessed objective response rate. Between May 13, 2014 and Nov 19, 2014, 315 individuals from 70 major academic medical centers and community oncology practices in Europe and North America were enrolled into the study. Of the 315, a total of 310 received atezolizumab (5 enrollees later did not meet eligibility criteria and were not dosed with study drug). The primary analysis showed that, compared with a historical control overall response rate of 10%, treatment with atezolizumab resulted in a significantly improved RECIST v1.1 objective response rate for each prespecified immune cell group (IC2/3: 27% [95% confidence interval (CI), 19-37], p<0.0001; IC1/2/3: 18% [13-24], p=0.0004) and in all subjects (15% [11-20], p=0.0058). Of note, the objective response rate was 8% in subjects who were classified as "negative" for PD-L1 expression lower than historical control objective response rate. At longer follow-up of all 310 subjects, objective response rates were 26% (95% CI, 18-36) in the IC2/3 group, 18% (13-24) in the IC1/2/3 group, and 15% (11-19) overall in all 310 subjects. At a median follow-up of 11.7 months (95% CI, 11.4-12.2), ongoing responses were recorded in 38 (84%) of 45 subjects. The Cancer Genome Atlas (TCGA) subtypes and mutation load were found to be independently predictive for response to atezolizumab. Grade 3-4 treatment-related adverse events, of which fatigue was the most common (5 individuals [2%]), were low and occurred in 50 (16%) of 310 treated subjects. There were no cases of febrile neutropenia. A total of 15 (5%) of 310 treated subjects had grade 3-4 immune-mediated adverse events, with pneumonitis, increased aspartate aminotransferase, increased alanine aminotransferase, rash, and dyspnea being the most common. There were no treatment-related deaths during the study. The authors concluded that atezolizumab showed durable activity and good tolerability in this particular population.

A single-arm, multi-center phase II trial (NCT02108652) (Balar, 2017) studied the safety and efficacy of atezolizumab as first-line chemotherapy for cisplatin-ineligible, locally advanced or metastatic urothelial carcinoma. A total of 47 academic medical centers and community oncology practices in seven countries participated. Cohort 1 consisted of subjects without previous treatment for metastatic urothelial cancer. Eligibility criteria included: inoperable, locally advanced or metastatic urothelial cancer (renal pelvis, ureters, bladder or urethra), measurable disease per RECIST, a tumor sample available for PD-L1 testing, and an ECOG performance status of 2 or less. Cisplatin ineligibility was defined as having one or more of the following: glomerular filtration rate (GFR) more than 30 mL/min and less than 60 mL/min (Cockcroft-Gault formula), a hearing loss measured by audiometry of 25 dB at two contiguous frequencies, grade 2 or greater peripheral neuropathy (that is, sensory alteration or paresthesias including tingling), or an ECOG performance score of 2. Cohort II was described earlier by Rosenberg and colleagues (2016) and had enrolled subjects previously treated with platinum-based chemotherapy. A total of 123 subjects were enrolled between June 9, 2014 and March 30, 2015. Of those, 119 were treated with at least one dose of intravenous atezolizumab every 21 days until unacceptable toxicity or investigator-assessed radiographic progression. At 17.2 months median follow-up, the objective response rate was 23% (95% CI, 16 to 31), the complete response rate was 9% (n=11), and 19 of 27 responses were ongoing. Median response duration was not reached. Responses occurred across all PD-L1 and poor prognostic factor subgroups. Median progression-free survival (PFS) was 2.7 months (2.1 to 4.2). Median overall survival (OS) was 15.9 months (10.4 to not estimable). Tumor mutation load was associated with response. A total of 114 (96%) of subjects had an adverse event and 79 (66%) had a treatment-related event. Treatment-related adverse events that occurred in at least 10% of subjects were fatigue, diarrhea and pruritus. One treatment-related death due to sepsis was reported. Adverse events leading to discontinuation of treatment occurred in 9 subjects and immune-mediated events occurred in 14 (12%) subjects. The authors concluded "overall, atezolizumab showed promising response durability and survival, coupled with a low incidence of clinically relevant toxicities despite numerous comorbidities in this population."

A phase III trial (NCT02302807) is currently ongoing, comparing atezolizumab with second-line chemotherapy. However, it is not available in the published literature at this time.

The National Comprehensive Cancer Network (NCCN) Bladder Cancer Guidelines (V2. 2017) and 2017 NCCN Drug Compendium currently indicate that atezolizumab may be used as a second line or systemic therapy for locally advanced or metastatic disease (2A designation) under specific conditions.

Non-Small Cell Lung Cancer (NSCLC)

On October 18, 2016 the FDA approved atezolizumab for treatment of metastatic NSCLC with disease progression during or following platinum-containing chemotherapy. The current 2016 prescribing information indicates that "patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving Tecentriq." Similar drugs for this indication are Opdivo and Keytruda. The FDA's approval was based on positive results of the randomized phase III OAK (NCT02008227) and phase II POPLAR (NCT01903993) studies. The OAK trial investigated the safety and effectiveness of atezolizumab as compared to docetaxel in 1225 individuals. The primary analysis population consisted of the first 850 randomized subjects. Median overall survival for the atezolizumab group (n=425) was 13.8 months compared to 9.6 months for those treated with docetaxel (n=425) (Tecentriq PI, 2016). At the time of this writing, the OAK trial is not available in the published literature.

The POPLAR trial (open-label, multicenter, randomized study to investigate the efficacy and safety of atezolizumab compared with docetaxel in patients with non-small cell lung cancer after platinum failure) (NCT01903993) by Fehrenbacher and colleagues (2016) studied the safety and efficacy of atezolizumab versus docetaxel. This phase II trial consisted of individuals with NSCLC who progressed on post-platinum chemotherapy that were recruited from 61 academic medical centers and community oncology practices in 13 countries in Europe and North America. Key inclusion criteria were ECOG performance status 0 or 1, measurable disease by RECIST v1.1, and adequate hematological and end-organ function. Key exclusion criteria were autoimmune or chronic viral diseases, active or untreated CNS metastases, history of pneumonitis, or previous treatment with docetaxel, CD137 agonists, anti-CTLA4, anti-PD-L1, or anti-PD-L1 therapeutic antibodies, or PD-L1-PD1 pathway-targeting agents. Individuals were stratified by PD-L1 tumor-infiltrating immune cell status, histology, and previous lines of therapy, and randomly assigned (1:1) to receive intravenous atezolizumab 1200 mg or docetaxel 75 mg/m2 once every 3 weeks. The primary endpoint was OS in the intention-to-treat population and PD-L1 subgroups at 173 deaths. Between Aug 5, 2013 and March 31, 2014, a total of 144 subjects were randomized to the atezolizumab group, and 143 to the docetaxel group. Of these, 142 individuals received at least one dose of atezolizumab and 135 received docetaxel. OS in the intention-to-treat population was 12.6 months (95% CI, 9.7-16.4) for atezolizumab versus 9.7 months (8.6-12.0) for docetaxel (hazard ratio [HR] 0.73 [95% CI, 0.53-0.99]; p=0.04). OS in individuals without PD-L1 expression in either tumor cells or tumor-infiltrating immune cells in the atezolizumab group was similar to that in the docetaxel group. An increase in OS was associated with increasing PD-L1 expression. In the exploratory analysis, individuals with pre-existing immunity had improved OS with atezolizumab. A total of 11 (8%) subjects in the atezolizumab group discontinued because of adverse events versus 30 (22%) subjects in the docetaxel group. Additionally, 16 (11%) subjects in the atezolizumab group versus 52 (39%) subjects in the docetaxel group had treatment-related grade 3-4 adverse events, and 1 (< 1%) subject in the atezolizumab group versus 3 (2%) subjects in the docetaxel group died from a treatment-related adverse event. The authors concluded that atezolizumab significantly improved survival compared with docetaxel in individuals with previously treated NSCLC. Improvement correlated with PD-L1 immunohistochemistry expression on tumor cells and tumor-infiltrating immune cells, suggesting that PD-L1 expression is predictive for atezolizumab benefit.

The NCCN NSCLC guidelines (V5.2017) and the 2017 NCCN Drug Compendium both indicate that atezolizumab may be used for the treatment of NSCLC following progression of metastatic disease (2A designation) under specific conditions.

Other Potential Uses

Other indications under investigation include breast cancer (García-Teijido, 2016); gastric cancer (Alsina, 2016); renal cancer (McDermott, 2016); colorectal cancer; soft tissue sarcoma, diffuse large B cell lymphoma, follicular lymphoma, hematological malignancies, malignant melanoma (Mahoney, 2015), multiple myeloma and myelodysplastic syndromes. The largest published study from this group is a phase 1 clinical trial by McDermott and colleagues (2016) of 63 individuals with renal cancer treated with atezolizumab. Although initial study results show potential promise, large randomized clinical trials are needed for further evaluation. At this time the published evidence supporting the use of atezolizumab is insufficient to demonstrate safety and efficacy for all uses other than for urothelial and non-small cell lung cancer under specific circumstances.

Background/Overview

Urothelial carcinoma is the most common type of bladder cancer and occurs in the urinary tract system, involving the bladder and related organs. The American Cancer Society estimates that in 2017 there will be approximately 79,030 new cases of bladder cancer (about 60,490 in men and 18,540 in women) and 16,870 deaths from bladder cancer (about 12,240 in men and 4630 in women) in the United States.

Non-small cell lung cancer is the most common type of lung cancer. Lung cancer (both small cell and non-small cell) is the second most common cancer in both men and women (not counting skin cancer). In men, prostate cancer is more common, while in women breast cancer is more common. About 14% of all new cancers are lung cancers. The American Cancer Society's estimates that in 2017 there will be about 222,500 new cases of lung cancer (116,990 in men and 105,510 in women) and 155,870 deaths from lung cancer (84,590 in men and 72,280 in women) in the United States. Lung cancer is by far the leading cause of cancer death among both men and women; about 1 out of 4 cancer deaths are from lung cancer. Each year, more people die of lung cancer than of colon, breast, and prostate cancers combined.

Tecentriq (atezolizumab) 2016 FDA Product Information label includes the following warnings and precautions:

Along with Tecentriq, the FDA simultaneously issued a premarket approval (PMA) for the Ventana PD-L1 (SP142) Assay (Ventana Medical Systems, Tucson, Arizona) as a complementary diagnostic test. The FDA noted that the immunohistochemistry test "may help identify patients who are more likely to respond to treatment." Unlike companion diagnostics, which may be necessary for the effective and safe use of a drug, complementary diagnostics are intended to aid but are not required to guide treatment strategies.

Definitions

Adjuvant treatment: Additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back. Adjuvant therapy may include chemotherapy, radiation therapy, hormone therapy, targeted therapy, or biological therapy.

ECOG Performance Status: A scale used to determine the individual's level of functioning. This scale may also be referred to as the WHO (World Health Organization) or Zubrod score which is based on the following scale:

Line of therapy:

Locally advanced cancer: Cancer that has spread from where it started to nearby tissue or lymph nodes.

Metastatic: The spread of cancer from one part of the body to another. A metastatic tumor contains cells that are like those in the original (primary) tumor and have spread.

Neoadjuvant treatment: Treatment given as a first step to shrink a tumor before the main treatment, which is usually surgery, is given. Examples of neoadjuvant therapy include chemotherapy, radiation therapy, and hormone therapy. It is a type of induction therapy

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

 

J9022

Injection, atezolizumab, 10 mg [Tecentriq]

 

 

ICD-10 Diagnosis

 

 

C34.00-C34.92

Malignant neoplasm of bronchus and lung

 

C61

Malignant neoplasm of prostate

 

C65.1-C65.9

Malignant neoplasm of renal pelvis

 

C66.1-C66.9

Malignant neoplasm of ureter

 

C67.0-C67.9

Malignant neoplasm of bladder

 

C68.0

Malignant neoplasm of urethra

 

Z85.118

Personal history of other malignant neoplasm of bronchus and lung

 

Z85.51

Personal history of malignant neoplasm of bladder

 

Z85.53-Z85.54

Personal history of malignant neoplasm of renal pelvis, ureter

 

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. Alsina M, Moehler M, Hierro C, et al. Immunotherapy for gastric cancer: a focus on immune checkpoints. Target Oncol. 2016; 11(4):469-477.
  2. Balar AV, Galsky MD, Rosenberg JE, et al; IMvigor210 Study Group. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017; 389(10064):67-76.
  3. Fehrenbacher L, Spira A, Ballinger M, et al.; POPLAR Study Group. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016; 387(10030):1837-1846.
  4. García-Teijido P, Cabal ML, Fernández IP, Pérez YF. Tumor-infiltrating lymphocytes in triple negative breast cancer: the future of immune targeting. Clin Med Insights Oncol. 2016; 10(Suppl 1):31-39.
  5. Mahoney KM, Freeman GJ, McDermott DF. The next immune-checkpoint inhibitors: PD-1/PD-L1 blockade in melanoma. Clin Ther. 2015; 37(4):764-782.
  6. McDermott DF, Sosman JA, Sznol M, et al. Atezolizumab, an anti-programmed death-ligand 1 antibody, in metastatic renal cell carcinoma: long-term safety, clinical activity, and immune correlates from a phase Ia study. J Clin Oncol. 2016; 34(8):833-842.
  7. Powles T, Eder JP, Fine GD, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014; 515(7528):558-562.
  8. Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016; 387(10031):1909-1920.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Atezolizumab. In: DrugPoints System [Electronic Version]. Truven Health Analytics. Greenwood Village, Colo. Last updated March 31, 2017. Available at: http://www.micromedexsolutions.com. Accessed on April 10, 2017.
  2. Atezolizumab Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS® ) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised January 25, 2017. Accessed on April 10, 2017.
  3. Hoffmann-La Roche. A randomized phase 3 study of atezolizumab (an engineered anti-PDL1 antibody) compared to docetaxel in patients with locally advanced or metastatic non-small cell lung cancer who have failed platinum therapy - "OAK". NLM Identifier: NCT02008227. Last updated on November 1, 2016. Available at: https://clinicaltrials.gov/ct2/show/record/NCT02008227 . Accessed on April 10, 2017.
  4. National Comprehensive Cancer Network®. NCCN Drugs & Biologic Compendium™ (electronic version). For additional information visit the NCCN website: http://www.nccn.org. Accessed on April 10, 2017.
  5. NCCN Clinical Practice Guidelines in Oncology™. © 2016 National Comprehensive Cancer Network, Inc.  For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on April 10, 2017.
    • Bladder Cancer. V2.2017. Revised February 15, 2017.
    • Non-Small Cell Lung Cancer. V5.2017. Revised March 16, 2017.
  6. U.S. Food and Drug Administration Premarket Approval (PMA) Database. Ventana PD-L1(SP142) CDX Assay. Rockville, MD: FDA. May 18, 2016. Available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P160002. Accessed on April 10, 2017.
  7. Tecentriq™ [Product Information]. South San Francisco, CA. Genentech, Inc. April 2017. Available at: http://www.gene.com/download/pdf/tecentriq_prescribing.pdf. Accessed on May 4, 2017.
Websites for Additional Information
  1. American Cancer Society. Bladder Cancer. Available at: http://www.cancer.org/cancer/bladdercancer/detailedguide/index. Accessed on April 10, 2017.
  2. American Cancer Society. Lung Cancer - Non-Small Cell. Available at: http://www.cancer.org/Cancer/LungCancer-Non-SmallCell/DetailedGuide/index. Accessed on April 10, 2017.
Index

Anti-PD-L1 Monoclonal Antibody
Atezolizumab
MPDL3280A
MPDL 3280A
Tecentriq

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
  12/27/2017 The document header wording updated from “Current Effective Date” to “Publish Date.” Updated Coding section with 01/01/2018 HCPCS changes;  added J9022, removed C9483 deleted 12/31/2017 and NOC codes.
Revised 05/04/2017 Medical Policy & Technology Assessment Committee (MPTAC) review.
Revised 05/03/2017 Hematology/Oncology Subcommittee review. Trademark symbol in title of document replaced with the registered symbol. Medically necessary statements reformatted. Added a medically necessary statement for first-line treatment of locally advanced or metastatic urothelial carcinoma. Added PD-L1 to existing criteria as an agent that the individual has not received treatment with. Rationale, Background and References sections updated.
Revised 11/03/2016 MPTAC review.
Revised 11/02/2016 Hematology/Oncology Subcommittee review. Medically Necessary statement added for metastatic NSCLC. Removed "solid tumors" from the Investigational and Not Medically Necessary list. Description, Rationale, Background, Coding and Reference sections updated.
  10/01/2016 Updated Coding section with 10/01/2016 HCPCS changes.
New 07/27/2016 MPTAC review.
New 07/12/2016 Hematology/Oncology Subcommittee review. Initial document development.