Medical Policy

 

Subject: Avelumab (Bavencio®)
Document #: DRUG.00107 Publish Date:    12/27/2017
Status: Revised Last Review Date:    08/03/2017

Description/Scope

This document addresses the use of avelumab (Bavencio, Pfizer, New York, NY), a programmed death ligand-1 (PD-L1) blocking antibody approved by the United States Food and Drug Administration (FDA) for treatment of metastatic Merkel cell carcinoma and locally advanced or metastatic urothelial carcinoma.

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

Position Statement

Medically Necessary:

Merkel cell Carcinoma:
The use of avelumab is considered medically necessary for the treatment of metastatic Merkel cell carcinoma when all of the following criteria are met:

  1. Individual is 12 years of age or older; and
  2. Has a current Eastern Cooperative Oncology Group (ECOG) performance status of 0-2; and
  3. Has not received treatment with another PD-1 agent (for example, nivolumab or pembrolizumab); and
  4. Not receiving therapy for an autoimmune disease or chronic condition requiring treatment with a systemic immunosuppressant.

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

  1. Being used as a single agent: and
  2. Individual meets one of the following criteria:
    1. Has demonstrated disease progression on or after platinum-containing chemotherapy: or
    2. Has demonstrated disease progression within 12 months of receiving neoadjuvant or adjuvant treatment with platinum-containing chemotherapy; and
  3. Has a current ECOG performance status of 0-2; and
  4. Has not received treatment with another PD-1 agent (for example, nivolumab or pembrolizumab); and
  5. Not receiving therapy for an autoimmune disease or chronic condition requiring treatment with a systemic immunosuppressant.

Investigational and Not Medically Necessary:
The use of avelumab is considered investigational and not medically necessary when the above criteria are not met and for all other uses.

Rationale

Merkel cell carcinoma:
On March 23, 2017, avelumab achieved accelerated approval status by the FDA for the treatment of metastatic Merkel cell carcinoma for individuals age 12 years and older. This approval was based on tumor response and duration of response. Continued approval for this indication may be subject to verification and description of clinical benefit in confirmatory trials which are underway. Avelumab belongs to a group of cancer drugs called checkpoint inhibitors. They act by stimulating the immune system to destroy tumor cells. Avelumab specifically acts to block PD-L1.

The FDA accelerated approval of avelumab was based on a 2016 phase II open-label, single-arm, multicenter trial by Kaufman and colleagues which evaluated the safety and efficacy of avelumab. The participants (n=88) had histologically confirmed metastatic Merkel cell carcinoma (stage IV) and had already received chemotherapy. Participant eligibility included ECOG status of 0 or 1, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, adequate hematological, hepatic, and renal function, and immune-competent status. Exclusion criteria of the study participants included those with autoimmune disease; medical conditions which required systemic immunosuppression; prior transplant of organs or allogeneic stem cell; prior treatment with anti-PD-1, anti-PD-L1 or anti-CTLA-4 antibodies; metastases of the central nervous system; infection with human immunodeficiency virus, hepatitis B or C; or ECOG performance score greater than or equal to 2. The primary endpoint was an objective response (either complete response or partial response) which was assessed by RECIST version 1.1. Avelumab was given intravenously every 2 weeks. The median follow-up was 10.4 months. An objective response was achieved in 28 participants (31.8% [95.9% confidence interval (CI), 21.9-43.1]). Of those participants with an objective response, 8 had complete response and 20 had partial responses. At the time of analysis, responses were ongoing in 23 of 28 subjects. Grade 3 adverse events occurred in 4 participants (lymphopenia, blood creatinine phosphokinase increase, aminotransferase increase, and blood cholesterol increase). Serious adverse events were reported in 5 participants (enterocolitis, infusion-related reaction, aminotransferases increased, chondrocalcinosis, synovitis, and interstitial nephritis). There were no grade 4 adverse events or treatment-related deaths reported.

Urothelial carcinoma:
In May 2017, the FDA expanded the label indications for avelumab to include those individuals with locally advanced or metastatic urothelial carcinoma. This accelerated approval was based on tumor response rate and duration of response for those individuals who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy (Product Information Label, 2017). The FDA approval was based on the JAVELIN solid tumor trial, an open-label, single-arm study of avelumab in 242 participants who had metastatic or locally advanced urothelial carcinoma. The participants had disease progression on or after platinum-containing chemotherapy or had disease progression within 12 months of treatment with a platinum-containing neoadjuvant or adjuvant chemotherapy regimen. The participants received avelumab every 2 weeks until signs of progression or unacceptable toxicity. Response to tumor was assessed every 6 weeks. Efficacy outcome measures included overall response rate using RECIST v1.1 and duration of response and was evaluated for a minimum of both 13 weeks and 6 months. A total of 226 participants had a minimum of 13 weeks of follow-up and 161 participants had a minimum of 6 months of follow-up. At the 13 weeks follow-up, 30 participants had an overall response, 9 with complete response and 21 with partial response. At the 6 month follow-up, 26 participants had an overall response, 9 with complete response and 17 with partial response. At both follow-up times (13 weeks and 6 months), 22 participants had an ongoing response of 6 months or longer and 4 participants had ongoing responses of 12 months or longer.

In a phase Ib expansion trial, Apolo and colleagues (2017) used 44 individuals with metastatic urothelial carcinoma from the JAVELIN study to report on a dose-expansion study. The included participants had metastatic urothelial carcinoma of the renal pelvis, ureter, urinary bladder, or urethra. Eligible participants had relapsed, refractory, or progressive disease as measured by RECIST v1.1 after at least one prior line of treatment. The primary outcome was safety and tolerability of avelumab with a primary endpoint of occurrence of dose-limiting toxicities during the first 3 weeks of treatment. Secondary endpoints included overall response, duration of response, progression-free survival, overall survival, and evaluation of PD-L1 expression. Participants were followed for a median of 16.5 months. Participants received avelumab every 2 weeks with a median of 7 doses and a median duration of 14.1 weeks. All participants had an adverse event with 29 participants having a treatment-related adverse event. The most common treatment-related adverse events were fatigue (n=9), infusion-related reaction (n=9), asthenia (n=5), and nausea (n=5). Complete response was found in 5 participants, partial response in 3 participants, stable disease in 15 participants, progressive disease in 15 participants and 6 participants were not available for evaluation. The median progression-free survival was 11.6 weeks (95% CI, 6.1-17.4). Median overall survival was 13.7 months (95% CI, 8.5-not estimable). There was a 12-month overall survival rate of 54.3% (95% CI, 37.9-68.1). Confirmed overall response rate was 18.2% (95% CI, 8.2-32.7). Median duration of response was not reached. A total of 37 participants were able to be evaluated for PD-L1 expression and 7 of 8 responding participants had PD-L1-positive tumors.

The 2017 National Comprehensive Cancer Network® Clinical Practice Guidelines in Oncology (NCCN Guidelines® ) for bladder cancer gives a 2A recommendation for avelumab for locally or advanced metastatic disease for urothelial carcinoma.

Background/Overview

Merkel cell carcinoma:
Skin cancer is the most common type of cancer in the United States. Merkel cell carcinoma is a rare, aggressive type of skin cancer. It is considered to be aggressive because it can grow quickly and spread and it returns after treatment. According to the American Cancer Society (2016), it is estimated there are 1500 new cases of Merkel cell carcinoma diagnosed each year with an overall 5-year survival rate of 30% to 64%. A major risk factor for Merkel cell carcinoma is a history of extensive sun exposure, particularly to the head and neck. Clinical suspicion of Merkel cell carcinoma is rare as the primary tumor lacks distinguishing characteristics. The initial workup of a suspicious lesion starts with an exam of the skin and lymph nodes following a biopsy. The primary treatment for Merkel cell carcinoma is surgery. The literature for the benefits of radiation therapy has been mixed and the literature is sparse on the use of chemotherapy for Merkel cell carcinoma.

Urothelial carcinoma:
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.

Avelumab (Bavencio) 2017 FDA Product Information label includes the following warnings and precautions:
Immune-mediated adverse reactions:

Additional precautions:

Information for use in specific populations:

Adverse reactions:

The most common adverse reactions for those with metastatic Merkel cell carcinoma (reported in less than or equal to 20% of people) included fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reaction, rash, decreased appetite, and peripheral edema. The most common adverse reactions for those with locally advanced or metastatic urothelial carcinoma (reported in less than or equal to 20% of people) included fatigue, infusion-related reaction, musculoskeletal pain, nausea, decreased appetite, and urinary tract infection.

Definitions

Disease progression: Cancer that continues to grow or spread.

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:

Merkel cell carcinoma: A rare, aggressive skin cancer.

Metastasis: A cancer that has spread 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 beyond the local lymph nodes.

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

Urothelial carcinoma: A type of bladder cancer which occurs in the urinary tract system.

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

 

J9023

Injection, avelumab, 10 mg [Bavencio]

 

 

ICD-10 Diagnosis

 

C4A.0-C4A.9

Merkel cell carcinoma

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

C7B.1

Secondary Merkel cell carcinoma

Z85.51

Personal history of malignant neoplasm of bladder

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. Apolo AB, Infante JR, Balmanoukian A, et al. Avelumab, an anti-programmed death-ligand 1 antibody, in patients with refractory metastatic urothelial carcinoma: results from a multicenter, phase Ib study. J Clin Oncol. 2017 Apr 4:JCO2016716795. [Epub ahead of print].
  2. Hamilton G, Rath B. Avelumab: combining immune checkpoint inhibition and antibody-dependent cytotoxicity. Expert Opin Biol Ther. 2017; 17(4):515-523.
  3. Kaufman HL, Russell J, Hamid O, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol. 2016; 17(10):1374-1385.
  4. Llombart B, Kindem S, Chust M. Merkel Cell Carcinoma: An update of key imaging techniques, prognostic factors, treatment, and follow-up. Actas Dermosifiliogr. 2017; 108(2):98-107.
  5. Nghiem P, Kaufman HL, Bharmal M, et al. Systematic literature review of efficacy, safety and tolerability outcomes of chemotherapy regimens in patients with metastatic Merkel cell carcinoma. Future Oncol. 2017 Mar 28.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. American Cancer Society. Cancer facts & figures 2017. Atlanta: American Cancer Society; 2017.
  2. Avelumab [Product Information]. New York, NY. Pfizer; May 9, 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761078s000lbl.pdf . Accessed on May 30, 2017.
  3. NCCN Clinical Practice Guidelines in Oncology® . © 2017 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on May 25, 2017.
    • Bladder Cancer (V.5.2017). Revised May 25, 2017.
    • Merkel Cell Carcinoma (V.1.2017). Revised October 3, 2016.
Websites for Additional Information
  1. American Academy of Dermatology. Merkel cell carcinoma overview. Available at: https://www.aad.org/public/diseases/skin-cancer/merkel-cell-carcinoma . Accessed on May 25, 2017.
  2. American Cancer Society. Bladder cancer. 2017. Available at: https://www.cancer.org/cancer/bladder-cancer/about/key-statistics.html . Accessed on May 25, 2017.
  3. American Cancer Society. Merkel cell skin cancer. 2016. Available at: https://www.cancer.org/cancer/merkel-cell-skin-cancer.html . Accessed on May 25, 2017.
  4. National Cancer Institute. Merkel cell carcinoma treatment. Available at: https://www.cancer.gov/types/skin/hp/merkel-cell-treatment-pdq . Accessed on May 25, 2017.
Index

Anti-PD-L1 Monoclonal Antibody
Avelumab
Bavencio
Merkel cell carcinoma
Urothelial carcinoma

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 J9023, removed C9491 deleted 12/31/2017 and NOC codes.
  10/01/2017 Updated Coding section with 10/01/2017 HCPCS changes.
Revised 08/03/2017 Medical Policy & Technology Assessment Committee (MPTAC) review.
Revised 07/24/2017 Hematology/Oncology Subcommittee review. Added MN criteria for urothelial carcinoma. Updated Description/Scope, Rationale, Definitions, Coding, References, and Index sections.
New 05/04/2017 MPTAC review.
New 05/03/2017 Hematology/Oncology Subcommittee review. Initial document development.