Commercial

Avelumab (Bavencio®)
08.01.64

Policy


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NoteNew policy number 08.01.64 supersedes 08.01.20j for avelumab (Bavencio®​​​) 



The Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition.

MEDICALLY NECESSARY

MERKEL CELL CARCINOMA
Avelumab (Bavencio®) is considered medically necessary and, therefore, covered in adult and pediatric individuals 12 years and older with metastatic (i.e., disseminated, clinical M1 disease) Merkel cell carcinoma with or without surgery and/or radiation therapy and an Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (National Comprehensive Cancer Network [NCCN] alternative preferred regimen).

UROTHELIAL CARCINOMA
Avelumab (Bavencio®) is considered medically necessary and, therefore, covered as single-agent therapy for the treatment of one of the following indications:
  • Locally advanced or metastatic urothelial carcinoma in individuals with disease progression, in one of the following scenarios:
    • During or post-platinum-containing chemotherapy
    • Within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy
  • Recurrent or metastatic primary carcinoma of the urethra that is not recurrent stage T3-4 disease and is without palpable inguinal lymph nodes, as a single-agent, second-line systemic therapy, post-platinum containing chemotherapy (NCCN alternative preferred)
  • Metastatic urothelial carcinoma of the prostate or metastatic upper genitourinary tract tumors, as a single-agent, second-line systemic therapy, post-platinum containing chemotherapy (NCCN alternative preferred)
  • Locally advanced or metastatic bladder cancer, as a single-agent, second-line systemic therapy, post-platinum containing chemotherapy (NCCN alternative preferred) in any of the following clinical stages:
    • Stage IIIB (T1-T4a, N2,3) disease following partial response or progression after primary treatment with downstaging systemic therapy or concurrent chemoradiotherapy
    • Stage IVA (T4b, any N, M0) disease if tumor is present following reassessment of tumor status after primary treatment with first-line systemic therapy or concurrent chemoradiotherapy
    • Stage IVA (any T, any N, M1a) disease if stable disease or progression following reassessment of tumor status after primary treatment with first-line systemic therapy
    • Stage IVB (any T, any N, M1b) disease
    • Muscle invasive local recurrence or persistent disease in a preserved bladder
    • Metastatic or local recurrence post cystectomy

RENAL CELL CARCINOMA
Avelumab (Bavencio®) in combination with axitinib is considered medically necessary and, therefore, covered for individuals with advanced renal cell carcinoma and ECOG performance status 0-1, as first-line therapy for relapse or stage IV disease and clear cell histology.

EXPERIMENTAL/INVESTIGATIONAL

All other uses for avelumab (Bavencio®) are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the Company medical policy on off-label coverage for prescription drugs and biologics.

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the drug.


Guidelines


BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, avelumab (Bavencio®) is covered under the medical benefits of the Company’s products when the medical necessity criteria listed in this medical policy are met.

THE EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) PERFORMANCE STATUS

The Eastern Cooperative Oncology Group (ECOG), established in 1955, was one of the first groups to coordinate multicenter cancer clinical trials. The National Cancer Institute (NCI) is the primary funding source, and ECOG has evolved from a small consortium of institutions in the eastern United States to one of the largest clinical cancer research organizations in the country. As part of their work in the treatment of cancer, ECOG has developed the ECOG Performance Status (EPS), originally published in 1982 in the American Journal of Clinical Oncology. The use of the scales and the criteria in the EPS allows clinicians and researchers to determine an individual’s disease progression in terms of how the activities of daily living (ADL) are affected.
ECOG Performance Status
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (eg, light house work, office work)
2
Ambulatory and capable of all self care but unable to carry out any work activities. Up and about more than 50 percent of waking hours
3
Capable of only limited self care, confined to bed or chair more than 50 percent of waking hours
4
Completely disabled. Cannot carry on any self care: Totally confined to bed or chair
5
Dead
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol.1982;5(6):649-655.

TNM STAGING SYSTEM

According to the American Joint Committee on Cancer (AJCC), the TNM system is based on 3 key pieces of information:
  • T describes how far the main (primary) tumor has grown through the bladder wall and whether it has grown into nearby tissues.
  • N indicates any cancer spread to lymph nodes near the bladder. Lymph nodes are bean-sized collections of immune system cells, to which cancers often spread first.
  • M indicates whether or not the cancer has spread (metastasized) to distant sites, such as other organs or lymph nodes that are not near the bladder.

Numbers or letters appear after T, N, and M to provide more details about each of these factors. Higher numbers mean the cancer is more advanced.

American Cancer Society. Bladder cancer stages. Last Revised: 05/23/2016.

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

Avelumab (Bavencio®) was approved by the FDA on March 23, 2017 for the treatment of adult and pediatric individuals ages 12 years and older with metastatic Merkel cell carcinoma. Supplemental approvals for avelumab (Bavencio®) have since been issued by the FDA. Avelumab (Bavencio®) is administered as an intravenous infusion over 60 minutes.

PEDIATRIC USE

The safety and effectiveness of Avelumab (Bavencio®) have not been established in pediatric individuals for indications other than metastatic Merkel cell carcinoma.


Description


In a normal immune response, the body can recognize the presence of tumors and mount a response to eradicate them. The process of eradicating a tumor begins with antigen-presenting cells that gather and process the antigens released by tumors. This activates the T-cells, which proliferate and attack the tumor.

Tumors have learned to evade the normal immune response by exploiting the immune checkpoint pathway. The Programmed Death Receptor-1 (PD-1) is a checkpoint protein expressed on the membrane of activated T-cells. The Programmed Death-Ligand 1 (PD-L1) and The Programmed Death-Ligand 2 (PD-L2) are checkpoint proteins expressed on tumor cells and tumor-infiltrating immune cells. When PD-L1 and PD-L2 attach to PD-1 receptors on the T-cells, the T-cells become inhibited and won't attack the tumor; thus, the tumor can continue to proliferate.

MERKEL CELL CARCINOMA (MCC)

Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer with an incidence of approximately 1,500 cases per year in the United States, with 12 percent of these cases presenting at stage 4. Merkel cell carcinoma has a high mortality rate, with a five-year survival of only 30-64 percent. Common sites of metastasis are the lymph nodes and distant skin sites.

On March 23, 2017, the US Food and Drug Administration (FDA) granted approval for avelumab (Bavencio®) for the treatment of adult and pediatric individuals 12 years and older with metastatic Merkel cell carcinoma (MCC). The safety and efficacy of avelumab (Bavencio®) was demonstrated in the JAVELIN Merkel 200 trial (NCT02155647), a phase 2, open-label, single-arm, multi-center study conducted in individuals with histologically confirmed metastatic MCC whose disease had progressed on or after chemotherapy administered for distant metastatic disease. The trial excluded individuals with autoimmune disease; medical conditions requiring systemic immunosuppression; prior organ or allogeneic stem cell transplantation; prior treatment with anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibodies; CNS metastases; infection with HIV, hepatitis B, or hepatitis C; or ECOG performance score ≥ 2.

Study participants received avelumab (Bavencio®) 10 mg/kg as an intravenous infusion over 60 minutes every two weeks until disease progression or unacceptable toxicity. Individuals with radiological disease progression not associated with significant clinical deterioration, defined as no new or worsening symptoms, no change in performance status for greater than two weeks, and no need for salvage therapy, could continue treatment. Tumor response assessments were performed every six weeks. The major efficacy outcome measures were confirmed overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as assessed by a blinded independent central review committee (IRC) and IRC-assessed duration of response. To note, RECIST provides a standardized set of rules for response assessment using tumor shrinkage, based upon imaging modalities that are globally available and interpretable by most clinicians. This standardization, and the rules and criteria established, provide a framework for reproducible analysis and reporting of changes in tumor size. The reproducibility of these criteria and the correlations with historical trial results serve an important purpose in drug discovery. The efficacy analysis was conducted when the last patient enrolled had completed 12 months of follow-up.

A total of 88 individuals were enrolled. Baseline characteristics were a median age of 73 years (range: 33 to 88), and the ECOG performance score was 0 (56 percent) or 1 (44 percent). Seventy-five percent of individuals were 65 years or older, 35 percent were 75 or older, and 3 percent were 85 or older. Sixty-five percent of individuals were reported to have had one prior anti-cancer therapy for metastatic MCC and 35 percent had two or more prior therapies. Fifty-three percent of individuals had visceral metastases. All individuals had tumor samples evaluated for PD-L1 expression; of these, 66 percent were PD-L1-positive (≥ 1 percent of tumor cells), 18 percent were PD-L1 negative, and 16 percent had non-evaluable results by an investigational immunohistochemistry assay. Archival tumor samples were evaluated for Merkel cell polyomavirus (MCV) using an investigational assay; of the 77 individuals with evaluable results, 52 percent had evidence of MCV.


The study showed an overall response rate (ORR) of 33 percent (95 percent confidence interval [CI]: 23.3–43.8 percent). Eleven percent of individuals experienced a complete response (95 percent CI: 6.6-19.9 percent) and 22 percent of individuals experienced a partial response (95 percent CI: 13.5-31.7 percent). Tumor responses were durable, with 86 percent of responses lasting for at least six months (n=25). Forty-five percent of responses lasted at least 12 months (n=13). Duration of response ranged from 2.8 to over 23.3 months.

This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.


UROTHELIAL CARCINOMA

The urinary tract is composed of the the renal pelvis, ureters, bladder, and urethra. The innermost lining of the urinary tract is composed of urothelial cells. Urothelial carcinoma, also known as transitional cell carcinoma (TCC), is the ninth most common cancer overall worldwide and it accounts for 90 percent of all bladder cancers. Squamous cell carcinoma comprises 1-7 percent of upper tract urothelial tumors. Adenocarcinoma accounts for less than 1 percent of upper tract tumors. Urothelial tumors of the renal pelvis and ureters are rare. Tumors of the renal pelvis account for approximately 5 percent of all urothelial tumors of the urinary tract.

On May 9, 2017, avelumab (Bavencio®) was approved by the US FDA for the treatment of individuals with locally advanced or metastatic urothelial carcinoma (UC) who have disease progression during or following platinum-containing chemotherapy, or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

The efficacy and safety of avelumab (Bavencio®) was demonstrated in the UC cohorts of the JAVELIN Solid Tumor trial, an open-label, single-arm, multi-center study that included 242 individuals with locally advanced or metastatic UC with disease progression on or after platinum-containing chemotherapy or who had disease progression within 12 months of treatment with a platinum-containing neoadjuvant or adjuvant chemotherapy regimen. Individuals with active or history of central nervous system metastasis; other malignancies within the last five years; organ transplant; conditions requiring therapeutic immune suppression; or active infection with HIV, hepatitis B, or hepatitis C were excluded. Individuals with autoimmune disease, other than type 1 diabetes, vitiligo, psoriasis, or thyroid disease that did not require immunosuppressive treatment, were excluded. Individuals were included regardless of their PD-L1 status.


Study participants received avelumab (Bavencio®) at a dose of 10 mg/kg intravenously every two weeks until radiographic or clinical progression or unacceptable toxicity. Tumor response assessments were performed every six weeks. Efficacy outcome measures included confirmed overall response rate (ORR), as assessed by an Independent Endpoint Review Committee (IERC) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, and duration of response (DOR). Efficacy was evaluated in individuals who were followed for a minimum of both 13 weeks and 6 months at the time of data cut-off.


Baseline demographic and disease characteristics for the 226 individuals with a minimum of 13 weeks of follow-up were median age 68 years (range: 30 to 89), and 66 percent of individuals had an ECOG performance status 0 or 1. Forty-four percent of individuals had non-bladder urothelial carcinoma including 23 percent of individuals with upper tract disease, and 83 percent of individuals had visceral metastases (baseline target and/or non-target lesions present outside of the lymph nodes). Nine individuals (4 percent) had disease progression following prior platinum-containing neoadjuvant or adjuvant therapy only. Forty-seven percent of individuals only received prior cisplatin-based regimens, 32 percent received only prior carboplatin-based regimens, and 20 percent received both cisplatin and carboplatin-based regimens. At baseline, 17 percent of individuals had a hemoglobin < 10 g/dL and 34 percent of individuals had liver metastases.


The median time to response was 2.0 months (range:1.3 to 11.0) among individuals followed for either > 13 weeks or > 6 months. Using a clinical trial assay to assess PD-L1 staining, with 16 percent of individuals not evaluable, there were no clear differences in response rates based on PD-L1 tumor expression. Among the total 30 responding individuals followed for > 13 weeks, 22 individuals (73 percent) had an ongoing response of six months or longer and 4 individuals (13 percent) had ongoing responses of 12 months or longer. Among the total 26 responding individuals followed for > 6 months, 22 individuals (85 percent) had ongoing responses of 6 months or longer and 4 individuals (15 percent) had ongoing responses of 12 months or longer.


For disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.


RENAL CELL CARCINOMA (RCC)

In adults, renal cell carcinoma (RCC) accounts for 80-95 percent of all primary kidney cancers. When diagnosed, 65 percent of individuals have localized disease confined to the kidney. At 75-85 percent, the clear cell subtype of RCC accounts for the highest percentage among other subtypes of the disease.

The efficacy and safety of avelumab (Bavencio®) in combination with axitinib was demonstrated in the JAVELIN Renal 101 trial (NCT02684006), a phase 3, randomized, multicenter, open-label, study of avelumab (Bavencio®) in combination with axitinib in 886 individuals with untreated advanced RCC regardless of tumor PD-L1 expression [intent-to-treat (ITT) population]. Individuals with autoimmune disease or conditions requiring systemic immunosuppression were excluded.

Randomization was stratified according to Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) (0 vs. 1) and region (United States vs. Canada/Western Europe vs. the rest of the world). Participants were randomized (1:1) to one of the following treatment arms:

  • Avelumab (Bavencio®) 10 mg/kg intravenous infusion every two weeks in combination with axitinib 5 mg twice daily orally (N=442). Individuals who tolerated axitinib 5 mg twice daily without Grade 2 or greater axitinib-related adverse events for two consecutive weeks could increase to 7 mg and then subsequently to 10 mg twice daily. Axitinib could be interrupted or reduced to 3 mg twice daily and subsequently to 2 mg twice daily to manage toxicity.
  • Sunitinib 50 mg once daily orally for 4 weeks followed by two weeks off (N=444) until radiographic or clinical progression or unacceptable toxicity.

Treatment with avelumab (Bavencio®) and axitinib continued until RECIST version 1.1 defined progression of disease by Blinded Independent Central Review (BICR) assessment or unacceptable toxicity. Administration of avelumab (Bavencio®) and axitinib was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumor status was performed at baseline, after randomization at 6 weeks, then every 6 weeks thereafter up to 18 months after randomization, and every 12 weeks thereafter until documented confirmed disease progression by BICR.

Baseline characteristics were a median age of 61 years (range: 27 to 88), 38 percent of individuals were 65 years or older, and the ECOG PS was 0 (63 percent) or 1 (37 percent), respectively. Individual distribution by International Metastatic Renal Cell Carcinoma Database (IMDC) risk groups was 21 percent favorable, 62 percent intermediate, and 16 percent poor.


The major efficacy outcome measures were progression-free survival (PFS), as assessed by an BICR using RECIST v1.1 and overall survival (OS) in individuals with PD-L1-positive tumors using a clinical trial assay (PD-L1 expression level ≥ 1 percent). Since PFS was statistically significant in individuals with PD-L1-positive tumors [HR 0.61 (95 percent CI: 0.48, 0.79)], it was then tested in the ITT population and a statistically significant improvement in PFS in the ITT population was also demonstrated.


Among individuals with previously untreated advanced RCC, treatment with avelumab (Bavencio®) plus axitinib continued to result in a statistically significant improvement in PFS versus sunitinib; OS data were still immature.


OFF-LABEL INDICATIONS

There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.



References


American Cancer Society. Bladder cancer stages. [American Cancer Society Web site]. 01/30/2019. Available at: http://www.cancer.org/cancer/bladdercancer/detailedguide/bladder-cancer-staging. Accessed June 18, 2020.

American Cancer Society. What is bladder cancer? [American Cancer Society Web site]. 01/30/2019. Available at:
http://www.cancer.org/cancer/bladdercancer/detailedguide/bladder-cancer-what-is-bladder-cancer. Accessed June 18, 2020.

Avelumab (Bavencio®). American Hospital Formulary Service (AHFS). Drug Information 2020. [Lexicomp Online Web Site]. 03/02/2020. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed June 18, 2020.

Avelumab (Bavencio). Lexi-Drugs Compendium. [Lexicomp Web site]. 06/18/2020. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed June 18, 2020.

Avelumab (Bavencio® ). Micromedex Solutions. [Micromedex® Web site]. 12/16/2019. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed June 18, 2020.

Avelumab (Bavencio®). Package insert. EMD Serona, Inc. Rockland, MA. October 2019. Available at: https://www.bavencio.com/en_US/for-us-healthcare-professionals.html. Accessed June 18, 2020.

Bellmunt J. Treatment of metastatic urothelial cancer of the bladder and urinary tract. Up to Date. [UpToDate Web site]. 04/02/2020. Available at:https://www.uptodate.com/contents/treatment-of-metastatic-urothelial-cancer-of-the-bladder-and-urinary-tract?source=search_result&search=tecentriq&selectedTitle=4~22 [via subscription only]. Accessed June 18, 2020.

National Cancer Institute (NCI). NCI dictionary of cancer terms. RECIST. [Cancer.gov Web site]. Available at:
https://www.cancer.gov/publications/dictionaries/cancer-terms/def/recist#:~:text=A standard way to measure,CT scans, or MRI scans. Accessed June 18, 2020.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 2.2020. Kidney Cancer. [NCCN Website]. 08/05/2019. Available at:
https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf [via free subscription only]. Accessed June 18, 2020.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 2.2019. Merkel Cell Carcinoma. [NCCN Website]. 01/18/2019. Available at: https://www.nccn.org/professionals/physician_gls/pdf/mcc.pdf [via free subscription]. Accessed June 18, 2020.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 02.2019. Bladder cancer. [NCCN Website]. 04/04/2019. Available at: https://www.nccn.org/professionals/physician_gls/f_guidelines.asp#bladder [via free subscription only]. Accessed June 18, 2020.

National Comprehensive Cancer Network (NCCN). NCCN Drugs & Biologics Compendium.avelumab (Bavencio®). [NCCN Web site]. May 2020. Available at: https://www.nccn.org/professionals/drug_compendium/content/ . Accessed June 18, 2020.

National Institutes of Health. Clinical trials: A phase II, open label, multicenter trial to investigate the clinical activity and safety of avelumab (MSB0010718C) in subjects with merkel cell carcinoma (NCT02155647 ). [Clinical Trials Web site]. 06/04/2014. Updated 04/13/2020. Available at:
https://clinicaltrials.gov/ct2/show/results/NCT02155647?view=results. Accessed June 18, 2020.

National Institutes of Health. Clinical trials: A phase 3, multicenter, multinational, randomized, open-label, parallel-arm study of avelumab (msb0010718c) plus best supportive care versus best supportive care alone as a maintenance treatment in patients with locally advanced or metastatic urothelial cancer whose disease did not progress after completion of first-line platinum-containing chemotherapy (NCT02603432). [Clinical Trials Web site]. 11/11/2015. Updated 06/16/2020. Available at: https://clinicaltrials.gov/ct2/show/NCT02603432. Accessed June 18, 2020.

National Institutes of Health. Clinical trials: A phase 3, multinational, randomized, open-label, parallel-arm study of avelumab (msb0010718c) in combination with axitinib (inlyta(registered)) versus sunitinib (sutent(registered)) monotherapy in the first-line treatment of patients with advanced renal cell carcinoma (NCT02684006). [Clinical Trials Web site]. 02/17/2016. Updated 02/25/2020. Available at:
https://clinicaltrials.gov/ct2/show/NCT02684006 . Accessed June 18, 2020.

Sachdeva K, Curti B, Jana BRP. Renal Cell Carcinoma. [Medscape Web site]. 04/10/2019. Available at: http://emedicine.medscape.com/article/281340-overview#showall. Accessed June 18, 2020.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Drugs @FDA. Avelumab (Bavencio) Prescribing Information. [FDA Web site]. 05/14/2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761049s006lbl.pdf. Accessed June 18, 2020.


Coding

CPT Procedure Code Number(s)

N/A

ICD - 10 Procedure Code Number(s)
N/A

ICD - 10 Diagnosis Code Number(s)
See Attachment A

HCPCS Level II Code Number(s)
J9023 Injection, avelumab, 10 mg

Revenue Code Number(s)




Coding and Billing Requirements


Policy History

9/14/2020
9/14/2020
08.01.64
Medical Policy Bulletin
Commercial
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No