Notification



Notification Issue Date:



Medical Policy Bulletin


Title:Ramucirumab (Cyramza®)

Policy #:08.01.25c

This policy is applicable to the Company’s commercial products only. Policies that are applicable to the Company’s Medicare Advantage products are accessible via a separate Medicare Advantage policy database.


The Company makes decisions on coverage based on Policy Bulletins, benefit plan documents, and the member’s medical history and condition. Benefits may vary based on contract, and individual member benefits must be verified. The Company determines medical necessity only if the benefit exists and no contract exclusions are applicable.

When services can be administered in various settings, 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. This decision is based on the member’s current medical condition and any required monitoring or additional services that may coincide with the delivery of this service.

This Medical Policy Bulletin document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy Bulletin will be reviewed regularly and be updated as scientific and medical literature becomes available. For more information on how Medical Policy Bulletins are developed, go to the About This Site section of this Medical Policy Web site.



Policy

MEDICALLY NECESSARY

Coverage is subject to the terms, conditions, and limitations of the member's contract.

Ramucirumab (Cyramza®) is considered medically necessary and, therefore, covered for any of the following indications when the corresponding criteria are met:

COLORECTAL CANCERS
  • In combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil) for the treatment of metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.
  • Primary treatment for unresectable metachronous metastases in individuals previously treated with adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) within the past 12 months
    • in combination with irinotecan
    • in combination with FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen
  • Subsequent therapy for progression of unresectable advanced or metastatic disease in combination with irinotecan or with FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen in individuals not previously treated with irinotecan-based therapy

ESOPHAGEAL, ESOPHAGOGASTRIC JUNCTION AND GASTRIC CANCERS
  • As a single agent, or in combination with paclitaxel for the treatment of advanced or metastatic gastric or gastroesophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.
  • As a single agent, or in combination with paclitaxel as a National Comprehensive Cancer Network (NCCN)-preferred second-line or subsequent, palliative therapy for individuals who are not surgical candidates or have unresectable locally advanced, recurrent or metastatic esophageal adenocarcinoma, esophagogastric junction adenocarcinoma, or gastric adenocarcinoma who have a Karnofsky performance score ≥60% or ECOG performance status ≤2.

HEPATOCELLULAR CARCINOMA
Subsequent treatment as a single agent for progressive disease in individuals with Alpha-fetoprotein (AFP*) ≥ 400 ng/mL only, who meet any of the following criteria:
  • Unresectable disease and not a transplant candidate
  • Inoperable by performance status or comorbidity, or have local disease or local disease with minimal extrahepatic disease only
  • Metastatic disease or extensive liver tumor burden

*Alpha-fetoprotein (AFP) is an oncofetal protein produced by hepatocellular carcinoma.

NON-SMALL CELL LUNG CANCER (NSCLC)
  • In combination with docetaxel for the treatment of metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy.
    • Individuals with EGFR or ALK genomic tumor aberrations should have disease progression on a US Food and Drug Administration (FDA)--approved therapy (e.g., erlotinib, crizotinib) prior to receiving ramucirumab (Cyramza®).
  • As subsequent therapy in combination with docetaxel (if not previously given) for recurrent, advanced or metastatic NSCLC when the individual has ECOG performance status 0-2


EXPERIMENTAL/INVESTIGATIONAL

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.

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

BLACK BOX WARNINGS

Refer to the specific manufacturer's prescribing information for any applicable Black Box Warnings.

PEDIATRIC USE

The safety and effectiveness of ramucirumab (Cyramza®) in pediatric individuals have not been established.

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.

THE KARNOFSKY PERFORMANCE STATUS

The Karnofsky Performance Status (KPS) is a standard way of measuring the ability of individuals with cancer to perform ordinary tasks. Performance scores range from 0 to 100; a higher score indicates that the individual is better able to perform activities. KPS may be used to determine an individual's prognosis, to measure changes in an individual's ability to function, or to decide if an individual can participate in a clinical trial.

The Karnofsky Performance Status Scale
100 percentNormal, no complaints; no signs of disease
90 percentCapable of normal activity; few symptoms or signs of disease
80 percentNormal activity with some difficulty; some symptoms or signs of disease
70 percentCaring for self; not capable of normal activity or work
60 percentRequiring some help; can take care of most personal requirements
50 percentRequires help often; requires frequent medical care
40 percentDisabled; requires special care and help
30 percentSeverely disabled, but no risk of death
20 percentVery ill; requires supportive measures or treatment
10 percentMoribund; rapidly progressive fatal disease processes
0 percentDeath

BENEFIT APPLICATION

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

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

Ramucirumab (Cyramza®) was approved by the FDA on April 21, 2014 for the treatment of advanced gastric cancer or gastroesophageal junction adenocarcinoma, as a single-agent after prior fluoropyrimidine- or platinum-containing therapy. Supplemental approvals for ramucirumab (Cyramza®) have since been issued by the FDA.

Description

Ramucirumab (Cyramza®) is a recombinant human IgG1 monoclonal antibody that blocks the binding of vascular endothelial growth factor (VEGF) receptor 2 to VEGFR ligands (VEGF-A, VEGF-C, and VEGF-D). By attaching itself to the VEGF receptor 2 of cancer cells, ramucirumab (Cyramza®) is able to prevent the receptor from being activated, thus inhibiting proliferation and migration of the cells, and inhibiting angiogenesis (the formation of new blood vessels).

The US Food and Drug Administration (FDA) has issued several approvals for its use, including the treatment of:
  • Metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine, when given in combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil)
  • Advanced or metastatic, gastric or gastroesophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy, when given as a single agent or in combination with paclitaxel
  • Metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy, when given in combination with docetaxel


PEER-REVIEWED LITERATURE

SUMMARY
Colorectal Cancer

In April 2015, the FDA approved the use of ramucirumab (Cyramza®) in combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil) for the treatment of individuals with metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. This indication was based on a multinational, randomized, double-blind, study of ramucirumab (Cyramza®) plus FOLFIRI versus placebo plus FOLFIRI performed in individuals with mCRC with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (N=1072). Those in the ramucirumab (Cyramza®) plus FOLFIRI group had a statistically significant improvement in median overall survival (13.3% vs 11.7%) and median progression-free survival (5.7 vs 4.5 months) compared to the placebo plus FOLFIRI group.

Gastric or Gastroesophageal Junction Adenocarcinoma

The initial FDA approval for ramucirumab (Cyramza®) in April 2014 was for the treatment of advanced or metastatic, gastric or gastroesophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy, as a single agent, or in combination with paclitaxel. Studies on which the approval was based are listed below.

Monotherapy
A multinational, randomized, double-blind, multicenter study of ramucirumab (Cyramza®) plus best supportive care (BSC) versus placebo plus BSC was performed in 355 individuals (randomized 2:1) with locally advanced or metastatic gastric cancer (including adenocarcinoma of the gastroesophageal junction [GEJ]) who previously received platinum- or fluoropyrimidine-containing chemotherapy. Results of this trial reported ramucirumab (Cyramza®) monotherapy, significantly improved median overall survival (5.2 vs 3.8 months) and median progression-free survival (2.1 vs 1.3 months) when compared with placebo, but did not affect the response rates in individuals with metastatic or unresectable, locally recurrent gastric or gastroesophageal junction adenocarcinoma.

Combination Therapy with Paclitaxel
Another multinational, randomized, double-blind study randomized (1:1) 665 individuals with locally advanced or metastatic gastric cancer (including adenocarcinoma of the gastroesophageal junction) who had previously received platinum- and fluoropyrimidine-containing chemotherapy. The study reported ramucirumab (Cyramza®) plus paclitaxel significantly improved median overall survival (9.6 vs 7.4 months), median progression-free survival (4.4 vs 2.9 months), and objective response rate (28% vs 16%) when compared with placebo plus paclitaxel. The quality of life measurement was similar in both arms.

Hepatocellular Carcinoma

The placebo-controlled REACH trial had suggested a potential survival benefit in a subset of patients with hepatocellular carcinoma (HCC) who were previously treated with sorafenib and had high serum levels of alfa-fetoprotein (AFP). In a preliminary report of the follow-up placebo-controlled REACH-2 trial, which was restricted to patients with AFP >400 ng/mL, second-line ramucirumab improved overall survival. However, the magnitude of benefit over placebo alone was numerically less than that seen in the REACH trial high AFP subset (1.2 versus 3.6 months). The objective response rate with ramucirumab was low (5 versus 1 percent), but the overall disease control rate (objective response plus stable disease) was 60 percent (versus 39 percent with placebo). Phase 3 REACH-2 study of ramucirumab (Cyramza®) as a single agent in the second-line treatment of individuals with hepatocellular carcinoma (HCC) met its primary endpoint of overall survival (OS) as well as the secondary endpoint of progression-free survival (PFS). ramucirumab (Cyramza®) has now demonstrated a survival benefit in four aggressive, tumor types in Phase 3 studies, including as a single agent in both gastric cancer and HCC.

Non-Small Cell Lung Cancer (NSCLC)

In December 2014, ramucirumab (Cyramza®) ramucirumab (Cyramza®) received FDA-approval for the treatment of individuals with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy, when given in combination with docetaxel. The FDA approved this indication with the criteria that individuals with EGFR or ALK genomic tumor aberrations should have disease progression on an FDA-approved therapy (e.g., erlotinib, crizotinib) for these aberrations prior to receiving ramucirumab (Cyramza®). This indication resulted from a multinational, randomized, double-blind study of 1253 individuals with squamous or nonsquamous non-small cell lung cancer performed using ramucirumab (Cyramza®) plus docetaxel or placebo plus docetaxel. These individuals had progressed during or after first-line platinum-based chemotherapy. The median overall survival (10.5 vs 9.1 months) and median progression-free survival (4.5 vs 3 months) were statistically significant in those randomized to ramucirumab (Cyramza®) plus docetaxel, compared to those who received placebo plus docetaxel.


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 Hospital Formulary Service (AHFS). Drug Information 2018. Ramucirumab. [Lexicomp Online Web site]. 02/27/2018. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed November 6, 2018.

Elsevier’s Clinical Pharmacology Compendium. Ramucirumab. 06/29/2016. [ClinicalKey Web site]. Available at: https://www.clinicalkey.com/#!/ [via subscription only]. Accessed November 6, 2018.

Lexi-Drugs Compendium. Ramucirumab. [Lexicomp Online Web site]. 09/29/2018. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed November 6, 2018.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Colon Cancer. Version 4.2018. [NCCN Website]. 10/19/2018 Available at: https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf [via free subscription]. Accessed November 6, 2018.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Esophageal and Esophagogastric Junction Cancers. Version 2.2018. [NCCN Website]. 05/22/2018. Available at:https://www.nccn.org/professionals/physician_gls/pdf/esophageal.pdf [via free subscription]. Accessed November 6, 2018.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Gastric Cancer. Version 2.2018. [NCCN Website]. 05/22/2018. Available at: https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf [via free subscription]. Accessed November 6, 2018.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Hepatobiliary Cancers. Version 5.2018. [NCCN Website]. 11/19/2018. Available at: https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf [via free subscription]. Accessed November 6, 2018.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Non-Small Cell Lung Cancer. Version 1.2019. [NCCN Website]. 10/19/2018. Available at: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf [via free subscription]. Accessed November 6, 2018.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Rectal Cancer. Version 3.2018. [NCCN Website]. 08/07/2018. Available at: https://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf [via free subscription]. Accessed November 6, 2018.

National Comprehensive Cancer Network (NCCN). NCCN Drugs & Biologics Compendium. Ramucirumab. [NCCN Web site]. 2018. Available at: http://www.nccn.org/professionals/drug_compendium/content/contents.asp [via subscription only]. Accessed November 6, 2018.

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.

OncologyPro. Performance scales: Karnofsky & ECOG scores. [OncologyPro Web site]. Available at: http://oncologypro.esmo.org/Guidelines-Practice/Practice-Tools/Performance-Scales. Accessed November 6, 2018.

Ramucirumab (Cyramza®). [prescribing information]. Eli Lilly and Company: Indianapolis, IN. 02/2017. Available at: http://www.cyramzahcp.com/. Accessed November 6, 2018.

Truven Health Analytics. Micromedex® DrugDex® Compendium. Ramucirumab. Greenwood Village, CO. [Micromedex® Solutions Web site]. 08/16/2018. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed November 6, 2018.

US Food and Drug Administration (FDA). Center for Drug evaluation and Research. Drugs @FDA. Ramucirumab (Cyramza®) approval letter. [FDA Web site]. 04/21/2014. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2014/125477Orig1s000ltr.pdf . Accessed November 6, 2018.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Drugs @FDA. Ramucirumab (Cyramza®) drug label [FDA Web site]. 08/14/2018. Available at:
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails. Accessed November 6, 2018.





Coding

Inclusion of a code in this table does not imply reimbursement. Eligibility, benefits, limitations, exclusions, precertification/referral requirements, provider contracts, and Company policies apply.

The codes listed below are updated on a regular basis, in accordance with nationally accepted coding guidelines. Therefore, this policy applies to any and all future applicable coding changes, revisions, or updates.

In order to ensure optimal reimbursement, all health care services, devices, and pharmaceuticals should be reported using the billing codes and modifiers that most accurately represent the services rendered, unless otherwise directed by the Company.

The Coding Table lists any CPT, ICD-9, ICD-10, and HCPCS billing codes related only to the specific policy in which they appear.

CPT Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD - 10 Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD -10 Diagnosis Code Number(s)

C15.3 Malignant neoplasm of upper third of esophagus

C15.4 Malignant neoplasm of middle third of esophagus

C15.5 Malignant neoplasm of lower third of esophagus

C15.8 Malignant neoplasm of overlapping sites of esophagus

C15.9 Malignant neoplasm of esophagus, unspecified

C16.0 Malignant neoplasm of cardia

C16.1 Malignant neoplasm of fundus of stomach

C16.2 Malignant neoplasm of body of stomach

C16.3 Malignant neoplasm of pyloric antrum

C16.4 Malignant neoplasm of pylorus

C16.5 Malignant neoplasm of lesser curvature of stomach, unspecified

C16.6 Malignant neoplasm of greater curvature of stomach, unspecified

C16.8 Malignant neoplasm of overlapping sites of stomach

C16.9 Malignant neoplasm of stomach, unspecified

C17.0 Malignant neoplasm of duodenum

C17.1 Malignant neoplasm of jejunum

C17.2 Malignant neoplasm of ileum

C17.3 Meckel's diverticulum, malignant

C17.8 Malignant neoplasm of overlapping sites of small intestine

C17.9 Malignant neoplasm of small intestine, unspecified

C18.0 Malignant neoplasm of cecum

C18.1 Malignant neoplasm of appendix

C18.2 Malignant neoplasm of ascending colon

C18.3 Malignant neoplasm of hepatic flexure

C18.4 Malignant neoplasm of transverse colon

C18.5 Malignant neoplasm of splenic flexure

C18.6 Malignant neoplasm of descending colon

C18.7 Malignant neoplasm of sigmoid colon

C18.8 Malignant neoplasm of overlapping sites of colon

C18.9 Malignant neoplasm of colon, unspecified

C19 Malignant neoplasm of rectosigmoid junction

C20 Malignant neoplasm of rectum

C21.8 Malignant neoplasm of overlapping sites of rectum, anus and anal canals

C22.0 Liver cell carcinoma

C22.8 Malignant neoplasm of liver, primary, unspecified as to type

C22.9 Malignant neoplasm of liver, not specified as primary or secondary

C33 Malignant neoplasm of trachea

C34.00 Malignant neoplasm of unspecified main bronchus

C34.01 Malignant neoplasm of right main bronchus

C34.02 Malignant neoplasm of left main bronchus

C34.10 Malignant neoplasm of upper lobe, unspecified bronchus or lung

C34.11 Malignant neoplasm of upper lobe, right bronchus or lung

C34.12 Malignant neoplasm of upper lobe, left bronchus or lung

C34.2 Malignant neoplasm of middle lobe, bronchus or lung

C34.30 Malignant neoplasm of lower lobe, unspecified bronchus or lung

C34.31 Malignant neoplasm of lower lobe, right bronchus or lung

C34.32 Malignant neoplasm of lower lobe, left bronchus or lung

C34.80 Malignant neoplasm of overlapping sites of unspecified bronchus and lung

C34.81 Malignant neoplasm of overlapping sites of right bronchus and lung

C34.82 Malignant neoplasm of overlapping sites of left bronchus and lung

C34.90 Malignant neoplasm of unspecified part of unspecified bronchus or lung

C34.91 Malignant neoplasm of unspecified part of right bronchus or lung

C34.92 Malignant neoplasm of unspecified part of left bronchus or lung



HCPCS Level II Code Number(s)

J9308 Injection, ramucirumab, 5 mg


Revenue Code Number(s)

N/A

Coding and Billing Requirements


Cross References


Policy History

08.01.25c
12/31/2018This version of the policy will become effective 12/31/2018.

This policy has been updated to be consistent with the US Food and Drug Administration (FDA) labeling and NCCN compendia. Hepatobiliary Cancers. Version 4.2018. 11/19/2018
Policy criteria for colorectal, esophageal, esophagogastric, gastric cancers and hepatocellular were updated to reflect NCCN recommendations. Non-small cell lung cancer (NSCLC) criteria updated to reflect FDA recommendations.

The following ICD-10 CM codes have been added to this policy:
    C22.0 Liver cell carcinoma
    C22.8 Malignant neoplasm of liver, primary, unspecified as to type
    C22.9 Malignant neoplasm of liver, not specified as primary or secondary

08.01.25b
12/27/2017This version of the policy will become effective 12/27/2017.

This policy has been updated to be consistent with the US Food and Drug Administration (FDA) labeling and NCCN compendia.

Policy criteria for esophageal, esophagogastric, and gastric adenocarcinoma, and Non-small cell lung cancer (NSCLC) were updated to reflect NCCN recommendations.


Effective 10/05/2017 this policy has been updated to the new policy template format.


Version Effective Date: 12/31/2018
Version Issued Date: 12/31/2018
Version Reissued Date: N/A

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