Subject:
Carfilzomib (Kyprolis)
Description:
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IMPORTANT NOTE:
The purpose of this policy is to provide general information applicable to the administration of health benefits that Horizon Blue Cross Blue Shield of New Jersey and Horizon Healthcare of New Jersey, Inc. (collectively “Horizon BCBSNJ”) insures or administers. If the member’s contract benefits differ from the medical policy, the contract prevails. Although a service, supply or procedure may be medically necessary, it may be subject to limitations and/or exclusions under a member’s benefit plan. If a service, supply or procedure is not covered and the member proceeds to obtain the service, supply or procedure, the member may be responsible for the cost. Decisions regarding treatment and treatment plans are the responsibility of the physician. This policy is not intended to direct the course of clinical care a physician provides to a member, and it does not replace a physician’s independent professional clinical judgment or duty to exercise special knowledge and skill in the treatment of Horizon BCBSNJ members. Horizon BCBSNJ is not responsible for, does not provide, and does not hold itself out as a provider of medical care. The physician remains responsible for the quality and type of health care services provided to a Horizon BCBSNJ member.
Horizon BCBSNJ medical policies do not constitute medical advice, authorization, certification, approval, explanation of benefits, offer of coverage, contract or guarantee of payment.
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Carfilzomib (Kyprolis) is a tetrapeptide epoxyketone proteasome inhibitor that irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome. Carfilzomib had antiproliferative and proapoptotic activities in vitro in solid and hematologic tumor cells.
Carfilzomib is indicated for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy.
Multiple myeloma is a malignancy of plasma cells, which accumulate in the bone marrow, resulting in the destruction of boney structures and marrow failure. Signs and symptoms of multiple myeloma include bone pain and damage, hypercalcemia, renal failure, anemia, frequent infections, weight loss and weakness or numbness.
Carfilzomib is marketed as Kyprolis by Onyx Pharmaceuticals, Thousand Oaks, California and was approved by the FDA on July 20, 2012.
Approval was based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.
Death due to cardiac arrest has occurred within a day of carfilzomib administration. New onset or worsening of pre-existing congestive heart failure with decreased left ventricular function or myocardial ischemia and pulmonary complications, mainly dyspnea, have also occurred following administration.
In January 2015, two new precautions were added to the Kyprolis package insert warning prescribers and patients of the possibility of experiencing thrombotic thrombocytopenic purpura/hemolytic uremic syndrome and posterior reversible encephalopathy syndrome. If either diagnosis is suspected, Kyprolis should be discontinued and the patient should be evaluated. The safety of reinitiating the medication is unknown.
In July 2015, the FDA approved a new indication for Kyprolis. It can now be used in combination with lenalidomide and dexamethasone for the treatment of patients with relapsed multiple myeloma who have received one to three prior lines of therapy.
In September 2018, the FDA approved a once-weekly dosing regimen for Kyprolis in combination with dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy.
In August 2020, the FDA approved a new indication for Kyprolis. It can now be used in combination with daratumumab and dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy.
Policy:
(NOTE: For Medicare Advantage, please refer to the Medicare Coverage Section below for coverage guidance)
The requirements of the Horizon BCBSNJ Carfilzomib (Kyprolis) Program may require a precertification/prior authorization via MagellanRx Management. These requirements are member-specific: please verify member eligibility and requirements through the Horizon Provider Portal (www.horizonblue.com/provider). Ordering clinicians should request pre-certification from MagellanRx Management at ih.magellanrx.com or call 1-800-424-4508 (when applicable).
1. Kyprolis (carfilzomib) is considered medically necessary for the following FDA approved indications when the following criteria are met:
a. As a single agent for adult members with relapsed or refractory multiple myeloma who have received one or more lines of therapy (including bortezomib, bortezomib + immunomodulatory agent, or lenalidomide) , OR
b. For adult members in combination with dexamethasone, or with lenalidomide and dexamethasone, or with daratumumab and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy (including bortezomib, transplant for multiple myeloma, thalidomide, lenalidomide, or bortezomib + immunomodulatory agent) AND
c. The prescriber is a specialist in the area of the patient’s diagnosis (e.g. oncologist) or has consulted with a specialist in the area of the patient’s diagnosis
[INFORMATIONAL NOTE: Carfilzomib was approved under the U.S. Food and Drug Administration (FDA) accelerated approval program with the phase II 003-A1 study. The open-label, single-arm study evaluated 266 patients with relapsed multiple myeloma; the primary endpoint for the trial was Overall Response Rate (ORR) as assessed by an Independent Response Review Committee using International Myeloma Working Group criteria. The ORR in 003-A1 was 22.9% (95% CI: 18.0, 28.5).
In order for patients to be eligible for the 003-A1 study they had to have measurable disease, evidence of response to previous treatment, at least two or more prior regimens for relapsed disease (induction therapy and stem cell transplant were to be considered as one regimen) with bortezomib and either thalidomide or lenalidomide being one of the therapies, absolute neutrophil count ≥ 1000/m3, hemoglobin ≥ 8.0 g/dL, platelet count ≥ 50,000/mm3, and be platelet transfusion independent.]
2. Kyprolis (carfilzomib) is considered medically necessary at FDA approved doses initially for 6 months:
o 20/27 regimen (single agent):
· Cycle 1: 20 mg/m2 on days 1 and 2; if tolerated, increase to 27 mg/m2 on days 8, 9, 15, and 16 of a 28-day treatment cycle
· Cycles 2 to 12: 27 mg/m2 on days 1, 2, 8, 9, 15, and 16 of a 28-day treatment cycle
· Cycle 13 and beyond: 27 mg/m2 on days 1, 2, 15, and 16 of a 28-day treatment cycle; continue until disease progression or unacceptable toxicity
o 20/56 regimen (single agent):
· Cycle 1: 20 mg/m2 on days 1 and 2; if tolerated, increase to 56 mg/m2 on days 8, 9, 15, and 16 of a 28-day treatment cycle.
· Cycles 2 to 12: 56 mg/m2 on days 1, 2, 8, 9, 15, and 16 of a 28-day treatment cycle.
· Cycle 13 and beyond: 56 mg/m2 on days 1, 2, 15, and 16 of a 28-day treatment cycle; continue until disease progression or unacceptable toxicity.
o 20/27 regimen (combination with lenalidomide and dexamethasone):
· Cycle 1: 20 mg/m2 on days 1 and 2; if tolerated, increase to 27 mg/m2 on days 8, 9, 15, and 16 of a 28-day treatment cycle.
· Cycles 2 to 12: 27 mg/m2 on days 1, 2, 8, 9, 15, and 16 of a 28-day treatment cycle.
· Cycles 13 to 18: 27 mg/m2 on days 1, 2, 15, and 16 of a 28-day treatment cycle; discontinue carfilzomib after Cycle 18.
o 20/56 regimen (combination with dexamethasone):
· Cycle 1: 20 mg/m2 on days 1 and 2; if tolerated, increase to 56 mg/m2 on days 8, 9, 15, and 16 of a 28-day treatment cycle.
· Cycle 2 and beyond: 56 mg/m2 on days 1, 2, 8, 9, 15, and 16 of a 28-day treatment cycle; continue until disease progression or unacceptable toxicity.
o 20/70 regimen (combination with dexamethasone):
· Cycle 1: 20 mg/m2 on day 1; if tolerated increase to 70 mg/m2 on day 8 and 15 of a 28-day treatment cycle.
· Cycle 2 and beyond: 70 mg/m2 on days 1, 8 and 15 of a 28-day treatment cycle; continue until disease progression or unacceptable toxicity.
o 20/56 regimen (combination with daratumumab and dexamethasone):
· Cycle 1: 20 mg/m2 on days 1 and 2; if tolerated, increase to 56 mg/m2 on days 8, 9, 15, and 16 of a 28-day treatment cycle.
· Cycle 2 and beyond: 56 mg/m2 on days 1, 2, 8, 9, 15, and 16 of a 28-day treatment cycle; continue until disease progression or unacceptable toxicity.
o 20/70 regimen (combination with daratumumab and dexamethasone):
· Cycle 1: 20 mg/m2 on day 1; if tolerated increase to 70 mg/m2 on day 8 and 15 of a 28-day treatment cycle.
· Cycle 2 and beyond: 70 mg/m2 on days 1, 8 and 15 of a 28-day treatment cycle; continue until disease progression or unacceptable toxicity.
[INFORMATIONAL NOTE: As per the FDA approved package insert: the dose is calculated using the patient’s actual body surface area at baseline. Patients with body surface area greater than 2.2 m2 should receive a dose based upon body surface of 2.2 m2. Dose adjustments do not need to be made for weight changes of less than or equal to 20%.
From Cycle 13, omit the Day 8 and 9 doses of Kyprolis for all indications.
As per the FDA approved package insert warnings and precautions section: Premedicate with the recommended dose of dexamethasone for monotherapy or the recommended dexamethasone dose if on combination therapy. Administer dexamethasone orally or intravenously at least 30 minutes but no more than 4 hours prior to all doses of Kyprolis during Cycle 1 to reduce the incidence and severity of infusion reactions.]
3. Kyprolis (carfilzomib) is considered medically necessary for continued therapy at 6 months if:
- There is stabilization of disease and/or absence of progression of disease; AND
- Absence of unacceptable toxicity from the drug. (e.g.: cardiac events (heart failure and ischemia), pulmonary hypertension, dyspnea, infusion reactions, tumor lysis syndrome, thrombocytopenia, elevations of transaminases, bilirubin, or other liver abnormalities, increased blood creatinine acute renal failure, thrombotic microangiopathy (TTP/HUS), severe hypertension, posterior reversible encephalopathy syndrome (PRES), venous thromboembolic events, hemorrhage, pulmonary toxicity, etc.) AND
- When used in combination with lenalidomide and dexamethasone, Kyprolis will be discontinued after cycle 18.
4. Kyprolis (carfilzomib) is considered medically necessary for the off label indications that have in effect a rating of ‘Category 1’ or ‘Category 2A’ in the current recommendations in the National Comprehensive Cancer Network (NCCN) compendium. Refer to National Comprehensive Cancer Network: Drugs and Biologics Compendium - [carfilzomib]. Available at: https://www.nccn.org/professionals/drug_compendium/content/
5. The use of Kyprolis (carfilzomib) in other indications not listed above is considered investigational.
Medicare Coverage
There is no National Coverage Determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of Local Medicare Carriers. Novitas Solutions, Inc, the Local Medicare Carrier for jurisdiction JL, has not issued a determination for this service. Therefore, Medicare Advantage Products will follow the Horizon Policy.
Medicaid Coverage
For Horizon NJ Health members, please follow this link for the corresponding HNJH drug policy https://services3.horizon-bcbsnj.com/ddn/NJhealthWeb.nsf
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Horizon BCBSNJ Medical Policy Development Process:
This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.
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Index:
Carfilzomib
Kyprolis
References:
1. Kyprolis (carfilzomib) Package insert. Onyx Pharmaceuticals. Thousand Oaks, CA. August 2020.
2. U.S. Food and Drug Administration. FDA approves Kyprolis for some patients with multiple myeloma. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm312920.htm. (Accessed 7/24/12)
3. National Comprehensive Cancer Network: Drugs and Biologics Compendium. Carfilzomib. 2020. Available at http://www.nccn.org/professionals/drug_compendium/MatrixGenerator/Matrix.aspx?AID=385. [Accessed August 2020].
4. MICROMEDEX® 2.0 (Healthcare Series). DRUGDEX® Evaluations. Carfilzomib. Available at: http://www.thomsonhc.com/hcs/librarian/ND_T/HCS/ND_PR/Main/CS/178424/DUPLICATIONSHIELDSYNC/C0CA75/ND_PG/PRIH/ND_B/HCS/SBK/2/ND_P/Main/PFPUI/zR129UG31fkFUT/PFActionId/hcs.common.RetrieveDocumentCommon/DocId/1537/ContentSetId/31#therapeuticUsesSection October 4, 2017.
5. Treon SP, Tripsas CK, Meid K. Carfilzomib, rituximab, and dexamethasone (CaRD) treatment offers a neuropathy – sparing approach for treating Waldenström’s macroglobulinemia. Blood. 2014 Jul 24;124(4):503-10. doi: 10.1182/blood-2014-03-566273. Epub 2014 May 23.
6. Clinicaltrials.gov. Phase 3 Study with Carfilzomib and Dexamethasone Versus Bortezomib and Dexamethasone for Relapses Multiple Myeloma Patients (ENDEAVOR). Accessed from: https://clinicaltrials.gov/ct2/show/NCT01568866
7. Stewart et al., Carfilzomib, Lenalidomide, and Dexamethasone for Relapsed Multiple Myeloma. N Engl J Med. 2015;372(2):142-52.
8. Papadopoulos et al., Phase I study of 30-minute infusion of carfilzomib as single agent or in combination with low-dose dexamethasone in patients with relapsed and/or refractory multiple myeloma. J Clin Oncol. 2015; 33(7): 732-9.
9. Siegel et al., A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120(14):2817-25.
10. Moreau P, Mateos M-V, Berenson JR, et al. Once weekly versus twice weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma (A.R.R.O.W.): interim analysis results of a randomised, phase 3 study. Lancet. 2018:19(7):953-964.
11. Clinicaltrials.gov. Carfilzomib. Accessed from: https://clinicaltrials.gov/ct2/results?cond=&term=kyprolis&cntry=&state=&city=&dist=
Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)
CPT*
HCPCS
* CPT only copyright 2020 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.
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Medical policies can be highly technical and are designed for use by the Horizon BCBSNJ professional staff in making coverage determinations. Members referring to this policy should discuss it with their treating physician, and should refer to their specific benefit plan for the terms, conditions, limitations and exclusions of their coverage.
The Horizon BCBSNJ Medical Policy Manual is proprietary. It is to be used only as authorized by Horizon BCBSNJ and its affiliates. The contents of this Medical Policy are not to be copied, reproduced or circulated to other parties without the express written consent of Horizon BCBSNJ. The contents of this Medical Policy may be updated or changed without notice, unless otherwise required by law and/or regulation. However, benefit determinations are made in the context of medical policies existing at the time of the decision and are not subject to later revision as the result of a change in medical policy
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