Medical Policies - Prescription Drugs


Kyprolis (carfilzomib)

Number:RX502.040

Effective Date:06-15-2018

Coverage:

*CAREFULLY CHECK STATE REGULATIONS AND/OR THE MEMBER CONTRACT*

Medical policies are a set of written guidelines that support current standards of practice. They are based on current peer-reviewed scientific literature. A requested therapy must be proven effective for the relevant diagnosis or procedure. For drug therapy, the proposed dose, frequency and duration of therapy must be consistent with recommendations in at least one authoritative source. This medical policy is supported by FDA-approved labeling and nationally recognized authoritative references. These references include, but are not limited to: MCG care guidelines, DrugDex (IIb level of evidence or higher), NCCN Guidelines (IIb level of evidence or higher), NCCN Compendia (IIb level of evidence or higher), professional society guidelines, and CMS coverage policy.

When the requested chemotherapeutic agent is being utilized in a regimen in combination with other chemotherapeutic agents, the entire regimen (including dose, frequency, and duration) must be consistent with recommendations in at least one authoritative source, including but not limited to FDA labeling and nationally recognized compendia or clinical guidelines such as National Comprehensive Cancer Network (NCCN) and CMS coverage policy. HCSC may require a provider to submit documentation from nationally recognized compendia, clinical guidelines, or active Phase III clinical trials supporting the requested regimen.

Kyprolis (carfilzomib) may be considered medically necessary for the following:

In combination with dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma (MM) who have received one to three lines of therapy; OR

In combination with lenalidomide plus dexamethasone for:

o Patients with relapsed or refractory MM, or

o Primary treatment of transplant eligible patients with MM, or

o Treatment of all patients with newly diagnosed MM including those who are not eligible for stem-cell transplant (SCT); OR

As a single agent for the treatment of patients with relapsed or refractory MM who have received one or more lines of therapy, OR

In combination with pomalidomide and dexamethasone for patients with MM who have received at least two prior regimens, a proteasome inhibitor and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy, OR

In combination with panobinostat for patients with previously treated MM, OR

As a treatment for Waldenström’s macroglobulinemia/lymphoplasmacytic lymphoma.

Kyprolis (carfilzomib) is considered experimental, investigational and/or unproven for all other indications.

Description:

Kyprolis™ (carfilzomib) targets and inhibits the proteasome enzyme complex within the cell. The proteasome (a multi-catalytic protease present in all eukaryotic cells), is part of the cellular machinery and has many functions. The proteasome plays an important role in the regulation of cell cycle, neoplastic growth, and metastasis. In the laboratory, it has been shown that cancer cells are more susceptible to the effects of proteasome inhibitors, than normal cells are. Proteasome inhibitors (PIs) specifically induce apoptosis (cell suicide) in cancer cells.

Regulatory Status

Carfilzomib was first U.S. Food and Drug Administration (FDA) approved for multiple myeloma (MM) in 2012, as a single agent in patients who had received at least two prior therapies including bortezomib and an immunomodulatory agent. Carfilzomib was also FDA approved in July 2015 for use in combination with lenalidomide and dexamethasone (KRd) for the treatment of patients with relapsed MM who have received one to three prior lines of therapy. In 2016 the U.S. Food and Drug Administration (FDA) approved the supplemental New Drug Application (sNDA) of carfilzomib in combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy. The FDA also approved Kyprolis as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy. This FDA decision converted to full approval the initial accelerated approval Kyprolis received in July 2012 as a single agent.

Carfilzomib is administered intravenously over 2 to 10 minutes, on two consecutive days weekly for three weeks (i.e., days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (i.e., days 17 to 28). The recommended cycle one dose is 20 mg/m2/day, and, if tolerated, the recommended dose for the second and succeeding cycles is 27 mg/m2/day.

Rationale:

The policy originated in 2016 and was based on the U.S. Food and Drug Administration (FDA) approved label. (1) A literature search of scientific literature was conducted through June 2017. The following is a summary of key literature to date.

Multiple Myeloma (MM)

In Combination with Dexamethasone for the Treatment of Patients with Relapsed or Refractory MM:

Dimopoulos et al. (7) conducted a randomized, open-label, multicenter superiority trial of Kyprolis plus dexamethasone (Kd) versus bortezomib plus dexamethasone (Vd) in patients with relapsed or refractory MM who had received 1 to 3 lines of therapy. A total of 929 patients were enrolled and randomized (464 in the Kd arm; 465 in the Vd arm). Randomization was stratified by prior proteasome inhibitor therapy (yes versus no), prior lines of therapy (1 versus 2 or 3), current International Staging System stage (1 versus 2 or 3), and planned route of bortezomib administration. Patients were excluded if they had less than partial response (PR) to all prior regimens; creatinine clearance < 15 mL/min; hepatic transaminases ≥ 3 × upper limits of normal (ULN); or left-ventricular ejection fraction < 40% or other significant cardiac conditions. This trial evaluated Kyprolis at a starting dose of 20 mg/m2, which was increased to 56 mg/m2 on Cycle 1, Day 8 onward. Kyprolis was administered twice weekly as a 30-minute infusion on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Dexamethasone 20 mg was administered orally or intravenously on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each cycle. In the Vd arm, bortezomib was dosed at 1.3 mg/m2 intravenously or subcutaneously on Days 1, 4, 8, and 11 of a 21-day cycle, and dexamethasone 20 mg was administered orally or intravenously on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each cycle. Concurrent use of thromboprophylaxis was optional, and prophylaxis with an antiviral agent and proton pump inhibitor was required. Of the 465 patients in the Vd arm, 381 received bortezomib subcutaneously. Treatment continued until disease progression or unacceptable toxicity. The efficacy of Kyprolis was evaluated by progression free survival (PFS) as determined by an independent review committee (IRC) using International Myeloma Working Group (IMWG) response criteria. The trial showed a median PFS of 18.7 months in the Kd arm versus 9.4 months in the Vd arm. Other endpoints included overall survival (OS) and overall response rate (ORR). At the time of analysis, OS data were not mature. ORR was 77% for patients in the Kd arm and 63% for patients in the Vd arm. The median duration of response (DOR) in subjects achieving PR or better was 21.3 months (95% CI: 21.3, not estimable) in the Kd arm and 10.4 months (95% confidence interval (CI): 9.3, 13.8) in the Vd arm. The median time to response was 1 month (range < 1 to 8 months) in both arms.

In Combination with Lenalidomide with Dexamethasone for the treatment of Patients with Relapsed or Refractory Multiple Myeloma (MM)

Stewart et al. (8) conducted a randomized, open-label, multicenter superiority trial which evaluated the combination of Kyprolis with lenalidomide and dexamethasone (KRd) versus lenalidomide and dexamethasone (Rd) alone in patients with relapsed or refractory MM who had received 1 to 3 lines of therapy without an interruption for lack of efficacy, such as for relapse or progressive disease). Patients who had the following were excluded from the trial: refractory to bortezomib in the most recent regimen, refractory to lenalidomide and dexamethasone in the most recent regimen, not responding to any prior regimen, creatinine clearance < 50 mL/min, ALT/AST > 3.5 × ULN and bilirubin > 2 × ULN, New York Heart Association Class III to IV congestive heart failure, or myocardial infarction within the last 4 months. In the KRd arm, Kyprolis was evaluated at a starting dose of 20 mg/m2, which was increased to 27 mg/m2 on Cycle 1, Day 8 onward. Kyprolis was administered as a 10-minute infusion on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle for Cycle 1 through 12. Kyprolis was dosed on Days 1, 2, 15, and 16 of each 28-day cycle from Cycle 13 through 18. Dexamethasone 40 mg was administered orally or intravenously on Days 1, 8, 15 and 22 of each cycle. Lenalidomide was given 25 mg orally on Days 1 to 21 of each 28-day cycle. The Rd treatment arm had the same regimen for lenalidomide and dexamethasone as the KRd treatment arm. Kyprolis was administered for a maximum of 18 cycles unless discontinued early for disease progression or unacceptable toxicity. Lenalidomide and dexamethasone administration could continue until progression or unacceptable toxicity. Concurrent use of thromboprophylaxis and a proton pump inhibitor were required for both arms, and antiviral prophylaxis was required for the KRd arm.

The 792 patients in the study were randomized 1:1 to the KRd or Rd arm. The demographics and baseline characteristics were well-balanced between the two arms. Only 53% of the patients had testing for genetic mutations; a high-risk genetic mutation was identified for 12% of patients in the KRd arm and in 13% in the Rd arm. Patients in the KRd arm demonstrated improved PFS compared with those in the Rd arm (HR = 0.69, with 2-sided P-value = 0.0001) as determined using standard International Myeloma Working Group (IMWG)/European Blood and Marrow Transplantation (EBMT) response criteria by an Independent Review Committee (IRC). The median PFS was 26.3 months in the KRd arm versus 17.6 months in the Rd arm.

The OS results were not significantly different at the interim analysis. The median duration of response (DOR) was 28.6 months (95% CI: 24.9, 31.3) for the 345 patients achieving a response in the KRd arm and 21.2 months (95% CI: 16.7, 25.8) for the 264 patients achieving a response in the Rd arm. The median time to response was 1 month (range 1 to 14 months) in the KRd arm and 1 month (range 1 to 16 months) in the Rd arm.

Monotherapy for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma

Siegel et al. (9) conducted a single-arm, multicenter clinical trial of Kyprolis monotherapy by up to 10-minute infusion. Eligible patients were those with relapsed and refractory MM who had received at least two prior therapies (including bortezomib and thalidomide and/or lenalidomide) and had ≤ 25% response to the most recent therapy or had disease progression during or within 60 days of the most recent therapy. Patients were excluded from the trial if they were refractory to all prior therapies or had a total bilirubin ≥ 2 × ULN; creatinine clearance < 30 mL/min; New York Heart Association Class III to IV congestive heart failure; symptomatic cardiac ischemia; myocardial infarction within the last 6 months; peripheral neuropathy Grade 3 or 4, or peripheral neuropathy Grade 2 with pain; active infections requiring treatment; or pleural effusion. Kyprolis was administered intravenously up to 10 minutes on two consecutive days each week for three weeks, followed by a 12-day rest period (28-day treatment cycle), until disease progression, unacceptable toxicity, or for a maximum of 12 cycles. Patients received 20 mg/m2 at each dose in Cycle 1, and 27 mg/m2 in subsequent cycles. Dexamethasone 4 mg orally or intravenously was administered prior to Kyprolis doses in the first and second cycles. A total of 266 patients were enrolled. Efficacy was evaluated by ORR as determined by IRC assessment using IMWG criteria. The median number of cycles started was four. The ORR (PR or better) was 23% (95% CI: 18, 28). The median DOR was 7.8 months (95%CI: 5.6, 9.2).

The National Comprehensive Cancer Network Drug and Biologics Compendium (NCCN, Multiple Myeloma, Version 3. 2017)

The NCCN recommends the use of carfilzomib for the following indications in multiple myeloma:

Used in combination with dexamethasone for:

o Patients with relapsed/refractory MM (category 1B)

Used in combination with lenalidomide and dexamethasone for:

o Primary treatment of transplant eligible patients with MM (category 2B)

o Treatment of all patients with newly diagnosed MM including those who are not eligible for stem-cell transplant (SCT). (category 2B recommendation)

o Patients with relapsed/refractory MM (category 1B recommendation)

Used in combination with pomalidomide and dexamethasone for patients who have received at least two prior regimens, including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. (category 2A recommendation)

Used in combination with panobinostat for patients with previously treated MM. (category 2A recommendation).

Waldenstrom’s macroglobulinemia (WM)/lymphoplasmacytic lymphoma

Carfilzomib, rituximab, and dexamethasone produced an overall response rate of 87.1% and a major response rate (partial response or better) of 67.7% in a single-arm study (N=31) of symptomatic patients with WM who were naive to bortezomib and rituximab, and had received no more than 1 prior therapy. At a median follow-up period of 15.4 months, the median time to progression had not been reached. Median time to best response was more than 12.8 months. Median IgM levels decreased from 3375 mg/dL at baseline to 749 mg/dL at best response; median bone marrow involvement decreased from 60% to 5%; and median hematocrit (HCT) increased from 32.3% to 41.3%. MYD88 (L265P) mutation was detected in 96.6% of the 30 patients with results, and the 1 patient with wild-type MYD88 achieved a very good partial response. Response rate was not significantly different in the 36.7% of patients with CXCR4 (WHIM) compared with CXCR wild-type (90.9% vs 85%). Grade 2 or higher toxicity included peripheral neuropathy (3.2%), dexamethasone-related hyperglycemia (77.4%), carfilzomib-related hyperlipasemia (41.9%), and rituximab-related infusion reactions (19.4%).

In 2014 Treon, et al. (2) noted that carfilzomib, rituximab and dexamethasone (CaRD) offers a neuropathy sparing approach for proteasome inhibitor based therapy for Waldenström’s macroglobulinemia. In this study carfilzomib, rituximab, and dexamethasone (CaRD) were examined in symptomatic WM patients’ naïve to bortezomib and rituximab. Protocol therapy consisted of intravenous carfilzomib, 20 mg/m2 (cycle 1) and 36 mg/m (2) (cycles 2-6), with intravenous dexamethasone, 20 mg, on days 1, 2, 8, and 9, and rituximab, 375 mg/m (2), on days 2 and 9 every 21 days. Maintenance therapy followed 8 weeks later with intravenous carfilzomib, 36 mg/m (2), and intravenous dexamethasone, 20 mg, on days 1 and 2, and rituximab, 375 mg/m(2), on day 2 every 8 weeks for 8 cycles. Overall response rate was 87.1% (1 complete response, 10 very good partial responses, 10 partial responses, and 6 minimal responses) and was not impacted by MYD88 (L265P) or CXCR4 (WHIM) mutation status. With a median follow-up of 15.4 months, 20 patients remain progression free. Grade ≥2 toxicities included asymptomatic hyperlipasemia (41.9%), reversible neutropenia (12.9%), and cardiomyopathy in 1 patient (3.2%) with multiple risk factors, and PN in 1 patient (3.2%) which was grade 2. Declines in serum IgA and IgG were common. This trial is registered at www.clinicaltrials.gov as #NCT01470196.

The National Comprehensive Cancer Network (NCCN, version 1.2017) recommends carfilzomib as a component of CaRD (carfilzomib, rituximab, and dexamethasone) regimen in Waldenstrom's macroglobulinemia/lymphoplasmacytic lymphoma as primary therapy. (3)

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

CODING:

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

None

HCPCS Codes

J9047

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

1. FDA – Department of Health and Human Services. Kyprolis® (carfilzomib) Label. Available at: <http://www.fda.gov> (accessed June 2017).

2. Treon SP, Tripsas CK, Meid K, et al. Carfilzomib, rituximab, and dexamethasone (CaRD) treatment offers a neuropathy-sparing approach for treating Waldenström's macroglobulinemia. Blood. 2014; 124(4):503-510. PMID: 24859363

3. NCCN Guidelines – Waldenström’s Macroglobulinemia/Lymphoplasmacytic Lymphoma Guidelines. – Version 1.2017. National Comprehensive Cancer Network. Available at <http://www.nccn.org> (accessed June 2017).

4. NCCN – Multiple Myeloma Guidelines – Version 3.2017. National Comprehensive Cancer Network. Available at <http://www.nccn.org> (accessed June 2017).

5. Truven Health Analytics Inc — Kyprolis® (carfilzomib). Micromedex Subscriptions. Available at <Micromedex.com> (accessed June 2017).

6. Kyprolis® (carfilzomib) prescribing information, Onyx Pharmaceuticals Inc., an Amgen Inc. subsidiary. Available at: < http://www.kyprolis-hcp.com> (accessed June 2017).

7. Dimopoulos MA, Moreau P, Palumbo A, et al. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2016; 17(1):27-38. PMID: 26671818

8. Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015; 372:142-152. PMID: 25482145

9. Siegel DS, Martin T, Wang M, 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):2817–2825. doi: 10.1182/blood-2012-05-425934.

Policy History:

Date Reason
6/15/2018 Reviewed. No changes.
8/15/2017 Document updated with literature review. The following coverage criteria was expanded or additional indications added: 1) In combination with dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma (MM) who have received one to three lines of therapy; or 2) In combination with lenalidomide plus dexamethasone for patients with relapsed/refractory MM, primary treatment of transplant eligible patients with MM, or treatment of all patients with newly diagnosed MM including those who are not eligible for stem cell transplant (SCT); or 3) as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy; or 4) In combination with pomalidomide and dexamethasone for patients with MM who have received at least two prior regimens, including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy; or 5) in combination with panobinostat for patients with previously treated MM.
7/1/2016 Reviewed. No changes.
3/1/2016 New medical document. Kyprolis (carfilzomib) may be considered medically necessary for the following: 1) In combination with lenalidomide and dexamethasone for the treatment of patients with relapsed multiple myeloma who have received at least one prior therapy, 2) As a single agent 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 and 3) As a treatment for Waldenström’s macroglobulinemia/lymphoplasmacytic lymphoma. Kyprolis is considered experimental, investigational and/or unproven for all other indications.

Archived Document(s):

Title:Effective Date:End Date:
Kyprolis (carfilzomib)08-15-201706-14-2018
Kyprolis (carfilzomib)07-01-201608-14-2017
Kyprolis (carfilzomib)03-01-201606-30-2016
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