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MP 8.01.53 Cellular Immunotherapy for Prostate Cancer

Medical Policy    
Section
Therapy
Original Policy Date
05/2010
Last Review Status/Date
Reviewed with literature search/7:2014
Issue
7:2014
  Return to Medical Policy Index

Disclaimer

Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract. Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage. Medical technology is constantly changing, and we reserve the right to review and update our policies periodically. 


Description 

Sipuleucel-T (Provenge®, Dendreon Corp.) is a new class of therapeutic agent used in the treatment of asymptomatic or minimally symptomatic, androgen-independent (hormone-refractory), metastatic prostate cancer. The agent consists of specially treated dendritic cells obtained from the patient with leukapheresis. The cells are then exposed in vitro to proteins that contain prostate antigens and immunologic-stimulating factors, and are then reinfused back into the patient. The proposed mechanism of action is that the treatment stimulates the patient’s own immune system to resist spread of the cancer.

Background

Prostate cancer is the second leading cause of cancer-related deaths among American men, with an estimated incidence of 218,890 cases and an estimated number of 27,050 deaths in 2007. In most cases, prostate cancer is diagnosed at a localized stage and is treated with prostatectomy or radiation therapy. However, some patients are diagnosed with metastatic disease or recurrent disease after treatment of localized disease. Androgen ablation is the standard treatment for metastatic or recurrent disease. However, most patients who survive long enough eventually develop androgen-independent prostate cancer. At this stage of metastatic disease, docetaxel, a chemotherapeutic agent, has been demonstrated to confer a survival benefit of 1.9 to 2.4 months in randomized clinical trials (RCTs). (1, 2) Chemotherapy with docetaxel causes adverse effects in large proportions of patients, including alopecia, fatigue, neutropenia, neuropathy, and other symptoms. The trials evaluating docetaxel included both asymptomatic and symptomatic patients, and results suggested a survival benefit for both groups. Because of the burden of treatment and its adverse effects, most patients therefore defer docetaxel treatment until the cancer recurrence is symptomatic.

Cancer immunotherapy has been investigated as a treatment which could potentially be instituted at the point of detection of androgen-independent metastatic disease before significant symptomatic manifestations have occurred. The quantity of cancer cells in the patient during this time interval is thought to be relatively low, and it is thought that an effective immune response against the cancer during this time period could effectively delay or prevent progression. Such a delay could allow a course of effective chemotherapy, such as docetaxel, to be deferred or delayed until necessary, thus providing an overall survival benefit.

Sipuleucel-T (Provenge®, Dendreon Corp.) is a new class of therapeutic agent used in the treatment of asymptomatic or minimally symptomatic, androgen-independent (hormone-refractory), metastatic prostate cancer. The agent consists of specially treated dendritic cells obtained from the patient with leukapheresis. The cells are then exposed in vitro to proteins that contain prostate antigens and immunologic-stimulating factors and are then reinfused back into the patient. At reinfusion, the cells are administered as 3 intravenous (IV) infusions, each infusion given approximately 2 weeks apart. The proposed mechanism of action is that the treatment stimulates the patient’s own immune system to resist spread of the cancer.

Regulatory Status

On April 29, 2010, the U.S. Food and Drug Administration (FDA) approved Provenge® (sipuleucel-T, Dendreon Corp.) via a Biologics Licensing Application (BLA) for "the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer (for autologous use only)." Approval was contingent on agreement of the manufacturer to conduct a postmarketing study, based on a registry design, to assess the risk of cerebrovascular events in 1,500 patients with prostate cancer who receive sipuleucel-T.


Policy 

Sipuleucel-T therapy may be considered medically necessary in the treatment of asymptomatic or minimally symptomatic, androgen-independent (hormone-refractory) metastatic prostate cancer.

Sipuleucel-T therapy is considered investigational in all other situations, including but not limited to treatment of hormone-responsive prostate cancer, treatment of moderate to severe symptomatic metastatic prostate cancer, and treatment of visceral (liver, lung, or brain) metastases.


Policy Guidelines

 

Starting in 2012, the following code is available for this product:

Q2043: Sipuleucel-T, minimum of 50 million autologous CD54+ cells activated with PAP-GM-CSF, including leukapheresis and all other preparatory procedures, per infusion

Between October 2010 and January 2012, the following HCPCS code was used:

C9273: Sipuleucel-T, minimum of 50 million autologous CD54+ cells activated with PAP-GM-CSF, including leukapheresis and all other preparatory procedures, per infusion


Benefit Application
BlueCard/National Account Issues

 

State or federal mandates (e.g., FEP) may dictate that all devices approved by the U.S. Food and Drug Administration (FDA) may not be considered investigational, and thus these devices may be assessed only on the basis of their medical necessity.
Rationale

 

This policy was created in May 2010 and updated annually with literature review. The most recent update covers the period through June 20, 2014..

Literature review

Metastatic, androgen-independent prostate cancer

Sipuleucel-T has been studied most definitively in a series of double-blind, placebo-controlled randomized controlled trials (RCTs). (3) Results of 2 of these studies have been published by Small et al. (4) and Higano et al. (5) and extensively presented in a briefing document available from the U.S. Food and Drug Administration (FDA). (6) Results of the third and largest trial are not published but were presented at the American Urological Association meeting in April 2009 and summarized in an FDA press release in April 2010. (7) Patients enrolled in these trials all had androgen-independent metastatic prostate cancer, were asymptomatic or mildly symptomatic, in good physical health characterized by Eastern Cooperative Oncology Group (ECOG ) performance status 0 or 1, and had tumors with positive staining for prostatic acid phosphatase (PAP).

 

Table 1 describes the 2 early identically designed studies.(3-5,7) Patients with asymptomatic metastatic prostate cancer were randomized to receive either sipuleucel-T or a control infusion of untreated dendritic cells. Principal outcome was time to disease progression, defined as the time from randomization to the first observation of disease progression. Disease progression could be defined as radiologic progression (based on several imaging criteria), clinical progression (based on prostate cancer-related clinical events, such as pathologic fracture), or pain progression (based on onset of pain corresponding to anatomic location of disease).

Studies were not designed to establish efficacy based on overall survival. On progression of cancer, patients were allowed to have additional treatment as needed including chemotherapy. Patients originally assigned to placebo were allowed to cross over by receiving their own dendritic cells pulsed with PA2024 antigen (recombinant fusion protein comprising human PAP linked to granulocyte-macrophage colonystimulating factor [GM-CSF]), but prepared from frozen dendritic cells harvested from their initial leukapheresis procedures.

Table 1. Description of Randomized Phase III Trials of Sipuleucel-T

Study name

Design

Eligibility

Treatment

Outcomes

9901A 9902A

Randomized, double blind, placebo-controlled

Metastatic prostate cancer by imaging, asymptomatic and progressing by imaging or rising PSA

Exp: 3 infusions of vaccine Ctl: 3 infusions of placebo dendritic cells

Primary: Disease progression (radiological, clinical, pain) Secondary: Time to pain, time to progression

IMPACT

Randomized, double blind, placebo-controlled

Metastatic prostate cancer by imaging, asymptomatic or minimally symptomatic and progressing by imaging or rising PSA

Exp: 3 infusions of vaccine Ctl: 3 infusions of placebo dendritic cells

Primary: Overall survival Secondary: Time to objective disease progression

Ctl: control arm; Exp: experimental arm; PSA: prostate-specific antigen

Table 2. Results of Randomized, Phase 3 Trials of Sipuleucel-T

Study 9901A

 

Vaccine n=82

Control n=45

p value

Median time to progression

11.7 weeks

10.0 weeks

0.052

Median time to clinical progression

10.7 weeks

9.1 weeks

0.061

Overall median survival

25.9 months

21.4 months

0.01

Overall survival at 36 months

34%

11%

0.005

Multivariable adjusted

0.002

Study 9902A

 

Vaccine n=65

Control n=33

p value

Median time to progression

10.9 weeks

9.9 weeks

0.719

Overall median survival

19.0 months

15.7 months

0.331

IMPACT study

 

Vaccine n=341

Control n=171

p value

Overall median survival

25.8 months

21.7 months

0.032

Overall survival at 36 months

31.7%

23.0%

0.036

Time to progression

Not reported

Not reported

Hazard ratio: 0.95

p=0.628

Results of study 9901A for the principal outcome of time to progression did not show a significant difference between vaccine and control. Median time to progression was 11.7 weeks for the vaccine group and 10.0 weeks for the control group.

A survival analysis of study 9901A was presented in the FDA briefing document, with the caveats that the study was not powered to show a survival effect and that a primary method of survival analysis was not prespecified in the protocol. The median survival times for vaccine-treated patients was 25.9 months and for placebo-treated patients was 21.4 months, which was statistically significant (p=0.011; log-rank test). At 36 months, the survival rate was 34% for vaccine-treated patients and 11% for placebo-treated patients.

The FDA briefing document shows analyses of possible confounders regarding the survival analysis(7). After disease progression, patients in both groups received chemotherapy, but the rate of chemotherapy was slightly higher in the placebo-treated groups (48% versus 36%, respectively). Examination of the causes of death did not reveal any obvious spurious elevation of non-cancer causes of death in the placebo group. The published version of study 9901A by Small et al. (2006)(4) analyzed the survival data after adjusting for prognostic factors and found a significant association of sipuleucel-T treatment and survival (hazard ratio [HR]: 2.12; 95% confidence interval [CI]: 1.31–3.44).

Because study 9901A did not meet its principal outcome endpoint for efficacy, enrollment for its partner study 9902A was suspended. Its sample size was therefore smaller, and the study subsequently had lower statistical power. Results for study 9902A showed a median time to progression of 10.9 weeks in the vaccine group versus 9.9 weeks in the placebo group, which was not statistically significant. A survival analysis of study 9902A showed that vaccine-treated patients had a median survival of 19 months, and control patients had a median survival of 15.7 months, which was also not statistically significant.

Higano et al (2009) pooled survival data from the 2 studies.(5) Pooled analysis showed a 33% reduction in the risk of death (HR=1.50; 95% CI, 1.10 to 2.05; p=0.011). The association was robust to adjustments in imbalances in baseline prognostic factors and postprogression chemotherapy use.

Because these earlier studies did not meet criteria for success for their principal end points, FDA did not approve sipuleucel-T in 2007. A larger phase 3 trial of similar design called IMPACT enrolling 512 patients was designed with a principal end point of overall survival.(6) Analyses used to support FDA approval reported a 22% reduction in overall mortality in patients treated with sipuleucel-T. Treatment extended median survival by 4.1 months, compared with placebo (25.8 months vs 21.7 months, respectively) and improved 3-year survival by a relative 38%, compared with placebo (31.7% vs 23.0%, respectively). Results adjusted for subsequent docetaxel use and timing, as well as analyses examining prostate cancer-specific survival showed similar magnitude and statistical significance of the survival benefit. Of note, 14% of enrolled subjects in this trial had received prior docetaxel. In retrospective, prespecified, multivariate subgroup analysis, several baseline factors were associated with overall survival: prostate-specific antigen (PSA), lactate dehydrogenase, hemoglobin, ECOG Performance Status, alkaline phosphatase, and Gleason score.(8) Analysis of PSA by quartiles showed that men in the lowest quartile had the greatest survival benefit with sipuleucel-T: 49% reduced mortality compared with 26% reduced mortality in the second quartile, 19% in the third quartile, and 16% in the highest quartile.

Regarding the safety of sipuleucel-T, most adverse effects were grade 1 and 2 and resolved within 48 hours. The rate of serious adverse events was not statistically different between vaccine- and placebotreated patients. However, 1 difficulty in assessing potential adverse effects by comparing sipuleucel-T with placebo is that placebo comprised infusion of untreated dendritic cells, which may cause adverse effects. FDA reviewers expressed concern regarding a possible association of sipuleucel-T with cerebrovascular events, as 8 (5%) of 147 vaccine-treated patients experienced cerebrovascular-related adverse events, compared with zero placebo-treated patients in the 2 early trials.(7) In the latest available report of adverse effects reported in the full prescribing information,(3) incidence of stroke was 3.5% in the sipuleucel-T group and 2.6% in the control group, but these figures appear to include data from trials evaluating a different indication. In the FDA review summarizing cerebrovascular event rates from studies 9901A, 9902A, and interim data from IMPACT, incidence of stroke was 4.9% (17/345) in sipuleucel-Ttreated patients and 1.7% (3/172) in placebo-treated patients (p=0.092). FDA review called the cerebrovascular event rate a “potential safety signal” and included as part of the approval a postmarketing study, based on a registry design, to assess the risk of cerebrovascular events in 1500 patients with prostate cancer who receive sipuleucel-T.

Section Summary

For patients with metastatic, androgen-independent prostate cancer, 3 RCTs of sipuleucel-T have been published. The 3 RCTs are consistent in reporting an improvement in overall survival of approximately 4 months compared with placebo. Two trials also reported that 36-month survival was significantly improved for patients receiving sipuleucel-T, with absolute improvements in survival of 9% and 23%. Time to progression was slightly longer in the sipuleucel-T groups, but this difference was not statistically significant. Serious adverse events were not increased in the sipuleucel-T group. There has been concern raised about a possible increase in stroke risk, but the available trials do not show a significantly increased incidence of stroke.

Other Indications

A phase 3 trial of sipuleucel-T in the setting of androgen-dependent, nonmetastatic prostate cancer was published in 2011.(9) Patients with prostate cancer detectable by PSA after radical prostatectomy received 3 to 4 months of androgen suppression therapy and were then randomized (2:1) to receive sipuleucel-T (n=117) or control (n=59). The primary end point was time to biochemical failure. There was
no difference in this end point between groups; median time to biochemical failure was 18.0 months for sipuleucel-T and 15.4 months for control (HR=0.936; p=0.737). Sipuleucel-T patients had a 48% increase in PSA doubling time after testosterone recovery (155 vs 105 days; p=0.038). Sixteen percent of patients developed distant failure. The treatment effect favored sipuleucel-T but was not statistically significant
(HR=0.728; p=0.421).

Section Summary

A single RCT has been performed in patients with nonmetastatic prostate cancer, and this trial did not show any benefit for sipuleucel-T compared with control. Therefore, evidence on treatment of nonmetastatic prostate cancer is not sufficient to determine that health outcomes are improved.

Ongoing Trials

Other indications are currently being investigated in clinical trials in progress. A trial to determine whether sipuleucel-T and androgen deprivation therapy augment each other in patients with recurrent but nonmetastatic prostate cancer is currently in progress (NCT01431391). Sipuleucel-T as neoadjuvant therapy for patients with localized prostate cancer undergoing prostatectomy is being investigated (NCT00715104). In men with metastatic, hormone-resistant prostate cancer, concurrent versus sequential sipuleucel-T plus abiraterone is under study (NCT01487863), as is sipuleucel-T in combination with enzalutamide (NCT01981122), radiotherapy (NCT01807065, NCT01818986, NCT01833208), the chemotherapeutic agents indoximod (NCT01560923) and cyclophosphamide (NCT01420965), the investigational agent tasquinimod (NCT02159950), and recombinant interleukin-7 (NCT01881867).

Summary

For patients with metastatic, androgen-independent prostate cancer, 3 randomized controlled trials of sipuleucel-T reported an improvement in median survival of approximately 4 months. The 2 early studies of sipuleucel-T were not specifically designed to demonstrate a difference in overall mortality but did show a survival difference. The third study, which was designed to demonstrate a mortality difference, showed a similar improvement in overall survival. All 3 studies also were consistent in demonstrating that sipuleucel-T does not delay time to measureable progression of disease. In all studies, many patients had further chemotherapy treatment at the discretion of the treating physician; thus, the survival benefit accrues in the context of additional treatment as needed for symptomatic recurrence. This evidence is
sufficient to conclude that sipuleucel-T is medically necessary for patients with androgen-independent, asymptomatic or minimally symptomatic, metastatic prostate cancer.

For patients who do not meet the above criteria, evidence does not demonstrate an improvement in health outcomes. One RCT of patients with androgen-dependent, nonmetastatic prostate cancer showed no statistical difference between sipuleucel-T and control in time to biochemical failure or PSA doubling time. This evidence does not support the use of sipuleucel-T for these patients, and therefore sipuleucel-
T is considered investigational for all other indications, including but not limited to hormone-responsive prostate cancer, treatment of moderate to severe symptomatic metastatic prostate cancer, and treatment of visceral (liver, lung, or brain) metastases.

Practice Guidelines and Position Statements

National Comprehensive Cancer Network (NCCN)

Current NCCN Guidelines for prostate cancer (version 2.2014) recommend sipuleucel-T as a category 1 treatment for patients with metastatic castration-recurrent prostate cancer.(10) A note states that sipuleucel-T is appropriate for asymptomatic or minimally symptomatic patients with ECOG Performance Status 0-1; and it is not indicated in patients with liver metastasis or life expectancy less than 6 months. Sipuleucel-T also is recommended for second-line treatment of symptomatic patients with metastatic castration-recurrent prostate cancer who fail chemotherapy and otherwise meet criteria for treatment with sipuleucel-T (category 2A recommendation). This recommendation was based on further analysis of the previously reviewed clinical trials, which showed similar benefit in both those who had and had not received prior chemotherapy.(11)

European Consensus Panel

On September 7, 2013, 21 experts in the field of prostate cancer met in France to “evaluate current opinion regarding the most appropriate sequencing of available therapies for metastatic castration-resistant prostate cancer,” among other objectives.(12) The panel used a modified Delphi method to obtain consensus, based on the biannual St. Gallen Early Breast Cancer Consensus Conference. The panel agreed (≥70% consensus) that sipuleucel-T is a reasonable option for patients with asymptomatic or minimally symptomatic metastatic hormone-refractory prostate cancer and should be considered before docetaxel, abiraterone, and enzalutamide. The panel considered sipuleucel-T a new treatment option “during the time period between development of hormone-refractory disease and becoming a candidate for chemotherapy.”

U.S. Preventive Services Task Force
The use of sipuleucel-T for prostate cancer is not a preventive service.

Medicare National Coverage
On June 30, 2011 a national coverage determination was released by CMS approving sipuleucel-T for treatment of asymptomatic or minimally symptomatic castrate-resistant prostate cancer.(13) Coverage for off-label indications was left to the discretion of local Medicare administrative contractors.

References: 

  1. Berry DL, Moinpour CM, Jiang CS et al. Quality of life and pain in advanced stage prostate cancer: results of a Southwest Oncology Group randomized trial comparing docetaxel and estramustine to mitoxantrone and prednisone. J Clin Oncol 2006; 24(18):2828-35.
  2. Tannock IF, de WR, Berry WR et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351(15):1502-12.
  3. Dendreon Corporation. Seattle W. Provenge® (sipuleucel-T) prescribing information.June 2011. Available online at: http://www.provenge.com/pdf/prescribing-information.pdf. Last accessed June 2014.
  4. Small EJ, Schellhammer PF, Higano CS et al. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 2006; 24(19):3089-94.
  5. Higano CS, Schellhammer PF, Small EJ et al. Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer 2009; 115(16):3670-9.
  6. Kantoff PW, Higano CS, Shore ND et al. Sipuleucel-T Immunotherapy for Castration-Resistant Prostate Cancer. N Engl J Med 2010; 363(5):411-22.
  7. U.S. Food and Drug Administration. Cellular, Tissue and Gene Therapies Advisory Committee Meeting, Clinical Briefing Document: Provenge® (sipuleucel T), 03/29/2007. Available online at:
    http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4291B1_2a.pdf. Last accessed June 2014.
  8. Schellhammer PF, Chodak G, Whitmore JB et al. Lower Baseline Prostate-specific Antigen Is Associated With a Greater Overall Survival Benefit From Sipuleucel-T in the Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) Trial. Urology 2013; 81(6):1297-302.
  9. Beer TM, Bernstein GT, Corman JM et al. Randomized trial of autologous cellular immunotherapy with sipuleucel-T in androgen-dependent prostate cancer. Clin Cancer Res 2011; 17(13):4558-567.
  10. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: prostate cancer, version 2.2014. Available online at:
    http://www.nccn.org/professionals/physician_gls/PDF/prostate.pdf. Last accessed June 2014.
  11. Mohler JL, Armstrong AJ, Bahnson RR et al. Prostate cancer, Version 3.2012: featured updates to the NCCN guidelines. J Natl Compr Canc Netw 2012; 10(9):1081-7.
  12. Fitzpatrick JM, Bellmunt J, Fizazi K et al. Optimal management of metastatic castration-resistant prostate cancer: Highlights from a European Expert Consensus Panel. Eur J Cancer 2014; 50(9):1617-27.
  13. Center for Medicare and Medicaid Services. National Coverage Determination (NCD) for Autologous Cellular Immunotherapy Treatment (110.22), 06/30/2011 . 2011. Available online at:
    http://www.cms.gov/medicare-coverage-database/details/ncddetails.aspx?NCDId=344&ncdver=1&bc=AAAAgAAAAAAA&. Last accessed June 2014.

Codes

Number

Description

CPT 36511 Therapeutic apheresis; for white cells
  96365 Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hout
ICD-9-CM diagnosis 185 Malignant neoplasm of prostate
  Q2043 Sipuleucel-t, minimum of 50 million autologous cd54+ cells activated with pap-gm-csf, including leukapheresis and all other preparatory procedures, per infusion
ICD-10-CM (effective 10/1/15) C61 Malignant neoplasm of prostate
ICD-10-PCS (effective 10/1/15)   ICD-10-PCS codes are only used for inpatient services. There is no specific ICD-10-PCS code for this procedure. 
   6A550Z1, 6A551Z1 Extracorporeal therapies, physiological systems, pheresis, circulatory, leukacytes, code by duration (single or multiple) 
  30233Q0, 30243Q0 Administration, circulatory, transfusion, percutaneous, white cells, autologous, code by body part (peripheral vein or central vein)

 


Index

Prostate Cancer Vaccine
Sipuleicel-T
Vaccine, Prostate Cancer


Policy History

 

Date Action Reason
05/13/10 Add to Therapy section new policy
7/14/11 Policy replaced  
8/11/11 Replace policy Previously unpublished preliminary trial information updated with published information. Medicare coverage decision granted 6/30/2011, section updated. Reference 8 added
08/09/12 Replace policy Policy updated with literature review. Reference 10 added. No change to policy statements
7/11/13 Replace policy Policy updated with literature review through May 2013. Reference 10 added. No change to policy statements
7/10/14 Replace policy Policy updated with literature review through June 20, 2014; references 6, 8, and 12 added; references 3, 7, 10,
and 13 updated; reference 7 deleted. No change to policy statements.