Medical Policy: 08.01.27
Original Effective Date: December 2017
Reviewed: December 2018
Revised: December 2018
Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.
This Medical Policy 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 will be reviewed regularly and be updated as scientific and medical literature becomes available.
Provenge (Sipuleucel-T) (also referred to as a vaccine) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer (mCRPC). The agent comprises specially treated dendritic cells (antigen presenting cells, also known as accessory cells) obtained from the patient through leukapheresis. The cells are then exposed in vitro to proteins that contain prostate antigens and immunologic-stimulating factors and reinfused into the patient. The proposed mechanism of action is that treatment stimulates the patient’s own immune system to resist cancer spread.
An estimated 164,690 new cases of prostate cancer will be diagnosed in 2018, accounting for 19% of new cancer cases in men. Researchers have estimated that prostate cancer will account for 9% of male cancer deaths in 2018. In most cases of prostate cancer, prostate cancer is diagnosed at a localized stage and is treated with prostatectomy or radiotherapy. However, some patients are diagnosed with metastatic or recurrent disease after treatment of localized disease.
Androgen deprivation therapy (ADT) (androgen ablation) is the standard treatment for metastatic or recurrent disease. Most patients who survive long enough eventually develop androgen-independent (castration resistant) prostate cancer. At this stage of metastatic disease, docetaxel, a chemotherapeutic agent, has demonstrated a survival benefit of 1.9 to 2.4 months in randomized clinical trials. Chemotherapy with docetaxel causes adverse events in large proportions of patients, including alopecia, fatigue, neutropenia, neuropathy, and other symptoms. Trials evaluating docetaxel included both asymptomatic and symptomatic patients, and results suggested a survival benefit for both groups. Due to the burden of treatment and its adverse events, most patients defer docetaxel treatment until cancer recurrence is symptomatic.
Cancer immunotherapy has been investigated as a treatment that could be instituted at the point of detection of androgen-independent metastatic disease (castration-resistant) before significant symptomatic manifestations have occurred. The quantity of prostate cancer cells in the patient during this time is thought to be relatively low, and it is thought that an effective immune response to the cancer during this interval 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.
Provenge (Sipuleucel-T) is a newer class of therapeutic agent used to treat asymptomatic or minimally symptomatic, androgen-independent (castrate resistant [hormone refractory]) metastatic prostate cancer. Provenge (Sipuleucel-T) consists of autologous peripheral blood mononuclear cells, including antigen presenting cells (APCs) (dendritic cells) that have been activated during a defined culture period with a recombinant human protein, PAP-CM-CSF, consisting of prostatic acid phosphatase (PAP), an antigen expressed in prostate cancer tissue, linked to granulocyte-macrophage colony-stimulating factor (GM-CSF), an immune cell activator. The patient’s peripheral blood mononuclear cells are obtained via a standard leukapheresis procedure approximately 3 days prior to the infusion date.
The active components of Provenge (Sipuleucel-T) are autologous APCs (dendritic cells) and PAP-GM-CSF. During culture, the recombinant antigen can bind to and be processed by APCs into smaller protein fragments. The recombinant antigen is designed to target APCs, and may help direct the immune response to PAP. Minimal residual levels of the intact PAP-GM-CSF are detectable in the final Provenge product.
The cellular composition of Provenge (Sipuleucel-T) is dependent on the composition of cells obtained from the patient’s leukaphersis. In addition to APCs (dendritic cells), the final product contains antigen presenting cells to include T-cells, B-cells, natural killer (NK) cells and other cells. The number of cells present and the cellular composition of each Provenge (Sipuleucel-T) dose will vary. Each does contains a minimum of 50 million autologous CD54+ cells activated with PAP-CM-CSF, suspended in 250 mL of Lactated Ringers injection.
The potency of Provenge (Sipuleucel-T) is in part determined by measuring the increased expression of the CD54 molecule, also known as ICAM-1, on the surface of APCs (dendritic cells) after culture with PAP-CM-CSF. CD54 is a cell surface molecule that plays a role in the immunologic interaction between APCs and T-cells, and is considered a marker of immune cell activation.
Provenge (Sipuleucel-T) is administered in 3 intravenous infusions given approximately 2 weeks apart. Each infusion takes about 60 minutes and following each infusion the patient will be monitored for at least 30 minutes. The most common side effects include chills, fatigue, fever, back pain, nausea, joint ache and headache. The proposed mechanism of action is that the treatment stimulates the patient’s own immune system to resist cancer spread.
Yi et.al. (2016) reported on a meta-analysis to investigate the efficacy and safety of sipuleucel-T and androgen receptor directed therapies in patients with castration-resistant prostate cancer (CRPC). Seven studies were included in the meta-analysis, with three studies in sipuleucel-T (totally 737 patients, 488 patients in treatment group, and 249 patients in placebo group) and four in AR-directed therapies (totally 5,199 patients, 3,015 patients in treatment group, and 2,184 patients in placebo group). Treatment with sipuleucel-T significantly improved overall survival in patients with CRPC and was not associated with increased risk of adverse event of grade ≥3 (p > 0.05). However, treatment with sipuleucel-T did not improve time-to-progression and reduction of prostate-specific antigen (PSA) level ≥50% was not significantly different from that with placebo. AR-directed therapies significantly improved overall survival in patients with CRPC and improved time-to-progression and reduction of PSA level ≥50%. AR-directed therapies did not increase risk of adverse event of grade ≥3 (p > 0.05).
The analyses used to support the FDA approval for Provenge (Sipuleucel-T) was based on three similar randomized, double blinded, placebo controlled, multicenter phase III trials in asymptomatic or minimally symptomatic mCRPC (metastatic castrate resistant prostate cancer). In study 1 (IMPACT Trial) (Kantoff, et. al) 512 patients were randomly assigned in a 2:1 ratio to receive either Sipuleucel-T (341 patients) or placebo (171 patients) administered intravenously every 2 weeks, for a total of three infusions. The primary end point was overall survival, analyzed by means of a stratified Cox regression model adjusted for baseline levels of serum prostate-specific antigen (PSA) and lactate dehydrogenase. In the Sipuleucel-T group, there was a relative reduction of 22% in the risk of death compared with the placebo group (hazard ratio, 0.78; 95% confidence interval [CI], 0.61 to 0.98; P=0.03). This reduction represented a 4.1 month improvement in median survival (25.8 months in the Sipuleucel-T group vs. 21.7 months in the placebo group). The 36 month survival probably was 31.7% in the Sipuleucel-T group versus 23.0% in the placebo group. The treatment effect was also observed with the use of an unadjusted Cox model and a log-rank test (hazard ratio, 0.77; 95% CI, 0.61 to 0.97; P=0.02) and after adjustment for use of docetaxel after the study therapy (hazard ratio, 0.78; 95% CI, 0.62 to 0.98; P=0.03), The time to objective disease progression was similar in the two study groups. Immune response to the immunizing antigen were observed in patients who receive Sipuleucel-T. Adverse events that were more frequently reported in the Sipuleucel-T group than in the placebo group included chills, fever and headache. The authors concluded the use of Sipuleucel-T prolonged overall survival among men with metastatic castration-resistant prostate cancer. No effect on the time to disease progression was observed. In study 2, 127 patients were randomly assigned to receive Sipuleucel-T (82 patients) or placebo (45 patients). This study demonstrated a significant reduction in the risk of death (overall survival) with Sipuleucel-T (25.9 months) versus control (placebo 21.4 months). In study 3, 98 patients were randomly assigned to receive Sipuleucel-T (65 patients) and placebo (33 patients) a trend towards improved survival was observed despite early discontinuation of enrollment Sipuleucel-T 19.0 months and placebo 15.7 months.
For individuals who have asymptomatic or minimally symptomatic metastatic castration resistant prostate cancer (mCRPC) who receive Provenge (Sipuleucel-T), the evidence includes 3 randomized controlled trials (RCTs). The 3 RCTs are consistent in reporting an improvement in overall survival (OS) of approximately 4 months compared with placebo placebo (25.8 months in the Sipuleucel-T group vs. 21.7 months in the placebo group). Additionally, 2 trials also reported that the 36 month survival was significantly improved in the Sipuleucel-T group versus the placebo group. However, the time to objective disease progression was similar in the two study groups. The most common adverse events in the Provenge (Sipuleucel-T) group at a rate ≥ 15% were chills, fatigue, fever, back pain, nausea, joint ache and headache. Serious adverse events were reported in 24% of the patients in Provenge (Sipuleucel-T) group which included acute infusion reactions and cerebrovascular events. Due to the increase risk of stroke, this risk is being evaluated in a post-marketing study. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
In 2011, Beer et. al. published a double blinded randomized controlled trial (RCT) (PROTECT – PROvenge Treatment and Early Cancer Treatment) evaluating patients with androgen-dependent prostate cancer. The trial was designed to examine time to biochemical failure (BF), the primary endpoint defined as serum PSA ≥ 3.0 ng/mL. PSA doubling time (PSADT), time to distant failure, immune response and safety were also evaluated. Patients with prostate cancer detectable by serum prostate specific antigen (PSA) following radical prostatectomy receiving 3 to 4 months of androgen suppression therapy, were randomized 2:1 to receive Sipuleucel-T (117 patients) or control (59 patients). Median time to BF 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 PSADT following testosterone recovery (155 vs 105 days, P = 0.038). With only 16% of patients having developed distant failure, the treatment effect favored Sipuleucel-T (HR = 0.728, P = 0.421). The most frequent adverse events in Sipuleucel-T patients were fatigue, chills and pyrexia. Immune response to the immunizing agent were greater in the Sipuleucel-T patients at weeks 4 and 13 (P = 0.0001, all) and were sustained prior to boosting as measured in a subset of patients a medial of 22.6 months (range 14.3-67.3 months) following randomization. The authors concluded that no significant different in time to biochemical failure (BF) could be shown. The finding of increased PSADT in the Sipuleucel-T arm is consistent with biologic activity in the ADPC. Long term follow-up will be necessary to determine if clinically important events, such as distant failure are affected by therapy. Additional studies in this patient population are needed.
Only one randomized controlled trial (RCT) has evaluated Provenge (Sipuleucel-T) in patients with non-metastatic androgen-dependent prostate cancer. This trial did not show a statistically significant difference between Provenge (Sipuleucel-T) and control in time to biochemical failure. The randomized controlled trial (RCT) was not designed to evaluate the impact of Provenge (Sipuleucel-T) on mortality. Also, society guidelines at this time do not include within their recommendations use of Provenge (Sipuleucel-T) in patients with non-metastatic androgen-dependent prostate cancer. The evidence is insufficient to determine the effects of the technology on net health outcomes.
NCCN guideline prostate cancer version 4.2018 has the following guideline for principles of immunotherapy and chemotherapy:
In April 2010, Sipuleucel-T became the first in the new class of cancer immunotherapeutic agents to be approved by the FDA. This autologous cancer “vaccine” involves collection of the white blood cell fraction containing antigen-presenting cells from each patient, exposure of the cells to the prostatic acid phosphatase-granulocyte macrophage colony-stimulating factor (PAP-CM-CSF recombinant fusion protein), and subsequent reinfusion of the cells. The pivotal study was a phase 3 multicenter, randomized, double-blind trial (D9902B). Five hundred twelve patients with minimally symptomatic or asymptomatic metastatic CRPC were randomized 2:1 to receive Sipuleucel-T or placebo. Median survival in the vaccine arm was 25.8 months compared to 21.7 months in the control arm. Sipuleucel-T treatment resulted in a 22% reduction in mortality risk (HR, 0.78; 95% CI, 0.61-0.98; P = .03). Common complications included mild to moderate chills (54.1%), pyrexia (29.3%) and headache (16.0%), which usually were transient.
Clinicians and patients should be aware that the usual makers of benefit (decline in PSA and improvement in bone or CT scans) are not usually seen, and therefore benefit to the individual patient cannot be ascertained using currently available testing.
In 2018, the American Urological Association amended their 2013 guideline on castration resistant prostate cancer (CRPC). The guideline includes the following statements on Sipuleucel-T:
Index Patient 1: Asymptomatic Non-Metastatic CRPC
Index Patient 2: Asymptomatic or Minimally Symptomatic, mCRPC Without Prior Docetaxel Chemotherapy
Index Patient 3: Symptomatic, mCPRC with Good Performance Status and no Prior Docetaxel Chemotherapy
Index Patient 4: Symptomatic, mCRPC with Poor Performance Status and No Prior Docetaxel Chemotherapy
Index Patient 6: Symptomatic, mCPRC with Poor Performance Status and Prior Docetaxel Chemotherapy
In 2014, the American Society of Clinical Oncology (ASCO) and Cancer Care Ontario issued a joint evidence-based guidelines on systemic therapy in men with metastatic castration-resistant prostate cancer (mCRPC). The guideline includes the following recommendations regarding sipuleucel-T:
Therapies with demonstrated survival benefit and unclear quality-of-life benefit:
In April 2010, the U.S. Food and Drug Administration (FDA) approved Provenge (Sipuleucel-T) (Dendreon Corp) via a biologics licensing application for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. Approval was contingent on the manufacturer conducting a post-marketing study based on a registry design to assess the risk of cerebrovascular events in 1500 men with prostate cancer who receive Provenge (Sipuleucel-T).
Provenge (Sipuleucel-T) therapy may be considered medically necessary for the treatment of individuals with metastatic castrate-resistant (mCRPC) (hormone refractory) prostate cancer who meet ALL the following criteria:
When Provenge (Sipuleucel-T) is considered medically necessary based on the above criteria, it will be covered for a one time only series of 3 completed doses (infusions) administered at approximately 2-week intervals.
Provenge (Sipuleucel-T) therapy is considered investigational for all other indications, including but not limitied to the following, due to the lack of scientific evidence demonstrating an impact on improved health outcomes:
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