Prostate Cancer Vaccine

Number: 0802

Policy

Note: REQUIRES PRECERTIFICATION

Precertification of sipuleucel-T is required of all Aetna participating providers and members in applicable plan designs.  For precertification of sipuleucel-T, call (866) 752-7021, or fax (866) 267-3277.

Aetna considers sipuleucel-T (Provenge) medically necessary for the treatment of adults with metastatic castrate-resistant (hormone-refractory) prostate cancer who are asymptomatic or minimally symptomatic with Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, and who have no liver metastases and a life expectancy of greater than 6 months.

Administration of more than 3 complete doses of sipuleucel-T is considered experimental and investigational.

Aetna considers sipuleucel-T experimental and investigational for the following indications (not an all-inclusive list) because its effectiveness for these indications has not been established:

• Prevention of prostate cancer
• Stage I to III prostate cancer
• Treatment of germ cell tumors
• Treatment of glioblastoma
• Treatment of localized prostate cancer
• Treatment of sarcoma
• Treatment of small cell / neuroendocrine prostate cancer
• Treatment of urogenital malignancies (e.g., bladder cancer).

Aetna considers use of sipuleucel-T in combination with abiraterone acetate (Zytiga), enzalutamide (Xtandi), or ipilimumab (Yervoy) experimental and investigational due to lack of evidence supporting safety and efficacy of these combinations. 

See also:

• CPB 0521 - Prostate Cancer Screening,
• CPB 0698 - Prostate Saturation Biopsy,
• CPB 0806 - Cabazitaxel (Jevtana), and
• CPB 0815 - Ipilimumab (Yervoy).

Dosing Recommendations

Each dose of Provenge (sipuleucel-T) contains a minimum of 50 million autologous CD54+ cells activated with PAP-GM-CSF, suspended in 250 mL of Lactated Ringer’s Injection, USP., for autologous use and intravenous use only.

According to the FDA-approved labeling of Provenge, the recommended course of therapy for sipuleucel-T is 3 complete doses, given at approximately 2-week intervals. Administration is per intravenous infusion delivered over approximately 60 minutes.

In controlled clinical trials, the median dosing interval between infusions was 2 weeks (range of 1 to 15 weeks); the maximum dosing interval has not been established.

Source: Dendreon, 2017

Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Provenge is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant (hormone-refractory) prostate cancer (Dendreon, 2017).

The National Comrehensive Cancer Network compendium (NCCN, 2020) includes sipuleucel-T as a category 1 recommendation for first-line treatment of asymptomatic or minimally symptomatic patients with castration-resistant distant metastatic (M1) prostate cancer, and a 2A recommendation for second-line treatment (preferred if received first-line abiraterone/enzalutamide).  The NCCN guidelines (2020) state that sipuleucel-T is appropriate for patients with ECOG performance status 0-1, estimated life expectancy greater than 6 months, and no hepatic (or other visceral) metastases. 

Provenge (sipuleucel‐T) is the first in a class of drugs called active cellular immunotherapies. Agents in this class are designed to stimulate a patient’s own immune system. Provenge (sipuleucel‐T) works by stimulating T‐cell immunity against prostatic acid phosphatase, a protein also known as prostatic specific acid phosphatase that is produced in large amounts by prostate cancer cells. The mature, autologous antigen ‐presenting cells (APCs), contained by Provenge (sipuleucel‐T), are co‐cultured with a recombinant fusion protein containing prostatic acid phosphatase. These activated antigen‐loaded APCs can now potentially stimulate a T cell response against prostate cancer cells.

Provenge (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. Provenge (sipuleucel‐T) is intended solely for autologous use and is supplied as a 250 mL suspension containing autologous CD54+ cells in Lactated Ringer’s Injection and supplied in an infusion bag labeled for the specific recipient.

Prostate cancer, accounting for 33 % of all male cancers worldwide, is the second leading cause of cancer death in men, exceeded only by lung cancer.  The disease is histologically evident in as many as 34 % of men during their fifth decade of life and in up to 70 % of men aged 80 years old and older.  In the United States, prostate cancer represents the most common cancer among men, with an estimated 192,280 new cases diagnosed in 2009.  The median survival for men with metastatic castrate-resistant prostate cancer is 1 to 2 years, with improvements in survival seen primarily with cytotoxic chemotherapy (docetaxel-based therapies).  In the field of metastatic castration-resistant prostate cancer, systemic therapy options are limited and survival benefit remains to be seen with the new therapies.  Staging of prostate cancer entails the size of the tumor, if lymph nodes are affected, if the tumor has metastasized, and the appropriate course of treatment. Circulating tumor cells may provide prognostic information and will likely become an important aspect of future clinical decision-making (Lassi and Dawson, 2010).

Standard systemic treatment of prostate cancer today is comprised of anti-hormonal and cytostatic agents.  Vaccine therapy of prostate cancer is attractive because of the presence of tumor-associated antigens such as prostate-specific antigen (PSA), prostatic acid phosphatase (PAP), prostate-specific membrane antigen, and others.  Most prostate cancer vaccine trials have demonstrated some activation of the immune system, limited clinical success, and few adverse effects.  One strategy to overcome the problem of limited clinical success of vaccine therapies in prostate cancer could be strict patient selection.  The clinical course of patients with prostate cancer (even in those with PSA relapse following surgery or radiotherapy with curative intention, or those with metastatic disease) can vary significantly.  In patients with organ-confined prostate cancer, the most promising immunotherapeutic approach would be an adjuvant therapy following surgery or radiotherapy.  Patients with PSA relapse following surgery or radiotherapy could also benefit from immunotherapy because tumor burden is usually low.  However, most patients in prostate cancer vaccine trials had metastatic hormone-refractory prostate cancer (HRPC).  High tumor burden correlates with immune escape phenomena.  Nevertheless, 2 years ago, it was reported, for the first time, that a tumor vaccine can prolong survival compared with placebo in patients with HRPC.  This was demonstrated with the vaccine sipuleucel-T (APC-8015; Provenge), a mixture of cells obtained from the patient's peripheral blood by leukapheresis followed by density centrifugation and exposition.  The biologics license application for this vaccine was denied by the U.S. Food and Drug Administration (FDA) in mid-2007, however, because the trial had failed to reach the primary endpoint (prolongation of time to tumor progression).  Another interesting approach is a vaccine made from whole tumor cells: GVAX.  This vaccine is presently being studied in phase III trials against, and in combination with, docetaxel.  The results from these trials will become available in the near future.  Besides the precise definition of the disease status of patients with prostate cancer, combinations of vaccine therapy with radiotherapy, chemotherapy, and/or hormonal therapy are approaches that look promising and deserve further investigation (Doehn et al, 2008).

Sipuleucel-T is an immunotherapeutic cellular product, which includes autologous dendritic cells pulsed ex vivo with a recombinant fusion protein (PA2024) consisting of granulocyte macrophage colony-stimulating factor and PAP.  It is designed to stimulate the patient's T-cells to recognize and attack prostate cancer cells that express PAP antigen (Harzstark and Small, 2008).

In a phase III clinical trial, Small and colleagues (2006) evaluated the safety and effectiveness of sipuleucel-T in patients with metastatic, asymptomatic HRPC.  A total of 127 patients were randomly assigned in a 2:1 ratio to receive 3 infusions of sipuleucel-T (n = 82) or placebo (n = 45) every 2 weeks.  On disease progression, placebo patients could receive APC8015F, a product made with frozen leukapheresis cells.  Of the 127 patients, 115 patients had progressive disease at the time of data analysis, and all patients were followed for survival for 36 months.  The median for time to disease progression (TTP) for sipuleucel-T was 11.7 weeks compared with 10.0 weeks for placebo (p = 0.052, log-rank; hazard ratio [HR], 1.45; 95 % confidence interval [CI]: 0.99 to 2.11).  Median survival was 25.9 months for sipuleucel-T and 21.4 months for placebo (p = 0.01, log-rank; HR, 1.70; 95 % CI: 1.13 to 2.56).  Treatment remained a strong independent predictor of overall survival after adjusting for prognostic factors using a Cox multi-variable regression model (p = 0.002, Wald test; HR, 2.12; 95 % CI: 1.31 to 3.44).  The median ratio of T-cell stimulation at 8 weeks to pre-treatment was 8-fold higher in sipuleucel-T-treated patients (16.9 versus 1.99; p < 0.001).  Sipuleucel-T therapy was well-tolerated.  The authors concluded that while the improvement in the primary end point of TTP did not achieve statistical significance, this study suggested that sipuleucel-T may provide a survival advantage to asymptomatic HRPC patients.

Patel and Kockler (2008) reviewed the design, efficacy, safety, dosing, therapeutic, and pharmaco-economic considerations of sipuleucel-T.  English-language literature searches of Medline (1966 to September 2007) and the Cochrane Database (2007, Issue 3) were performed using the terms sipuleucel-T, APC8015, and prostate cancer vaccine.  Other data sources were identified from bibliographies of selected articles and from press releases.  All published articles or abstracts on human studies of sipuleucel-T for androgen-independent prostate cancer (AIPC) were reviewed for inclusion.  Manufacturer Web sites, FDA documents, and the clinical trials registry were used to obtain information regarding ongoing clinical trials.  Androgen-independent prostate cancer is an incurable disease with a median survival rate of 18 to 20 months.  Docetaxel-based chemotherapy is currently the only FDA-approved treatment for AIPC with a survival benefit (2.4 months).  Sipuleucel-T is a novel active cellular immunotherapy under investigation for the treatment of metastatic, asymptomatic AIPC.  In clinical trials, the primary endpoint of TTP was not met; however, an under-powered analysis of data suggests that sipuleucel-T prolongs survival by a median of 4.5 months compared with placebo.  Sipuleucel-T has been relatively well-tolerated, although a possible increased risk of cerebrovascular events may exist.  In May 2007, the FDA did not approve the biologics license application for sipuleucel-T since the primary endpoint of the phase III trials was not met.  The authors concluded that metastatic AIPC is an incurable disease that currently has limited treatment options.  If improved survival is shown, sipuleucel-T may become the first approved active cellular immunotherapy for treating metastatic, asymptomatic AIPC.

Higano and colleagues (2009) examined the safety and effectiveness of sipuleucel-T in 2 identically designed, randomized, double-blind, placebo-controlled trials (D9901 and D9902A) conducted in men with advanced prostate cancer.  A total of 225 patients were randomized in D9901 or D9902A to sipuleucel-T (n = 147) or placebo (n = 78), given as 3 intravenous infusions approximately 2 weeks apart.  Patients were followed for survival until death or a pre-specified cut-off of 36 months after randomization.  In the integrated analysis of D9901 and D9902A, patients randomized to sipuleucel-T demonstrated a 33 % reduction in the risk of death (HR, 1.50; 95 % CI: 1.10 to 2.05; p = 0.011; log-rank).  The treatment effect remained strong after performing adjustments for imbalances in baseline prognostic factors, post-study treatment chemotherapy use, and non-prostate cancer-related deaths.  Additional support for the activity of sipuleucel-T is provided by the correlation between a measure of the product's potency, CD54 up-regulation, and overall survival.  The most common adverse events associated with treatment were asthenia, chills, dyspnea, headache, pyrexia, tremor, and vomiting.  These events were primarily grade 1 and 2, with durations of 1 to 2 days.  The authors concluded that the integrated results of D9901 and D9902A demonstrated a survival benefit for patients treated with sipuleucel-T compared with those treated with placebo.  The generally modest toxicity profile, coupled with the survival benefit, suggests a favorable risk-benefit ratio for sipuleucel-T in patients with advanced prostate cancer.

Drake and Antonarakis (2010) stated that prostate cancer is the second most common cause of cancer-related death among men in the United States.  Along with initial therapy using surgery, radiotherapy, or cryotherapy, hormonal therapy is the mainstay of treatment.  For men with metastatic disease, docetaxel-based chemotherapy is FDA-approved, and provides a significant survival advantage.  This relative paucity of treatment options drives an ongoing quest for additional treatment modalities; among these is immunotherapy.  The concept that prostate cancer is a malignancy that can be targeted by the immune system may seem counter-intuitive; certainly kidney cancer and melanoma are more traditionally thought of as immune responsive cancers.  However, prostate cancer arises in a relatively unique organ and may express a number of antigens against which an immune response can be generated.  More importantly, several of these agents have now demonstrated a significant survival benefit in randomized controlled clinical trials. 

On April 29, 2010, the FDA approved Provenge (sipuleucel-T, Dendreon Corporation, Seattle, WA) for the treatment of asymptomatic or minimally symptomatic prostate cancer that has metastasized and is resistant to standard hormone treatment.  The effectiveness of Provenge was studied in a randomized, double-blind, placebo-controlled, multi-center trial in patients with asymptomatic or minimally symptomatic metastatic HRPC.  Eligible patients had metastatic disease in the soft tissue and/or bone with evidence of progression either at these sites or by serial PSA measurements.  Exclusion criteria included visceral (liver, lung, or brain) metastases, moderate-to-severe prostate cancer-related pain, and use of narcotics for cancer-related pain.  A total of 512 patients were randomized in a 2:1 ratio to receive Provenge (n = 341) or control (n = 171).  The median age was 71 years, and 90 % of the patients were Caucasian; 35 % of patients had undergone radical prostatectomy, 54 % had received local radiotherapy, and 82 % had received combined androgen blockade.  All patients had baseline testosterone levels less than 50 ng/ml; 48 % of patients were receiving bisphosphonates and 18 % had received prior chemotherapy, including docetaxel.  A total of 82 % of patients had an Eastern Cooperative Oncology Group performance status of 0; 58 % had primary Gleason scores of 4 or more; 44 % had bone and soft tissue disease; 48 % had bone-only disease; 7 % had soft tissue-only disease; and 43 % had greater than 10 bony metastases.  Patients treated with Provenge showed an increase in overall survival of 4.1 months.  The median survival for patients receiving Provenge treatments was 25.8 months, as compared to 21.7 months for those who did not receive the treatment.  Overall, Provenge reduced the risk of death by 22.5 % compared to the control group (HR = 0.775).

Provenge is administered intravenously in a 3-dose schedule administered at about 2-week intervals (range of 1 to 15 weeks).  It is administered over a period of about 60 minutes.  Almost all of the patients who received Provenge had some type of adverse reaction.  Common adverse reactions included back pain, chills, fatigue, fever, headache, joint ache, and nausea.  The majority of adverse reactions were mild or moderate in severity.  Serious adverse reactions, reported in about 25 % of the patients receiving Provenge, included some acute infusion reactions and stroke.  Cerebrovascular events, including hemorrhagic and ischemic strokes, were observed in 3.5 % of patients in the Provenge group compared with 2.6 % of patients in the control group.

Provenge (sipuleucel‐T) is intended solely for autologous use.

Acute infusion reactions have been observed in patients treated with Provenge (sipuleucel‐T). In the event of an acute infusion reaction, the infusion rate may be decreased, or the infusion stopped, depending on the severity of the reaction. To minimize potential acute infusion reactions such as chills and/or fever, it is recommended that patients be premedicated orally with acetaminophen and an antihistamine such as diphenhydramine approximately 30 minutes prior to administration. Appropriate medical therapy should be administered as needed. Closely monitor members with cardiac or pulmonary conditions.

Provenge (sipuleucel‐T) is not routinely tested for transmissible infectious diseases and may transmit diseases to health care professionals handling the product. Universal precautions should be followed.

Use of either chemotherapy or immunosuppressive agents (such as systemic corticosteroids) given concurrently with the leukapheresis procedure or Provenge (sipuleucel‐T) has not been studied. Provenge (sipuleucel‐T) is designed to stimulate the immune system, and concurrent use of immunosuppressive agents may alter the efficacy and/or safety of Provenge (sipuleucel‐T). Therefore, members should be carefully evaluated to determine whether it is medically appropriate to reduce or discontinue immunosuppressive agents prior to treatment with Provenge (sipuleucel‐T).

Phase III clinical trials investigating the efficacy and safety of Provenge (sipuleucel‐T) excluded patients who had received systemic glucocorticoids in the previous 28 days and patients who had undergone chemotherapy within the previous 3 months. The survival findings were consistent across multiple subgroups in Phase 3 studies of Provenge (sipuleucel‐T) in men with metastatic castrate resistant prostate cancer. Provenge (sipuleucel‐T) increased median survival by 4.1 months compared to the control group (p=0.032). This absolute survival improvement offers a favorable risk/benefit profile given that the safety profile was consistent with prior studies. Importantly, the placebo arm demonstrated a median survival of 21.7 months indicating that the benefit was from drug effect versus poor performance in the control arm. Additionally, after adjustment for docetaxel use following Provenge (sipuleucel‐T), the Hazard Ratio maintained its robustness (HR=0.763; p‐value=0.036). Provenge (sipuleucel‐T) extended median overall survival by 4.1 months (25.8 months for Provenge vs. 21.7 months for placebo). Provenge (sipuleucel‐T) reduced the risk of death by 22.5%, though it is important to realize the AIPC is incurable. Provenge (sipuleucel‐T) improved 3 year survival by 38% compared to placebo. Member demographics were well balanced which included Gleason score, ECOG status, >10 bone metastasis, and bisphosphonate use. Baseline labs were also well balanced with similar PSA, Alk Phos, Hg, WBC, and LDH. Analyses of time to disease progression did not meet statistical significance in any Phase 3 study of Provenge (sipuleucel‐T). Provenge (sipuleucel‐T) is not recommended for patients with a life expectancy of less than six months.

Combination immunotherapy with Provenge plus other agents has been studied in patients with prostate cancer.  Rini and colleagues (2006) noted that bevacizumab is a recombinant antibody against vascular endothelial growth factor, a pro-angiogenic protein with inhibitory effects on antigen-presenting cells (APC).  These researchers carried out a clinical trial to determine the PSA and immunomodulatory effects of combination immunotherapy with sipuleucel-T plus bevacizumab in patients with serologic progression of prostate cancer after definitive local therapy.  Patients with androgen-dependent prostate cancer who had received prior definitive therapy with non-metastatic, recurrent disease as manifested by a rising PSA of between 0.4 ng/ml and 6.0 ng/ml were enrolled.  Sipuleucel-T was given intravenously (i.v.) on weeks 0, 2, and 4.  Bevacizumab was given at a dose of 10 mg/kg i.v. on weeks 0, 2, 4, and every 2 weeks thereafter until toxicity or disease progression.  Changes in PSA were recorded and the PSA doubling time (PSADT) was calculated.  Immune response versus PA2024 was measured at baseline and after treatment by T-cell proliferation and interferon-gamma enzyme-linked immunospot (ELISPOT) assays.  A total of 22 patients were treated.  One patient achieved a greater than or equal to 50 % decrease in PSA; 9 patients exhibited some decrease in PSA from baseline, ranging from 6 % to 72 %, with the PSA of 3 patients decreasing at least 25 %.  The median pre-treatment PSADT for the 20 evaluable patients was 6.9 months and the median post-treatment PSADT was 12.7 months (p = 0.01).  All patients demonstrated induction of an immune response against PA2024.  The authors concluded that the combination of sipuleucel-T and bevacizumab induces an immune response and modulates PSA in patients with biochemically recurrent prostate cancer.

Antonarakis and Drake (2010) stated that an emerging paradigm for the treatment of prostate cancer focuses on using immunotherapy plus check-point antagonists or in combination with conventional therapies in patients with early-stage disease.  Such approaches are likely to yield optimal results, but must carefully be explored in well-designed phase II studies.

Lubaroff (2012) presented important information about the current state of the art for vaccine immunotherapy of prostate cancer.  It included important preclinical research for each of the important prostate cancer vaccines to have reached clinical trials.  To-date, the only prostate cancer vaccine that has completed phase III trials and has been approved and licensed by the FDA is Sipuleucel-T, which immunizes patients against the prostate-associated antigen PAP.  A phase III trial is currently underway using the vaccinia-based PSA vaccine Prostvac-TRICOM.  Other immunotherapeutic vaccines in trials include the Ad/PSA vaccine Ad5-PSA and the DNA/PAP vaccine.  A cellular vaccine, GVAX, has been in clinical trials, but has not seen continuous study. 

Amato and Stepankiw (2012) reviewed the development of the combination of modified vaccinia Ankara (MVA) to deliver the tumor-associated antigen 5T4 as a novel immunotherapeutic vaccine.  The onco-fetal antigen 5T4 is highly expressed in 80 % of breast, kidney, colorectal, prostate and ovarian carcinomas, making it an ideal antigen for vaccine therapy.  To-date, more than 3,000 doses of MVA-5T4 have been administered to patients with colorectal, renal and prostate cancer, with rare occurrences of grade 3 or 4 vaccination-related adverse events being observed.  Studies have demonstrated that MVA-5T4 is safe and highly immunogenic, both as monotherapy and in combination with other standard of care therapies.  Although an immune response has been observed, anti-tumor activity has been modest or absent in clinical trials.  A phase III trial resulted in the development of an immune response surrogate that is to be applied to all future MVA-5T4 clinical trials.  The authors concluded that with minimal side effects and the ability to produce a strong immunogenic response, MVA-5T4 is a viable addition to the cancer therapy arsenal.

Reardon et al (2013) stated that outcome for glioblastoma (GBM) remains poor.  The overall survival benefit recently achieved with immunotherapeutics – ipilimumab for melanoma and sipuleucel-T for prostate cancer – support evaluation of immunotherapies for other challenging cancers, including GBM.  Much historical dogma depicting the central nervous system (CNS) as immune-privileged has been replaced by data demonstrating CNS immune-competence and active interaction with the peripheral immune system.  Several glioma antigens have been identified for potential immunotherapeutic exploitation.  Active immunotherapy studies for GBM, supported by pre-clinical data, have focused on tumor lysate and synthetic antigen vaccination strategies.  Results to-date confirmed consistent safety, including a lack of autoimmune reactivity; however, modest efficacy and variable immunogenicity have been observed.  The authors concluded that these findings underscored the need to optimize vaccination variables and to address challenges posed by systemic and local immunosuppression inherent to GBM tumors.  Moreover, they noted that additional immunotherapy strategies are also in development for GBM; future studies may consider combinatorial immunotherapy strategies with complimentary actions.

Goldberg (2013) stated that although molecularly targeted inhibitors are of great interest in treating sarcoma patients, immunotherapy is emerging as a plausible therapeutic modality because of the recent advances in other cancer types that may be translated to sarcoma.  The licensing of ipilimumab for melanoma and sipuleucel-T for prostate cancer, and the remarkable success of immunotherapy for some childhood cancers, suggest a role for immunotherapy in the treatment of tumors like sarcoma.  The author described the current advances in immunotherapy and how they can be applied to sarcoma, and discussed the recent literature and selected clinical trials.  Evidence supporting treatment with immunotherapy alone in sarcoma as well as potential incorporation of immunotherapy into treatment for sarcoma was reviewed.  The author concluded that sarcoma is a disease for which new treatments are needed.  Immunotherapies have different mechanisms of action from most current therapies and could work in concert with them.  Recent advances in sarcoma biology and cancer immunotherapy suggest that the understanding of the immune system has reached the point where it can be used to augment both targeted and multi-modality therapy for sarcoma.

Gulley et al (2014) stated that PSA-TRICOM (PROSTVAC) is a novel vector-based vaccine designed to generate a robust immune response against PSA-expressing tumor cells.  These researchers presented an overview of both published studies and new data in the evaluation of immune responses to the PSA-TRICOM vaccine platform, currently in phase III testing.  Of 104 patients tested for T-cell responses, 57 % (59/104) demonstrated a greater than or equal to 2-fold increase in PSA-specific T cells 4 weeks after vaccine (median 5-fold increase) compared with pre-vaccine, and 68 % (19/28) of patients tested mounted post-vaccine immune responses to tumor-associated antigens not present in the vaccine (antigen spreading).  The PSA-specific immune responses observed 28 days after vaccine (i.e., likely memory cells) are quantitatively similar to the levels of circulating T cells specific for influenza seen in the same patients.  Measurements of systemic immune response to PSA may under-estimate the true therapeutic immune response (as this does not account for cells that have trafficked to the tumor) and do not include antigen spreading.  Furthermore, although the entire PSA gene is the vaccine, only 1 epitope of PSA is evaluated in the T-cell responses.  Because this therapeutic vaccine is directed at generating a cellular/Th1 immune response (T-cell co-stimulatory molecules and use of a viral vector), it is not surprising that less than 0.6 % of patients (2/349) tested have evidence of PSA antibody induction following vaccine.  The authors concluded that this suggested that post-vaccine PSA kinetics were not affected by PSA antibodies.  Moreover, they stated that an ongoing phase III study will evaluate the systemic immune responses and correlation with clinical outcomes.

Jochems et al (2014) previously reported the clinical results of a phase I trial combining ipilimumab with a vaccine containing transgenes for PSA and for a triad of co-stimulatory molecules (PROSTVAC) in patients with metastatic castration-resistant prostate cancer.  A total of 30 patients were treated with escalating ipilimumab and a fixed dose of vaccine.  Of 24 chemotherapy-naïve patients, 58 % had a PSA decline.  Combination therapy did not exacerbate the immune-related adverse events associated with ipilimumab.  These researchers presented updated survival data and an evaluation of 36 immune cell subsets pre- and post-therapy.  Peripheral blood mononuclear cells were collected before therapy, at 13 days and at 70 days post-initiation of therapy, and phenotyped by flow cytometry for the subsets of T cells, regulatory T cells, natural killer cells, and myeloid-derived suppressor cells.  Associations between overall survival (OS) and immune cell subsets prior to treatment, and the change in a given immune cell subset 70 days post-initiation of therapy, were evaluated.  The median OS was 2.63 years (1.77 to 3.45).  There were trends toward associations for longer OS and certain immune cell subsets before immunotherapy: lower PD-1(+)Tim-3(NEG)CD4EM (p = 0.005, adjusted p = 0.010), higher PD-1(NEG)Tim-3(+)CD8 (p = 0.002, adjusted p = 0.004), and a higher number of CTLA-4(NEG) Tregs (p = 0.005, adjusted p = 0.010).  These investigators also found that an increase in Tim-3(+) natural killer cells post- versus pre-vaccination associated with longer OS (p = 0.0074, adjusted p = 0.015).  The authors concluded that these results should be considered as hypothesis generating and should be further evaluated in larger immunotherapy trials.

Lubaroff et al (2014) noted that pre-clinical studies demonstrated the ability of an adenovirus/PSA (Ad/PSA) vaccine to induce strong anti-PSA immune responses, and these responses were capable of destroying PSA-secreting mouse prostate tumors.  A series of pre-clinical studies have demonstrated the superiority of the Ad/PSA vaccine to other PSA vaccines for the induction of anti-PSA immune responses, the ability of Ad/PSA vaccination combined with cytokine gene therapy and the TLR9 agonist CpG to enhance the anti-prostate tumor immunotherapy, and the reduction of negative regulatory elements when the vaccine was combined with 5-fluoruracil administration.  A phase I clinical trial of the Ad/PSA vaccine in men with metastatic castrate-resistant prostate cancer demonstrated the safety of the vaccine even at the highest single dose permitted by the FDA.  Currently, a phase II trial of the Ad/PSA vaccine is underway treating patients in 2 protocols.  Thus far 81 patients have been enrolled and vaccinated.  The authors concluded that early results demonstrated the induction of anti-PSA T cell responses, and the majority of patients evaluated at this time had demonstrated an increase in PSA doubling times.

Simpson et al (2015) stated that the National Institute for Health and Care Excellence (NICE) invited Dendreon, the company manufacturing sipuleucel-T, to submit evidence for the clinical- and cost-effectiveness of sipuleucel-T for asymptomatic or minimally symptomatic, metastatic, non-visceral hormone-relapsed prostate cancer patients in whom chemotherapy is not yet clinically indicated, as part of NICE's single technology appraisal process. The comparator was abiraterone acetate (AA) or best supportive care (BSC). The School of Health and Related Research at the University of Sheffield was commissioned to act as the Evidence Review Group (ERG). The ERG had several concerns regarding the data and assumptions incorporated within the company's cost-effectiveness analyses and conducted exploratory analyses to quantify the impact of making alternative assumptions or using alternative data inputs. The deterministic incremental cost-effectiveness ratio (ICER) for sipuleucel-T versus BSC when using the ERG's preferred data and assumptions was £108,585 per quality-adjusted life-year (QALY) in the whole licensed population and £61,204/QALY in the subgroup with low PSA at baseline. The ERG also conducted an incremental analysis comparing sipuleucel-T with both AA and BSC in the chemotherapy-naive subgroup. Sipuleucel-T had a deterministic ICER of £111,682/QALY in this subgroup, when using the ERG's preferred assumptions, and AA was extendedly dominated. The ERG also concluded that estimates of costs and benefits for AA should be interpreted with caution given the limitations of the indirect comparison. The NICE Appraisal Committee noted that the ICER for sipuleucel-T was well above the range usually considered cost-effective, and did not recommend sipuleucel-T for the treatment of asymptomatic or minimally symptomatic, metastatic, non-visceral hormone-relapsed prostate cancer.

Germ Cell Tumors and Urogenital Malignancies

Geczi and colleagues (2016) provided information regarding advance and main achievements in the immunotherapy of genitourinary, particularly renal cell and prostate cancer. Nivolumab treatment became the new standard of care in locally advanced or metastatic renal cell cancer after failure on tyrosine kinase inhibitor treatment.  Sipuleucel-T prolonged survival in patients with asymptomatic or minimally symptomatic metastatic castration resistant prostate cancer; but had no effect on progression-free survival.  The authors stated that based on the results of phase I/II trials anti-PD-1/PD-L1 monoclonal antibodies are a new hope in the treatment of urothelial bladder cancer; regarding germ cell tumors basic research is ongoing.

Cattrini and associates (2016) stated that in the past few years, cancer immunotherapy has changed the natural history and treatment strategies of a number of solid tumors, including melanoma and lung cancer. The anti-PD-1 nivolumab showed a survival benefit compared with everolimus in the 2nd-line treatment of renal cell carcinoma, resulting in a radical shift in perspective in the treatment of this neoplasia and suggesting a new scenario beyond tyrosine kinase inhibitors.  Check-point inhibitors might also improve the treatment of urothelial cancer, considering the promising results achieved so far and the relatively low effectiveness of currently available treatments.  Sipuleucel-T was the first approved immunotherapy for PC, showing a clear benefit in OS, and paved the way for the clinical testing of other novel cancer vaccines.  The authors provided a comprehensive overview of the current knowledge and new perspectives of immunotherapy in the treatment of urogenital malignancies.

Radiation Therapy in Combination with Sipuleucel-T for Prostate Cancer

Twardowski and colleagues (2019) noted that sipuleucel-T is an autologous cellular immunotherapy indicated for patients with asymptomatic or minimally symptomatic mCRPC.  Since radiation therapy (RT) can suppress bone marrow function and immune responses, previous studies evaluating sipuleucel-T excluded patients who received RT less than or equal to 28 days prior to sipuleucel-T therapy.  Recent evidence suggested that RT may act synergistically with immunotherapy to enhance and broaden anti-tumor immune response.  In a randomized, phase-II clinical trial, patients who met standard criteria for sipuleucel-T were randomized to receive sipuleucel-T alone (Arm A) or sipuleucel-T initiated 1 week after completing sensitizing RT to single metastatic site (Arm B); RT was delivered at 300 cGy/day to 3,000 cGy total.  The primary end-point was the ability to safely combine sipuleucel-T preceded by RT and generate sipuleucel-T with adequate product immune activation parameters.  Secondary end-points included the measurement of systemic immune responses to prostatic acid phosphatase (PAP), a target for sipuleucel-T immune therapy and PA20204 (recombinant fusion protein utilized in the generation of sipuleucel-T).  A total of 51 patients were enrolled, 2 did not receive any sipuleucel-T because of vascular access problems and were excluded; 24 were treated on Arm A, 25 on Arm B; 47/49 patients received all 3 sipuleucel-T infusions.  Median age was 66 years (range of 45 to 90).  Sipuleucel-T product parameters including: total nucleated cell (TNC) count, APC count were similar in both groups.  Cumulative APC up-regulation was higher in Arm A; 1 patient in Arm A demonstrated PSA response.  Median progression free survival (PFS) was 2.46 months on Arm A, and 3.65 months on Arm B (p = 0.06).  Both arms showed similar increases in humoral responses to PA2024 and PAP.  Interferon-gamma (IFN-ƴ) ELISPOT T-cell activation responses to PA20204 were observed in both arms, but were more robust in the Arm A (p = 0.028).  Both arms were well-tolerated, with fatigue as the most common grade 2 adverse event (AE; 1 patient in Arm A and 3 patients in Arm B).  The authors concluded that sensitizing RT completed 1 week before generation of sipuleucel-T did not affect the majority of product parameters and the ability to deliver sipuleucel-T therapy.  Moreover, RT did not enhance the humoral and cellular responses associated with sipuleucel-T therapy.

Sipuleucel-T Combined with Ipilimumab (Yervoy)

In a phase I clinical trial, Scholz and colleagues (2017) examined the effects of sipuleucel-T combined with escalating doses of ipilimumab (IPI) in progressive metastatic castrate-resistant prostate cancer (mCRPC).  A total of 9 men with progressive mCRPC were treated prospectively with SIP-T followed immediately by IPI with one of the following doses of IPI: 1 mg/kg at 1 week after SIP-T; 1 mg/kg at 1 and 4 weeks after SIP-T; or 1 mg/kg at 1, 4, and 7 weeks after SIP-T; 3 patients were evaluated at each level.  Cancer-specific immunoglobulins directed at granulocyte-macrophage-colony-stimulating factor (GM-CSF)/ PAP fusion protein (PA2024) and PAP were measured prior to SIP-T, after SIP-T, 1 week after IPI, every other month for 5 months, then every 3 months for an additional 12 months.  Adverse events of SIP-T were consistent with previous reports; IPI only caused a transient grade 1 rash in 1 patient.  Median age, Gleason score, and number of previous hormonal interventions were 77 years, 8, and 3, respectively; 8 men had bone metastases and 1 had lymph node metastasis.  Statistically significant increases in serum immunoglobulin G (IgG) and IgG-IgM specific for PA2024 and PAP occurred after SIP-T.  An additional statistically significant increase in the afore-mentioned immunoglobulins – above the levels achieved by SIP-T – occurred after IPI.  Median clinical follow-up was 36 months (range of 26 to 40 months); 3 patients died from progressive disease after 9, 18, and 20 months.  Out of the remaining 6 patients, 5 of them needed further treatment that included abiraterone acetate, enzalutamide, radium-223 dichloride, and spot radiation.  One patient had an undetectable PSA, who did not receive any other treatment except spot radiation.  Median PSA at last follow-up for the surviving patients was 3.8 (range of 0.6 to 7.47).  The authors concluded that in this small trial, the addition of IPI to SIP-T was well-tolerated; IPI increased immunoglobulins specific for the PA2024 protein and PAP above the level achieved with SIP-T alone.  They stated that firm conclusions regarding the effectiveness of SIPIPI in such a small series such as this one are difficult to derive; moreover, these data support ongoing trials of SIPIPI in mCRPC with larger patient numbers, albeit with higher doses of IPI.

Sipuleucel-T for Small Cell / Neuroendocrine Prostate Cancer

National Comprehensive Cancer Network’s clinical practice guideline on “Prostate cancer” (Version 2.2020) states that sipuleucel-T is not recommended for patients with small cell/neuroendocrine prostate cancer. Benefit with sipuleucel-T has not been reported in patients with visceral metastases and is not recommended if visceral metastases are present.

Appendix

Table: 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, e.g., light house work, office work
2	Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50 % of waking hours
3	Capable of only limited selfcare, confined to bed or chair more than 50 % of waking hours
4	Completely disabled. Can not carry on any selfcare. Totally confined to bed or chair
5	Dead

Source: 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.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
Other CPT codes related to the CPB:
96401 - 96417	Chemotherapy administration
HCPCS codes covered if selection criteria are met:
Q2043	Sipuleucel-T, minimum of 50 million autologous CD54+ cells activated with PAP-GM-CSF, including leukapheresis and all other preparatory procedures, per infusion
Other HCPCS codes related to the CPB:
J9228	Injection, ipilimumab, 1 mg
ICD-10 codes covered if selection criteria are met:
C61	Malignant neoplasm of prostate [see criteria]
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C49.0 - C49.9	Malignant neoplasm of connective tissue and other soft tissue [sarcoma]
C60.0 - C60.9	Malignant neoplasm of penis
C62.00 - C62.92	Malignant neoplasm of testis [germ cell tumor]
C63.00 - C63.9	Malignant neoplasm of other and unspecified male genital organs
C64.1 - C68.9	Malignant neoplasm of urinary tract
C71.0 - C71.9	Malignant neoplasm of brain [glioblastoma]
C78.7	Secondary malignant neoplasm of liver and intrahepatic bile duct
D07.60 - D07.69	Carcinoma in situ of other and unspecified male genital organs [germ cell tumor]
D09.0	Carcinoma in situ of bladder
D09.10 - D09.19	Carcinoma in situ of other and unspecified urinary organs

The above policy is based on the following references: