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If the sipuleucel-T story were a movie, it would have most of the elements of a blockbuster: money, power, conflict, ethics, and even death threats.
What the prostate cancer vaccine doesn’t have, at least not yet, is the Hollywood ending: the "ah-ha" moment when the protagonist – in this case the first autologous cellular immunotherapy approved for any oncology indication – overcomes unbelievable odds and revolutionizes cancer treatment.
Instead, the momentum that propelled sipuleucel-T along the turbulent path to regulatory approval in April 2010 seems to have stalled. Acceptance in the prostate cancer market has been slower than expected, as sales fell substantially short of consensus estimates for the second quarter. Market analysts are skewering the manufacturer, Dendreon, for grossly overinflating expectations, and, at least in the business sector, the company’s claims that reimbursement concerns are at the root of the sluggish numbers seem to be falling on deaf ears.
Terms such as "implosion" and "derailment" in the business press have the ominous tone of a death knell for sipuleucel-T (Provenge), but oncologists and urologists in the trenches are more forgiving, albeit reasonably cautious. In an ironic twist, interviews show they want more data – a complaint that has dogged sipuleucel-T since the 2007 decision by the Food and Drug Administration’s Center for Biologics Evaluation and Research to act against its advisory panel’s favorable recommendations.
Instead of approval, the agency sent a complete response letter requesting further clinical evidence. Patient and lobbyist picketing outside of FDA offices and cancer conferences, death threats to panelists who had resisted approval, calls for congressional inquiries, and a lawsuit grabbed headlines but did not reverse the decision.
And even after the indication was won, though a Centers for Medicare & Medicaid Services (CMS) panel voted in favor of national coverage for all Medicare beneficiaries beginning July 1 of this year, the panelists expressed only intermediate confidence that the immunotherapy was safe and effective for its labeled indication and very low confidence on off-label use.
Against this backdrop, perhaps it is not surprising that, of 16 physicians approached for this article, many had strong opinions but only a few would speak on the record.
Paradigm Advance Called Huge
Dr. Philip Kantoff, lead author of the pivotal phase-III IMPACT trial in which sipuleucel-T prolonged overall survival among men with metastatic castration-resistant prostate cancer, maintains that the treatment "represents a huge paradigm advance and is a significant advance for prostate cancer patients."
In the IMPACT trial, sipuleucel-T was associated with a median 4.1-month increase in patient survival, compared with patients in the control condition (25.8 months vs. 21.7 months). The 36-month survival probability in the sipuleucel-T group was estimated to be 31.7%, compared with 23.0% in the placebo group, the investigators reported (N. Engl. J. Med. 2010;363:411-22).
Although many have suggested that the cost of the treatment, at $93,000, may be a barrier to adoption, given the seemingly modest survival benefit in the absence of any prostate-specific antigen (PSA) changes or time-to-disease progression benefit, Dr. Kantoff disagrees. He suggests that it is the fears over timely reimbursement and not the cost of the treatment that is keeping many clinicians from taking the plunge.
"The cost [of sipuleucel-T] treatment is comparable to other cancer therapies; the difference is it is given over a 4-week period rather than over many months," Dr. Kantoff, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute in Boston, said in an interview.
The "cost-density" of the treatment, rather than the overall cost per se, combined with the requirement by some private payers for special coverage authorization, might be keeping some clinicians from jumping on board, at least until they are more confident in the reimbursement process, he said.
Dendreon has also cited cost-density as an important contributing factor to sipuleucel-T’s lower-than-predicted uptake among clinicians. The company’s Aug. 3, 2011 and Sept. 8, 2011 press releases, in which it reported second-quarter performance statistics and the corporate restructuring plan to compensate for the lack of anticipated growth, respectively, stated that the "primary issue affecting the dynamics of our launch is the reimbursement knowledge around [sipuleucel-T]."
Both communications suggested that the National Coverage Determination (NCD) issued by CMS and assignment of a Q code will lead to increased physician adoption over time.
The direct costs of the treatment, as well as the indirect costs in terms of staff time needed to arrange preauthorization and administer the infusions (three doses at 2-week intervals, with each dose preceded by the leukapheresis procedure 3 days prior), are obvious concerns. Clarifying the reimbursement picture is important, but it will hardly address all of the reasons urologists and oncologists might be reluctant to prescribe sipuleucel-T to their patients.
Clinicians Want Efficacy Measures
That the treatment doesn’t drop patients’ PSA levels or improve time to progression are more pressing considerations, as they relate to the value of the treatment, rather than the cost, clinicians observed in interviews.
"The lack of PSA response, or more specifically, the lack of correlation of PSA changes, makes use of [sipuleucel-T] problematic, as it is unclear from the trial data how to measure treatment efficacy and when to initiate new treatments," said Dr. Edouard J. Trabulsi, a urologist at Thomas Jefferson University and director of the multidisciplinary genitourinary cancer clinic at the Kimmel Cancer Center, both in Philadelphia.
Although the treatment is indicated for asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer, the bottom line for Dr. Evan Yu, an oncologist at the University of Washington, Seattle, "is that we don’t know who will benefit from it. We know that the population that received Provenge lived longer in the IMPACT trial, but the fact that there was no improvement in time to progression, and the survival curves didn’t separate until 6 months, tells us that a reasonable portion of patients may not benefit from it."
That said, Dr. Yu added that "there clearly are patients who will receive significant benefit from sipuleucel. We just aren’t sure who those patients are. My best guess is that it may be patients with low-volume disease and slow progression, but it is not always easy to identify this patient population. As a result, predictive and response biomarkers are needed, and Dendreon is doing research in this area."
Although it is clear that clinicians in practice should probably be more selective than the IMPACT population, "we have no data or guidelines to aid us in this selection process," he said.
Indication Limits Likely Patients
The reality, for now, is that sipuleucel-T "is indicated for a very narrow space in prostate cancer – the minimally symptomatic metastatic hormone-refractory patient prior to chemo – and likely will not be expanded widely to the entire advanced prostate cancer spectrum in the absence of additional clinical trial data," said Dr. Trabulsi.
In addition to the relatively narrow patient population for sipuleucel-T, the recent FDA approval of Johnson & Johnson’s abiraterone acetate (Zytiga), an oral inhibitor of testosterone synthesis, in combination with prednisone and the anticipated approval of Medivation’s oral testosterone- and dihydrotestosterone-blocking MVD3100 may have taken some of the wind out of sipuleucel-T’s sails, he noted.
Still, the denouement of the sipuleucel-T story should not be scripted by analysts or angry investors. At the end of the day, the FDA approval of the cancer "vaccine" does represent a milestone in the history of oncology, Dr Trabulsi said.
"[Sipuleucel-T] is very important as it shows a survival benefit and confirms the principle of immunomodulation being effective for prostate cancer," he said. "It also is illustrative of the new process for approval we likely will be seeing for expensive new treatments, as its use off label is severely restricted from earlier prostate cancer populations, which is unprecedented for FDA-approved drugs."
Dr. Kantoff has served as a consultant/adviser for Amgen and has received research funding from Sanofi-Aventis. Dr. Yu has received research funding support from OncoGenex Technologies and is a member of the U.S. Dept. of Defense–supported Prostate Cancer Clinical Trials Consortium. Dr. Trabulsi disclosed no relevant financial relationships.
If the sipuleucel-T story were a movie, it would have most of the elements of a blockbuster: money, power, conflict, ethics, and even death threats.
What the prostate cancer vaccine doesn’t have, at least not yet, is the Hollywood ending: the "ah-ha" moment when the protagonist – in this case the first autologous cellular immunotherapy approved for any oncology indication – overcomes unbelievable odds and revolutionizes cancer treatment.
Instead, the momentum that propelled sipuleucel-T along the turbulent path to regulatory approval in April 2010 seems to have stalled. Acceptance in the prostate cancer market has been slower than expected, as sales fell substantially short of consensus estimates for the second quarter. Market analysts are skewering the manufacturer, Dendreon, for grossly overinflating expectations, and, at least in the business sector, the company’s claims that reimbursement concerns are at the root of the sluggish numbers seem to be falling on deaf ears.
Terms such as "implosion" and "derailment" in the business press have the ominous tone of a death knell for sipuleucel-T (Provenge), but oncologists and urologists in the trenches are more forgiving, albeit reasonably cautious. In an ironic twist, interviews show they want more data – a complaint that has dogged sipuleucel-T since the 2007 decision by the Food and Drug Administration’s Center for Biologics Evaluation and Research to act against its advisory panel’s favorable recommendations.
Instead of approval, the agency sent a complete response letter requesting further clinical evidence. Patient and lobbyist picketing outside of FDA offices and cancer conferences, death threats to panelists who had resisted approval, calls for congressional inquiries, and a lawsuit grabbed headlines but did not reverse the decision.
And even after the indication was won, though a Centers for Medicare & Medicaid Services (CMS) panel voted in favor of national coverage for all Medicare beneficiaries beginning July 1 of this year, the panelists expressed only intermediate confidence that the immunotherapy was safe and effective for its labeled indication and very low confidence on off-label use.
Against this backdrop, perhaps it is not surprising that, of 16 physicians approached for this article, many had strong opinions but only a few would speak on the record.
Paradigm Advance Called Huge
Dr. Philip Kantoff, lead author of the pivotal phase-III IMPACT trial in which sipuleucel-T prolonged overall survival among men with metastatic castration-resistant prostate cancer, maintains that the treatment "represents a huge paradigm advance and is a significant advance for prostate cancer patients."
In the IMPACT trial, sipuleucel-T was associated with a median 4.1-month increase in patient survival, compared with patients in the control condition (25.8 months vs. 21.7 months). The 36-month survival probability in the sipuleucel-T group was estimated to be 31.7%, compared with 23.0% in the placebo group, the investigators reported (N. Engl. J. Med. 2010;363:411-22).
Although many have suggested that the cost of the treatment, at $93,000, may be a barrier to adoption, given the seemingly modest survival benefit in the absence of any prostate-specific antigen (PSA) changes or time-to-disease progression benefit, Dr. Kantoff disagrees. He suggests that it is the fears over timely reimbursement and not the cost of the treatment that is keeping many clinicians from taking the plunge.
"The cost [of sipuleucel-T] treatment is comparable to other cancer therapies; the difference is it is given over a 4-week period rather than over many months," Dr. Kantoff, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute in Boston, said in an interview.
The "cost-density" of the treatment, rather than the overall cost per se, combined with the requirement by some private payers for special coverage authorization, might be keeping some clinicians from jumping on board, at least until they are more confident in the reimbursement process, he said.
Dendreon has also cited cost-density as an important contributing factor to sipuleucel-T’s lower-than-predicted uptake among clinicians. The company’s Aug. 3, 2011 and Sept. 8, 2011 press releases, in which it reported second-quarter performance statistics and the corporate restructuring plan to compensate for the lack of anticipated growth, respectively, stated that the "primary issue affecting the dynamics of our launch is the reimbursement knowledge around [sipuleucel-T]."
Both communications suggested that the National Coverage Determination (NCD) issued by CMS and assignment of a Q code will lead to increased physician adoption over time.
The direct costs of the treatment, as well as the indirect costs in terms of staff time needed to arrange preauthorization and administer the infusions (three doses at 2-week intervals, with each dose preceded by the leukapheresis procedure 3 days prior), are obvious concerns. Clarifying the reimbursement picture is important, but it will hardly address all of the reasons urologists and oncologists might be reluctant to prescribe sipuleucel-T to their patients.
Clinicians Want Efficacy Measures
That the treatment doesn’t drop patients’ PSA levels or improve time to progression are more pressing considerations, as they relate to the value of the treatment, rather than the cost, clinicians observed in interviews.
"The lack of PSA response, or more specifically, the lack of correlation of PSA changes, makes use of [sipuleucel-T] problematic, as it is unclear from the trial data how to measure treatment efficacy and when to initiate new treatments," said Dr. Edouard J. Trabulsi, a urologist at Thomas Jefferson University and director of the multidisciplinary genitourinary cancer clinic at the Kimmel Cancer Center, both in Philadelphia.
Although the treatment is indicated for asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer, the bottom line for Dr. Evan Yu, an oncologist at the University of Washington, Seattle, "is that we don’t know who will benefit from it. We know that the population that received Provenge lived longer in the IMPACT trial, but the fact that there was no improvement in time to progression, and the survival curves didn’t separate until 6 months, tells us that a reasonable portion of patients may not benefit from it."
That said, Dr. Yu added that "there clearly are patients who will receive significant benefit from sipuleucel. We just aren’t sure who those patients are. My best guess is that it may be patients with low-volume disease and slow progression, but it is not always easy to identify this patient population. As a result, predictive and response biomarkers are needed, and Dendreon is doing research in this area."
Although it is clear that clinicians in practice should probably be more selective than the IMPACT population, "we have no data or guidelines to aid us in this selection process," he said.
Indication Limits Likely Patients
The reality, for now, is that sipuleucel-T "is indicated for a very narrow space in prostate cancer – the minimally symptomatic metastatic hormone-refractory patient prior to chemo – and likely will not be expanded widely to the entire advanced prostate cancer spectrum in the absence of additional clinical trial data," said Dr. Trabulsi.
In addition to the relatively narrow patient population for sipuleucel-T, the recent FDA approval of Johnson & Johnson’s abiraterone acetate (Zytiga), an oral inhibitor of testosterone synthesis, in combination with prednisone and the anticipated approval of Medivation’s oral testosterone- and dihydrotestosterone-blocking MVD3100 may have taken some of the wind out of sipuleucel-T’s sails, he noted.
Still, the denouement of the sipuleucel-T story should not be scripted by analysts or angry investors. At the end of the day, the FDA approval of the cancer "vaccine" does represent a milestone in the history of oncology, Dr Trabulsi said.
"[Sipuleucel-T] is very important as it shows a survival benefit and confirms the principle of immunomodulation being effective for prostate cancer," he said. "It also is illustrative of the new process for approval we likely will be seeing for expensive new treatments, as its use off label is severely restricted from earlier prostate cancer populations, which is unprecedented for FDA-approved drugs."
Dr. Kantoff has served as a consultant/adviser for Amgen and has received research funding from Sanofi-Aventis. Dr. Yu has received research funding support from OncoGenex Technologies and is a member of the U.S. Dept. of Defense–supported Prostate Cancer Clinical Trials Consortium. Dr. Trabulsi disclosed no relevant financial relationships.
If the sipuleucel-T story were a movie, it would have most of the elements of a blockbuster: money, power, conflict, ethics, and even death threats.
What the prostate cancer vaccine doesn’t have, at least not yet, is the Hollywood ending: the "ah-ha" moment when the protagonist – in this case the first autologous cellular immunotherapy approved for any oncology indication – overcomes unbelievable odds and revolutionizes cancer treatment.
Instead, the momentum that propelled sipuleucel-T along the turbulent path to regulatory approval in April 2010 seems to have stalled. Acceptance in the prostate cancer market has been slower than expected, as sales fell substantially short of consensus estimates for the second quarter. Market analysts are skewering the manufacturer, Dendreon, for grossly overinflating expectations, and, at least in the business sector, the company’s claims that reimbursement concerns are at the root of the sluggish numbers seem to be falling on deaf ears.
Terms such as "implosion" and "derailment" in the business press have the ominous tone of a death knell for sipuleucel-T (Provenge), but oncologists and urologists in the trenches are more forgiving, albeit reasonably cautious. In an ironic twist, interviews show they want more data – a complaint that has dogged sipuleucel-T since the 2007 decision by the Food and Drug Administration’s Center for Biologics Evaluation and Research to act against its advisory panel’s favorable recommendations.
Instead of approval, the agency sent a complete response letter requesting further clinical evidence. Patient and lobbyist picketing outside of FDA offices and cancer conferences, death threats to panelists who had resisted approval, calls for congressional inquiries, and a lawsuit grabbed headlines but did not reverse the decision.
And even after the indication was won, though a Centers for Medicare & Medicaid Services (CMS) panel voted in favor of national coverage for all Medicare beneficiaries beginning July 1 of this year, the panelists expressed only intermediate confidence that the immunotherapy was safe and effective for its labeled indication and very low confidence on off-label use.
Against this backdrop, perhaps it is not surprising that, of 16 physicians approached for this article, many had strong opinions but only a few would speak on the record.
Paradigm Advance Called Huge
Dr. Philip Kantoff, lead author of the pivotal phase-III IMPACT trial in which sipuleucel-T prolonged overall survival among men with metastatic castration-resistant prostate cancer, maintains that the treatment "represents a huge paradigm advance and is a significant advance for prostate cancer patients."
In the IMPACT trial, sipuleucel-T was associated with a median 4.1-month increase in patient survival, compared with patients in the control condition (25.8 months vs. 21.7 months). The 36-month survival probability in the sipuleucel-T group was estimated to be 31.7%, compared with 23.0% in the placebo group, the investigators reported (N. Engl. J. Med. 2010;363:411-22).
Although many have suggested that the cost of the treatment, at $93,000, may be a barrier to adoption, given the seemingly modest survival benefit in the absence of any prostate-specific antigen (PSA) changes or time-to-disease progression benefit, Dr. Kantoff disagrees. He suggests that it is the fears over timely reimbursement and not the cost of the treatment that is keeping many clinicians from taking the plunge.
"The cost [of sipuleucel-T] treatment is comparable to other cancer therapies; the difference is it is given over a 4-week period rather than over many months," Dr. Kantoff, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute in Boston, said in an interview.
The "cost-density" of the treatment, rather than the overall cost per se, combined with the requirement by some private payers for special coverage authorization, might be keeping some clinicians from jumping on board, at least until they are more confident in the reimbursement process, he said.
Dendreon has also cited cost-density as an important contributing factor to sipuleucel-T’s lower-than-predicted uptake among clinicians. The company’s Aug. 3, 2011 and Sept. 8, 2011 press releases, in which it reported second-quarter performance statistics and the corporate restructuring plan to compensate for the lack of anticipated growth, respectively, stated that the "primary issue affecting the dynamics of our launch is the reimbursement knowledge around [sipuleucel-T]."
Both communications suggested that the National Coverage Determination (NCD) issued by CMS and assignment of a Q code will lead to increased physician adoption over time.
The direct costs of the treatment, as well as the indirect costs in terms of staff time needed to arrange preauthorization and administer the infusions (three doses at 2-week intervals, with each dose preceded by the leukapheresis procedure 3 days prior), are obvious concerns. Clarifying the reimbursement picture is important, but it will hardly address all of the reasons urologists and oncologists might be reluctant to prescribe sipuleucel-T to their patients.
Clinicians Want Efficacy Measures
That the treatment doesn’t drop patients’ PSA levels or improve time to progression are more pressing considerations, as they relate to the value of the treatment, rather than the cost, clinicians observed in interviews.
"The lack of PSA response, or more specifically, the lack of correlation of PSA changes, makes use of [sipuleucel-T] problematic, as it is unclear from the trial data how to measure treatment efficacy and when to initiate new treatments," said Dr. Edouard J. Trabulsi, a urologist at Thomas Jefferson University and director of the multidisciplinary genitourinary cancer clinic at the Kimmel Cancer Center, both in Philadelphia.
Although the treatment is indicated for asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer, the bottom line for Dr. Evan Yu, an oncologist at the University of Washington, Seattle, "is that we don’t know who will benefit from it. We know that the population that received Provenge lived longer in the IMPACT trial, but the fact that there was no improvement in time to progression, and the survival curves didn’t separate until 6 months, tells us that a reasonable portion of patients may not benefit from it."
That said, Dr. Yu added that "there clearly are patients who will receive significant benefit from sipuleucel. We just aren’t sure who those patients are. My best guess is that it may be patients with low-volume disease and slow progression, but it is not always easy to identify this patient population. As a result, predictive and response biomarkers are needed, and Dendreon is doing research in this area."
Although it is clear that clinicians in practice should probably be more selective than the IMPACT population, "we have no data or guidelines to aid us in this selection process," he said.
Indication Limits Likely Patients
The reality, for now, is that sipuleucel-T "is indicated for a very narrow space in prostate cancer – the minimally symptomatic metastatic hormone-refractory patient prior to chemo – and likely will not be expanded widely to the entire advanced prostate cancer spectrum in the absence of additional clinical trial data," said Dr. Trabulsi.
In addition to the relatively narrow patient population for sipuleucel-T, the recent FDA approval of Johnson & Johnson’s abiraterone acetate (Zytiga), an oral inhibitor of testosterone synthesis, in combination with prednisone and the anticipated approval of Medivation’s oral testosterone- and dihydrotestosterone-blocking MVD3100 may have taken some of the wind out of sipuleucel-T’s sails, he noted.
Still, the denouement of the sipuleucel-T story should not be scripted by analysts or angry investors. At the end of the day, the FDA approval of the cancer "vaccine" does represent a milestone in the history of oncology, Dr Trabulsi said.
"[Sipuleucel-T] is very important as it shows a survival benefit and confirms the principle of immunomodulation being effective for prostate cancer," he said. "It also is illustrative of the new process for approval we likely will be seeing for expensive new treatments, as its use off label is severely restricted from earlier prostate cancer populations, which is unprecedented for FDA-approved drugs."
Dr. Kantoff has served as a consultant/adviser for Amgen and has received research funding from Sanofi-Aventis. Dr. Yu has received research funding support from OncoGenex Technologies and is a member of the U.S. Dept. of Defense–supported Prostate Cancer Clinical Trials Consortium. Dr. Trabulsi disclosed no relevant financial relationships.