Provenge wild ride blazes trail for immunotherapy

Amidst controversy, the FDA finally approved the prostate cancer therapy. Hopes are high that Provenge represents the first in a long line of effective immunotherapeutics.

The trip from bench to bedside for sipuleucel-T (Provenge) would seem to be inversely proportional to the mechanics of the vaccine's delivery. From the time a vial of Provenge leaves the manufacturing plant, clinicians have a tight 18 hours to administer the dose to a patient with castration-resistant prostate cancer.

In contrast, the vaccine was birthed in the 1990s, underwent trials in the early part of the 21st century, and received a green light from an FDA advisory committee in less than 10 years, only to have the agency reject the vaccine and ask for more data. Amidst death threats and conspiracy theories, the FDA finally approved Provenge in April 2010 (see Related Reading on page 6). The vaccine is currently undergoing a National Coverage Analysis by the Centers for Medicaid and Medicare Services, which is expected to render a reimbursement recommendation by April 2011.

Of course, a protracted drug development and approval process is not unusual in oncology. But what is unique about this situation is that, despite decades of research and analysis, there are still more questions than answers about Provenge: How and why does it actually work? How readily available will the vaccine be? In the post–healthcare-reform era, is Provenge worth its price-tag?

Oncology News International sought answers to these questions from prostate cancer specialists, and the experts agree on one point: Immunotherapy is the future for cancer treatment. But whether Provenge represents a major leap forward in this field, or is merely a small step in the right direction, remains to be seen.

TABLE 1 Results for trials DD901 and DD9902A

DD9901
Provenge median survival = 25.9 months
Placebo median survival = 21.4 months
P = .010

DD9902A
Provenge median survival = 19 months
Placebo median survival = 15.7 months
P = .31

The path to Provenge
Sipuleucel-T is an autologous, active cellular immunotherapy product designed to stimulate an immune response against prostate cancer (see Fact box on page 5). In 1996, developer Dendreon submitted an investigational new drug (IND) application to the FDA for sipuleucel-T. Four years later, two studies reported that exposing dendritic cells to antigen induced an antigen-specific cellular immunity in patients with prostate cancer and that the vaccine showed clinical efficacy (Clin Cancer Res 6:2175-2182, 2000; J Clin Oncol 18:3894-3903, 2000).

Dendreon began enrollment for two phase III trials in 2000, including prostate cancer patients whose cancer was no longer responsive to androgen-deprivation therapy. In the spring of 2002, interim results from one trial (D9901) showed a clinical benefit with the vaccine. At nine weeks, the time to disease progression (TTP) came in slightly above statistical significance in 127 patients (P = .052)

A primary analysis of D9901 in summer 2002 demonstrated a statistically significant treatment effect of delayed TTP for a subgroup of men with a Gleason score ≤7. Based on these findings, the FDA agreed to split the second trial (D9902) into two parts: D9902A included 98 subjects with a range of Gleason scores; D9902B included 512 subjects with Gleason scores of ≤ 7. Study D9902A showed a trend in survival similar to that of D9901, but was terminated prematurely and efficacy results were inconclusive.

In June 2003, the FDA issued a Special Protocol Assessment stating it would recognize trial D9902B as the basis for Provenge's Biologics License Application. In addition, the FDA placed D9902B on fast-track status, which allowed Dendreon to file its application in steps rather than as one final document.

Meanwhile, further analysis from D9901 showed that of all surviving patients, the percentage treated with Provenge was three times higher than that of patients receiving a placebo. As a result, the D9902B trial was reopened to all patients regardless of Gleason score, with overall survival (OS) as the primary endpoint.

The results of D9901 and D9902A were encouraging enough (see Table) that in March 2007, Dendreon presented its case to the FDA's Advisory Committee of the Center for Biologics Evaluation and Research (CBER). The committee's reaction seemed promising: A 17 to 0 vote that sipuleucel-T was safe and a 13 to 4 vote that it was effective. But the agency declined to approve sipuleucel-T and chose to defer licensure until "mature survival data" from the larger D9902B study were submitted for review.

No signs of benefit
One of the CBER committee members who voted against FDA approval of Provenge was Howard Scher, MD, of New York's Memorial-Sloan Kettering Cancer Center. In a 2007 letter, Dr. Scher explained that he cast his "no" vote "based on the fact that neither of the two trials presented met their primary endpoint…as such, the results do not constitute proof of benefit or justify a conclusion that they are reasonably likely to predict benefit."

Dr. Scher went on to write "the trial data were not consistent. Even if one accepts the posthoc survival analysis results of the larger [D9901] patient trial (82 men treated with sipuleucel-T and 45 men treated with a placebo), the second [D9902A] trial (65 treated with sipuleucel-T and 33 with placebo) was not confirmatory. Consequently, the only conclusion that can be reached is that the survival difference observed may have occurred by chance alone, and that the results do not support an approval recommendation."

Finally, Dr. Scher pointed out that there was no proof of an antitumor effect. "Specifically, there were no data provided of a favorable effect on [prostate-specific antigen], regression or stabilization of soft-tissue or bony disease radiographically, or health-related quality of life, or that administration of the product delayed the development of pain," he wrote (The Cancer Letter 33, 2007).

Prostate cancer specialists who spoke with Oncology News International echoed some of Dr. Scher's concerns. "I'm not sure any clinician can tell who, exactly, will benefit from [Provenge] and it may be difficult to tell on an individual basis if anyone has benefited from it-even as time progresses," said Steven Clinton, MD, PhD, professor of medical oncology at The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute in Columbus.

"We do know from the clinical trials that there's at least an estimated four months' survival benefit associated with Provenge," Dr. Clinton said. "What we don't have in these clinical trials, though, is any other biomarker evidence that we can use to help us understand who is responding. We don't really see declines in PSA or reduction in the size of measurable tumor masses on bone scans or other imaging."

Making an IMPACT
Dendreon forged ahead and in April 2009 provided the FDA with data from the IMPACT (Immunotherapy for Prostate AdenoCarcinoma Treatment) trial. In this 512-person study, Provenge met the primary endpoint of improved OS with a median survival extension of four months vs placebo. In addition, three-year survival increased by 38% vs placebo, and the risk of death from prostate cancer was reduced by 22.5% vs placebo. Provenge's safety profile was similar to previous trials.

"These [IMPACT] results represent the beginning of a new era in the treatment of cancer, one in which a patient's own immune system is harnessed to fight the disease," wrote coprincipal investigator Philip Kantoff, MD, and his colleagues (N Engl J Med 363:411-422, 2010).

"Furthermore, the magnitude of the survival benefit, coupled with the side effect profile and short duration of therapy, place Provenge as a new standard of care for men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer."

But skepticism about the vaccine lingered. Dan Longo, MD, a New England Journal of Medicine deputy editor, once again raised the question of the absence of a measurable antitumor effect. "It is hard to understand how the natural history of a cancer can be affected without some apparent measurable change in the tumor, either evidence of tumor shrinkage or at least disease stabilization," Dr. Longo wrote in an editorial accompanying the study (363:479-481, 2010).

Supply and demand
Antitumor effect or not, Provenge is in demand among eligible prostate cancer patients. The vaccine has been commercially approved for less than a year, so Dendreon is in the early stages of ramping up production. In addition, this is a highly personalized product. "We can't warehouse drugs since every dose is unique to each patient," said Hans Bishop, COO of the Seattle-based company.

Mr. Bishop said the company's Morris Plains, N.J. manufacturing facility is operating at approximately 25% capacity and is on-target to achieve 100% capacity in early 2011. In a bold move, the company invested in the facility in New Jersey as well as two additional manufacturing facilities, in Georgia and Southern California, prior to FDA approval. Mr. Bishop said he also expects these plants to come online in mid-2011. The geographical distribution of the facilities will allow the company to meet its 18-hour postmanufacture infusion window throughout the U.S., he said.

Fact Provenge basics

The composition of sipuleucel-T depends on the composition of cells obtained from a patient’s leukapheresis. Each dose of sipuleucel-T contains autologous mononuclear cells, including antigen-presenting cells, which are activated ex vivo via culture with a recombinant fusion protein consisting of prostatic acid phosphatase linked to granulocyte-macrophage colony-stimulating factor, an immune cell activator. The recommended course of therapy for sipuleucel-T is three doses, given at approximately two-week intervals by intravenous infusion. Each dose is preceded by a standard leukapheresis procedure approximately two to three days in advance. Each batch is made using a patient’s own immune cells and therefore is patient-specific.

Because Dendreon is still in the process of bringing its manufacturing up to meet demand, it has currently restricted the drug to approximately 50 oncology and urology clinics that participated in Provenge clinical trials. One of these sites is Duke University in Durham, N.C.

Judd W. Moul, MD, director of the Duke Prostate Center and chief of urology at the university medical center, noted that because of the limited availability of Provenge, he and his colleagues strictly follow FDA indications for use. Patients who qualify are those "who have traditional advanced prostate cancer [with] bone or soft-tissue metastases," he said. "They have to have good performance status, and, for the most part, we are trying to select patients who are asymptomatic and earlier in their advanced course of disease. Their cancer has to have progressed despite hormonal therapy."

To meet the supply-demand constraint, Duke has created a Provenge selection committee, said Daniel J. George, MD, a director of the Duke Prostate Center and a medical oncologist at the university. The committee consists of medical oncologists who specialize in castration-resistant metastatic prostate cancer, two cancer ethicists, a patient advocate from outside Duke, physician extenders who act as patient liaisons, and a financial adviser to address reimbursement.

"We create a list of patients with castration-resistant metastatic prostate cancer, and they are treated with other standard therapies," Dr. George said. "When they are in between therapies, that's when they are eligible for Provenge therapy. The committee meets once a month to review the list, focus on the patients in between systemic therapies, and determine if they are reasonable candidates to go onto Provenge at that time. We can cover everybody in our group in that monthly meeting and determine the most appropriate patients for treatment."

‘Provenge’ Park

If author Michael Crichton, MD, were alive today, no doubt he’d have a field day with the drama surrounding Provenge. Here’s but a sample of the conspiracy theories that are worthy of a medicolegal thriller:

• During a 2005 show, Mad Money host Jim Cramer (CNBC) declared the FDA had rejected Provenge-two years before Dendreon even submitted the product for approval. Two years later, Mr. Cramer advised his viewers to sell Dendreon stock, the night before the FDA advisory panel recommended approval.

• In 2007, separate hedge funds allegedly linked to Bernard Madoff, prostate cancer survivor Michael Miliken, and the Gambino organized crime family were blamed for short-selling of Dendreon stock. Mr. Miliken was an investor in Novacea, a biotech firm dubbed a major Dendreon competitor (www.marketrap.com, July 24, 2009).

• Howard Scher, MD, and Maha Hussain, MD, FDA advisors who took a public stance against Provenge, attended ASCO 2007 accompanied by bodyguards after they received threats (New York Times, June 7, 2007).

• Provenge advocacy group CareToLive accused the FDA of destroying documents related to the vaccine as part of a conspiracy to jettison its approval (www.bnet.com, February 5, 2010).

• A short-selling scandal causes Dendreon’s stock to dive 65% in 75 seconds. The matter is under investigation by the Securities and Exchange Commission (www.bnet.com, March 3, 2010).

He said the committee generally selects two or three patients a month and then books them for Provenge at least two months in advance. "It's a difficult challenge," Dr. George said. "We look at the patients today who are alive and qualified for Provenge, but who might not qualify six months from now when access is expanded further. So those are the patients we might need to prioritize now-even though two or three years from now they might not be the ideal patient to treat. [But] their window of opportunity may be closing if we don't treat them sooner rather than later."

Cost concerns
The wholesale price of Provenge is another area that has raised concern. Dendreon has set an initial price point of $31,000 per infusion, for a total cost of $93,000 for treatment-and that's before a hospital or outpatient facility adds on its overhead. While that price-tag raised some eyebrows, Mr. Bishop pointed out that a single three-dose course of Provenge can hold its own against multiple courses of traditional therapy.

"You need to look at the total cost of using Provenge, which is $93,000 for the full [three] courses vs the total costs of using standard treatment," he said, citing a report by the actuarial and consulting firm Milliman, which found the average price of using a chemotherapy regimen in the U.S. was about $111,000 ("Cancer Patients Receiving Chemotherapy: Opportunities for Better Management," March 30, 2010).

These data have not gone unnoticed by private payers. Just six weeks after the FDA's Provenge approval, Aetna Insurance issued an opinion that Provenge was medically necessary and would be covered. In addition, Emblem Health, Humana, Kaiser, and several large Blue Cross Blue Shield plans have approved coverage, according to Tricia Larson, Dendreon's associate director of corporate communications. Mr. Bishop also noted that 14 of 15 Medicare administrative contractors currently have established coverage guidelines and/or provided customers with written or verbal guidance for the therapeutic vaccine.

What the future holds
One of the ongoing criticisms of Provenge is that it does not always meet the current criteria for oncology drugs in terms of efficacy. But it may be difficult to judge a product that is so highly specialized and individualized; perhaps new measurements need to be devised to study immunotherapeutics.

"No one really knows how [Provenge] works," Dr. Moul said. "Yet people given the vaccine live longer. However…you continue to hear '[Provenge] doesn't affect PSA; it doesn't extend disease-free survival.'"

Of course, Provenge is not the only player in the field for prostate cancer immunization. GVAX from BioSante turned in lackluster results in a phase III prostate cancer trial, but the company has plans for new studies in the near future. There is also Prostvac-VF from Bavarian Nordic, which received FDA fast-track status in April and demonstrated a marked increase in OS and the ability to reduce PSA and decrease soft-tissue disease in two phase II trials (American Society of Clinical Oncology [ASCO] 2010 abstract 2550).

The commercial availability of Provenge is a boon to the cancer community, Dr. Clinton said. "If one looks at the positive of this, what we have for the first time, after decades of research, is an immune-based therapy for a cancer that has traditionally been marching ahead without responding to any of our immune therapies," he said. "This is like getting your foot in the door. I think this is going to open up a great deal of interest by clinical investigators and basic scientists in [determining] how we are going to be better able to harness this knowledge and create even more effective immune-based interventions for this disease."