US FDA approves ipilimumab

The U.S. Food & Drug Administration today approved ipilimumab (brand name  Yervoy®) for the treatment of patients with metastatic melanoma (an aggressive form of skin cancer).

As we have noted previously, ipilimumab is currently in Phase III clinical trials for the treatment of chemotherapy-naïve and post-docetaxel chemotherapy-recurrent forms of metastatic, castration-resistant prostate cancer (mCRPC).

Data published to date also suggest that ipilimumab has significant activity in the treatment of men with much earlier forms of prostate cancer. However, larger trials will be needed to confirm the apparent ability of ipilimumab to be able to eliminate clinical signs of prostate cancer in men with locally advanced disease who were then able to undergo local treatment such as radical prostatectomy.

The important issue for prostate cancer patients from today’s approval is a full understanding of the risks associated with ipilimumab in clinical practice.

An e-mail issued to members by the American Society of Clinical Oncology (in conjunction with the FDA), states that clinical use of ipilimumab in the management of metastatic melanoma had been associated with a series of immune-mediated adverse reactions. The most common of these include diarrhea, pruritus, rash, and colitis.  In clinical trials, it was necessary to discontinue use of ipilimumab in 10 percent of patients because of such adverse reactions.  Furthermore, 13 percent of ipilimumab-treated patients had high-grade immune-mediated adverse reactions, the most common of which affected the colon, liver, skin, endocrine system, and nervous system. 

The full prescribing information for ipilimumab is available on line and includes a “boxed warning” that treatment with ipilimumab “can result in severe and fatal immune-mediated adverse reactions.” Most such reactions apparently occur relatively soon aftyer initial treatment, but they have also been observed to occur “weeks to months” after discontinuation of treatment with ipilimumab.

These risks may be acceptable in patients who are otherwise at high risk of an early death from malignant melanoma. Whether they are also acceptable in men with prostate cancer who still have a significant life expectancy (even if with progressive disease) is a very different question. The incidence of severe side effects in the treatment of mCRPC will be an important issue if ipilimumab is shown to extend the survival of such prostate cancer patients.

8 Responses

  1. Thanks for this hot news!

    I’ve been excited about ipilimumab for a while, especially after hearing Dr. Eugene D. Kwon’s talk about his Mayo Clinic research on it, supported by the DoD’s Prostate Cancer Research Program, at the IMPaCT conference a couple of weeks ago. Did anyone foresee that FDA approval coming so soon, prior to Sitemaster’s “heads up” a couple of days ago?

    Dr. Kwon emphasized ipilimumab’s role in amplifying the immune response and directing it to the target. He was especially excited about the clinical trials using ipilimumab in conjunction with hormonal therapy, observing that hormonal therapy causes T cells to go to tumors, and noting a robust response in earlier prostate cancer trials. At the conference he highlighted a trial in which 78 of 108 patients had a 70% to 100% response to treatment, involving all PSA levels, according to my scrawled notes. (Does anyone have a different version of that?) He told us that there were two Phase III clinical trials of the drug for metastatic, castration-resistant prostate cancer patients, and my impression was that the trials were well along.

    I found the following paper, available free online via PubMed, quite helpful: Thompson RH, Allison JP, Kwon, ED. Anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) immunotherapy for the treatment of prostate cancer. Urol Oncol. 2006; 24(5): 442–447.

    Among other points, the paper, published after Phase I and II results and looking toward Phase III trials, offers some reassurance about the worrisome side effects noted by Sitemaster, which are specifically discussed and cited. In essence, the side effects in the Phan et al. trial, though fortunately reversible after steroid therapy, occurred in patients dosed every 3 weeks (“closely spaced intervals of repeated CTLA-4/peptide vaccination treatment”); the authors note that, “In contrast, other groups have shown that single or reduced doses of anti-CTLA-4, given alone or in combination with other forms of immunotherapy, are associated with extremely tolerable rates of auto-immune toxicity.”

    The paper also addresses some preclinical work where ipilimumab was combined with GM-CSF, resulting in a robust response in TRAMP mice. This is exciting because GM-CSF is involved in both Leukine and Provenge therapy.

    Keeping up with all these breakthroughs is tiring me out, LOL, but keep that good news coming!

  2. Jim: I did suggest that ipilimumab would be approved fairly soon back in January.

  3. Washington Post reporter Rob Stein, who often covers cancer matters including prostate cancer, wrote that Bristol-Myers Squibb intended to charge $120,000 for a four-infusion course of ipilimumab for metastatic melanoma.

    I’m wondering if the dose for prostate cancer in the Phase III trials is just one infusion, as I believe to be the case. If so, I’m thinking the charge would be a quarter of $120,000 or $30,000.

  4. This is the first reference I have come across to any price for ipilimumab. And I don’t think it would be wise to speculate about what the manufacturer might expect to charge for any new drug until it is approved for that specific indication.

  5. One of my Yana men is on an ipilimumab trial.

    See his story at

  6. Thanks Terry. I just read Roy’s inspiring story. I e-mailed him about being tested for DHT and possibly adding finasteride or Avodart.

  7. The drug was invented by government-sponsored research, and CDMRP helped get quick FDA approval. The (San Diego) Veterens Administation hospital is still using IL-2 instead of ipilimumab for my neighbor’s melanoma due to cost. They should at least get a discount, but Congress has outlawed group buying discount agreements for all government programs. IL-2 has brutal side effects and is less effective. With FDA reform, the government could afford to do the clinical trial with VA patients and then contract the manufacturing.

  8. Dear Tom:

    Actually the VA can and does negotiate drug prices with drug companies, and the VA gets some of the largest levels of discount available. However, the VA is also not one of the fastest moving of government-run organizations, and my suspicion is that negotiations on the price of ipilimumab for VA patients just haven’t begun yet, which means that ipilimumab simply isn’t available to any VA patient. This process can take several months, and the VA has a very structured approach to these negotiations.

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