Tasquinimod, ipilimumab, and cabozatinib (XL184): an update

At the Genitourinary Cancers Symposium yesterday afternoon, new data were presented from Phase II studies of tasquinimod and cabozatinib (XL184) and conversations with opinions leaders gave us additional information about development of ipilimumab in the treatment of prostate cancer.

Let’s begin with ipilimumab. As regular readers are aware, ipilimumab is expected to be approved by the U.S. Food & Drug Administration some time this year for the treatment of malignant melanoma — a form of skin cancer for which there have been almost no really useful therapies, and which has an extremely high mortality rate among people with advanced disease. Although ipilimumab provided a very clear survival benefit for patients with advanced forms of melanoma, it was also associated with a small but significant number of serious complications, including some drug-related deaths as a consequence of immunologic reactions (particularly in the gastrointestinal system and the skin).

It appears that the risk of such complications may be a problem in relation to the use of ipilimumab for the management of early and late stage prostate cancer, and these complications also appear to be affecting the willingness of patients to enter the Phase III clinical trial of ipilimumab in the treatment of prostate cancer. We will need to monitor this with care, but in the meantime prostate cancer patients who are considering the possibility of participation in any trial of  ipilimumab should be sure to ask the trial center very specifically about the possible side effects of ipilimumab.

Armstrong et al. provided a detailed breakdown of data from the Phase II clinical trial of tasquinimod in the treatment of metastatic, castration-resistant prostate cancer (mCRPC) compared to placebo. The data breakdown further confirmed that tasquinimod demonstrated a clear improvement in progression-free survival in the patients enrolled in this study (and reported at the ASCO annual meeting last year). However, Armstrong’s poster (which can be downloaded from the developer’s web site) also informed us that a randomized, Phase III clinical trial of tasquinimod will be initiated within the next couple of months. This trial will be in the “pre-docetaxel setting.” We are a little unclear about what this implies. We assume that the developers would rather compare tasquinimod to a placebo than to docetaxel chemotherapy in a Phase III trial. Perhaps it is possible to do that, but we will have to await the details.

Smith et al. presented a poster giving a current update on data from the Phase II clinical trial of cabozatinib (XL184), also in the treatment of mCRPC. A total of 168 patients have now been enrolled into this trial, and the full poster is available on the Exelixis corporate web site (although it is a little slow to download), together with a media release from the company.

Clearly cabozatinib has significant short-term effects on a variety of factors that continue to suggest the clinical potential of this agent, but longer follow-up is needed before we can have a clear picture of the real potential of cabozatinib in mCRPC, and one or more Phase III trials will be needed before such data can be confirmed. What is important at this stage is that this agent represents another new type of treatment for very late stage prostate cancer.

It should be noted that cabozatinib has been associated with a series of adverse effects that have required dose reductions in > 50 percent of patients participating in the Phase II trial to date. These side effects include grade 3 and grade 4  fatigue (in 15 percent of patients), hypertension (8 percent), PPE syndrome (also known as hand-foot syndrome; 5 percent), back pain (3 percent), and a wide range of other side effects in 1 or 2 percent of patients. Exactly how many of these adverse effects are actually drug related is not known at this time.

One Response

  1. XL was a randomized discontinuation trial. Those patients who clearly benefited from the start stayed on the drug. Those who did not benefit, or had progression, were randomized to drug/placebo. This attempts to provide a placebo control and an open label on the same trial. Tricky.

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