Biotech Medarex Misses the Mark

Simply put: The response rates to be reported by Medarex from the MDX-010 study will be inflated a bit by using the WHO measurement system, probably by two or three percentage points.

The problem is that when you dig into previous melanoma studies for the drug, the objective response rates reported (all using RECIST criteria, by the way) are in the 5%-10% range. That's not a very robust response, and it doesn't bode well for the upcoming phase III study.

A Closer Look

Some details:

A phase I/II MDX-010 study presented at ASCO in June reported a 5% objective response rate in patients who had failed a previous treatment for melanoma. These patients were given various dose levels of MDX-010. A subset of 23 patients in this study dosed with 10 milligrams of MDX-010 (the same dose being used in the phase III study) performed marginally better -- a 9% response rate.

In a similar study presented at the 2005 ASCO meeting, 37 melanoma patients given MDX-010 as monotherapy managed just a 5% objective response rate. This study used a lower dose (3 mg) of MDX-010.

Another study of 56 melanoma patients published in 2005 also used a 3-mg dose of MDX-010, yielding an objective response rate of 13%. But some of the patients in this study hadn't failed previous treatment, so when they're excluded from the analysis, the response rate drops to 8%.

This isn't to say that MDX-010 doesn't have previous data that works in its favor. For one thing, the drug does seem to produce a high level of stable disease, which translated, means tumors that shrink minimally or just stay the same size. Moreover, the duration of the response seen with MDX-010 can be quite long.

When Medarex releases data from the phase III trials, the company will likely include stable disease patients together with those reporting an objective response. This will produce a "disease control rate," or DCR, that will probably look quite robust.

If significant tumor shrinkage (i.e., an objective response) is a best-case scenario, stable disease is a second-best outcome for cancer patients, because a tumor that isn't growing can also help patients live longer.

A key aspect of the Medarex bull case for MDX-010 is that while the objective response rate might be low, the DCR rate and the duration of response will be high. These latter data, the bull argument goes, will be enough to convince the FDA to approve MDX-010, especially since this is a desperate patient population lacking good treatment options.

Tracking Survival Rates

But I don't buy it for a couple of reasons. For starters, stable disease might be suggestive of a survival benefit, but the FDA will want to see actual survival data.

The phase III studies for MDX-010 aren't set up to collect survival data, at least not in a robust and objective format, because they're designed with a single arm only (i.e., no patients are being given a placebo or best supportive care, by which it could be determined if MDX-010 is really helping melanoma patients live longer.)

Medarex bulls point to the fact that the current MDX-010 studies are being conducted under a Special Protocol Assessment -- essentially an agreement between Medarex and the FDA that the trial design is robust enough to warrant a drug approval (contingent on posititve data, of course.)

That's true, but there's a lot of wiggle room in so-called SPAs, by which the FDA can change its mind or interpret things differently. The blowup of GPC Biotech and its prostate cancer drug satraplatin in July is a prime example.

Medarex is a good company with a deep and diversified pipeline. It has solid partnerships, and MDX-010 is an interesting drug that may end up succeeding against melanoma when combined with other drugs (as some other data suggest.) There are other, ongoing phase III studies of MDX-010 in melanoma that are tracking survival, but they won't be completed for some time. The drug is also being tested against prostate cancer.

I say that because I don't want to come across as a total curmudgeon. But when it comes to this most immediate and important study, which uses MDX-010 as a monotherapy in melanoma, the evidence on hand simply doesn't provide enough confidence to predict a successful outcome. That's especially true given the current mood at the FDA, which is taking a hard line on all drugs, even those for advanced cancer.

There's a 23% short interest in Medarex right now, so I know I'm not the only one skeptical about MDX-010's near-term prospects. We'll know soon enough whether the skeptics like myself are right.

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