FDA Approves Costly Drug Tandem for Advanced Melanoma

By Gil Ross — Oct 02, 2015
The FDA has approved a two-drug combination for advanced melanoma patients. The combo, made by Bristol-Myers Squibb, is expected to cost $250,000 for one year. Expected gain in life is measured in months, but some subsets may experience a dramatic benefit. The real question is: Who are those patients?
Early melanoma (CTV.CA) Early melanoma

Based upon two recently-published studies showing small but significant benefits among patients with advanced melanoma, the FDA has given its approval to the combination of Yervoy and Opdivo, marketed by Bristol-Myers Squibb (BMS).

Yervoy is ipilimumab, and Opdivo is nivolumab; both are monoclonal antibodies that work against cancer by unleashing the body's own immune system, and are administered intravenously every few weeks.

However, the price of the drug combination for just one year, according to the company, is a quarter of a million dollars.

The studies may be found here, and here; both appeared in The New England Journal of Medicine, the products of large groups of co-authors at multiple medical centers with an international flair.

One cohort of melanoma patients involved 142 subjects, the other, 945. Each study compared "progression-free survival" (PFS) among patients receiving either one or both drugs, or a placebo. Without going into detail about the various outcomes, suffice it to say that in both trials the two-drug combination worked better than either drug alone, and much better than placebo. (Progression-free survival is not the same thing as "survival." PFS merely measures how long it takes for a measurable cancer to become resistant to treatment and start to grow, after an initial regression.)

As for characterizing the two-drug approach as better, here's the thinking:

In the 142 patient study, the rate of confirmed objective response was 61% (44 of 72 patients) in the combination group, versus 11% (4 of 37 patients) in the group that received ipilimumab alone, with complete responses reported in 16 patients (22%) in the combination group and no patients in the ipilimumab-only group.

"In this double-blind, randomized study," the authors wrote, "the combination of nivolumab and ipilimumab resulted in a significantly higher objective response rate, more frequent complete responses, and significantly longer progression-free survival than ipilimumab alone among previously untreated patients with advanced melanoma."

There were not enough data to discern the PFS time for those responding. Unfortunately, over half of the patients had moderate or severe side effects of the therapy.

In the 945-patient study, the median PFS was 11.5 months with nivolumab plus ipilimumab, as compared with 2.9 months with ipilimumab alone, and 6.9 months with nivolumab alone. Again, side effects took their toll on more than half of the patients.

"Among previously untreated patients with metastatic melanoma, nivolumab alone or combined with ipilimumab resulted in significantly longer progression-free survival than ipilimumab alone," according to the authors.

But at $250,000 for one year's treatment, what's the real benefit? In most cases, a few months extra of living with advanced melanoma. And the side effects can be cruel.

So what's the answer?

Finding subsets of melanoma patients with biomarkers indicating a higher likelihood of response, but we don't have them yet. Maybe adding other immunomodulating drugs, e.g. cancer vaccines, might add that needed third punch to knock out those recalcitrant cancer cells not being killed by drugs #1 plus #2.

Here's what we had to say about this only four months ago, when these results were leaked in a preliminary presentation. Our Dr. Josh Bloom, Director of Chemical and Pharmaceutical Sciences, noted the exorbitant cost and the minimal benefit, and asked whether it was worth it.

"Since most new cancer drugs are very expensive," he wrote, "the developing science of determination of efficacy of a given drug at the molecular level will not only help control these costs, but will also help to prevent exposing patients to side effects, which can be severe, when the drug will not help them.

This is made clear by Dr. Jedd D. Wolchok, chief of the melanoma and immunotherapeutics service at the Memorial Sloan Kettering Cancer Center, and a co-author of both of the above-cited studies.

We don t want to be wrong, because these medicines have an effect that, in some cases, is durable for years," said Dr. Wolchok. "We don t want to have an imperfect biomarker.

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