Expert Financial Analysis and Reporting

A criticism that is heard over and over from lay people is that Provenge provides only marginal benefit with an increase of 4.5 months median overall survival. This view is in direct opposition to the views of the FDA and expert oncology community on the importance of improvements of this magnitude in mean overall survival. We have another example of this with the recent approval of Zelboraf (vemurafenib), a new drug for metastatic melanoma from Roche. This drug was the star attraction of the most recent American Society of Oncology Meeting along with Bristol-Myers Squibb’s Yervoy (ipilimumab). The FDA approved the drug on August 18, two and one-half months before its PDUFA date of October 28, 2011.

The data is not yet mature, but the estimated median overall survival for Zelboraf in its pivotal 675 patient BRIM 3 trial is estimated at 10.5 months versus 7.8 months for the control drug decarbazine, which is a marginally effective drug. The improvement in mean overall survival is 2.7 months. The vocal critics of Provenge’s efficacy should now turn their guns on Zelboraf, if they are to be consistent. However, they are in direct opposition to the key opinion leaders in oncology and the FDA in their belief that this 2.7 month or so increase in overall median survival is clinically meaningless.

What explains the difference between the view of lay people that improvements of this magnitude are meaningless while the key opinion leaders of oncology and the FDA, an agency not known to be industry friendly, are eager to get such drugs into clinical practice? I can site a number of possibilities. The first is that only in very rare cases such as Gleevec do we get cancer drugs that offer anything close to a cure. Gleevec in chronic myelogenous leukemia (CML) beautifully targets one genetic mutation that is responsible for most CML cases and results in very long increases in survival. More often, there are multiple cause of cancer and drugs target only one mechanism so that they block one means of proliferation, but others allow the cancer to continue to grow. If we demanded only Gleevec type performance in new drugs, there might only be one cancer drug approved per decade. More likely, there would be none because drug companies could not afford to develop drugs under a paradigm in which almost all of their drugs in development would be considered ineffective. Society is in the position of either abandoning the effort to cure cancer or be willing to accept evolutionary advances.

The approval of drugs like Provenge and Zelboraf is also only the beginning of the story. Over time, new drugs are often synergistically combined with other therapies to further increase mean overall survival. Physicians also learn over time which patients benefit most from a drug. In the case of Zelboraf, it is known right from the start that it inhibits the BRAF V600E gene mutation that leads to the production of the BRAF protein which causes metastatic cancer cells to proliferate. If Zelboraf were to be used against all metastatic melanoma cancer patients, it is possible that the increase in median overall survival would not be significant.

With all of this said, it is important to understand that there are differences between Provenge and Zelboraf that may affect some physicians’ judgments. We know that Zelboraf is effective for one easily identified group of patients. We don’t know if some patients respond better than others to Provenge. The mode of action of Zelboraf is clear cut while we aren’t quite sure what Provenge is doing. Zelboraf acts like a cancer drug as it measurably shrinks the tumor. With Provenge use, the tumor may continue to grow and PSA, a close watched measure of tumor growth, continues to increase even though survival is increased. Provenge is perplexing to the medical community because it just doesn’t act the way that cancer drugs should. For those who ignore these issues and look only at increases in median overall survival, the results with Provenge are impressive.

There appear to be two diametrically opposed explanations for Provenge. The first is that the trials that led to its approval are spurious and it doesn’t really work. The second is that something is going on with Provenge that we don’t yet understand and that leads to Provenge’s efficacy. One theory that I have heard is that Provenge is not that effective in shrinking large tumor masses but might be more effective against the smaller metastases that are the real culprits in causing disease progression and death. This could explain the survival benefit.

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