What Can We Learn from EMILIA?

Chris Adams at Fight Colorectal Cancer's 2012 Call-on Congress

Written by: Christopher P. Adams, Ph.D.*

Chris Adams, one of Fight Colorectal Cancer’s research advocates, shares his thoughts about the results of a large breast cancer trial presented at the 2012 ASCO in Chicago, and aspects of the regulatory process. Thank YOU Chris!

On Sunday June 3 2012, at the American Society of Clinical Oncology (ASCO) annual meeting in Chicago, Dr Kimberly Blackwell from the Duke Cancer Institute, got on stage in front of over 10,000 doctors, researchers and worldwide media representatives to present initial results from the EMILIA trial.** The trial looked at the safety and effectiveness of a novel drug for a particular type of breast cancer. Despite its obvious applicability to breast cancer, the colorectal cancer community and the larger cancer community can learn a number of important things from EMILIA.

EMILIA was a large worldwide trial enrolling approximately one thousand patients whose cancer continued to progress after standard treatments. The patients were randomly assigned one of two drug treatment regimes. One group received an approved standard treatment regime while the other group received a new drug with the name of T-DM1. Dr Blackwell presented results on a number of measures including something called progression-free survival. The chart (below) presents the probability that a patient’s cancer will not continue to grow at each point in time after the patient begins the trial. The two lines represent each of the two drug treatments. The higher line represents patients on the T-DM1 treatment. The chart shows that the patients in the T-DM1 group have a significantly lower probability of having their cancer progress than patients taking the standard drug treatment. Perhaps more exciting is the fact that the curve flattens out.

Flat curves are best, but curves that flatten out mean that for some patients the probability of their cancer progressing is very low. Dr Blackwell also reported that at the 2-year mark more patients on T-DM1 were still alive compared to patients on the standard treatment. Neither of these results show that T-DM1 will cure patients with this type of breast cancer. However, the trial results definitely show that T-DM1 has a large effect on the disease. Hopefully, T-DM1 will follow a well-worn path of showing initial impact on the disease to providing curative effect for at least some patients. Whether T-DM1 does or not will not be known for many years and after a lot more money, time and hope is spent by doctors, pharmaceutical companies, researchers, patients and their families.

See the trial results posted on the ASCO website.

Dr Lou Weiner of Georgetown Lombardi was given the honor of discussing the results of the EMILIA trial at ASCO. Dr Weiner’s discussion focused on the fact that T-DM1 is a brand new type of drug. T-DM1 is actually a combination of two existing drugs that have been joined together at the molecular level. It is an amazing engineering accomplishment. The first drug is a standard breast cancer therapy called trastuzumab (or the trade name Herceptin®). In its standard form trastuzumab targets a molecule in the tumor and blocks certain activity which in turn slows or stops cancer growth. In T-DM1, trastuzumab is being used as a delivery vehicle. The trastuzumab molecule still attaches to the molecule in the tumor but this time it is carrying a toxic payload, a chemo-drug that was tested many years ago but found to be simply too toxic for patients ([M] aytansine [D]erivative). By targeting the cancer cells and only the cancer cells, the hope is that trastuzumab allows the toxic chemo-drug to be delivered only to those cells we want to hit and so the combination is less toxic to patients than the original failed chemo agent.

Dr Weiner suggested that T-DM1 was finally an example of Paul Ehrlich’s “magic bullet” for cancer. EMILIA certainly showed that one of our standard “targeted” therapies can be engineered to become a delivery vehicle for toxic chemo agents. We must wait to see if this engineering feat can be successfully achieved in other molecules leading to a whole new stable of anti-cancer drugs.

While trastuzumab is predominantly used in breast cancer patients with a particular molecular marker called “HER2”, this marker does appear in tumors that are located in other parts of the body. To date, trastuzumab has been approved for various forms of gastric cancer. It remains to be seen whether T-DM1 will similarly be effective for other forms of cancer that have the “HER2” marker.

As an economist, the most interesting part of the presentation of the trial was the fact that the sponsors needed to do a large and expensive drug trial in the first place. One of the legacies of the HIV/AIDS patient advocacy in the 80s and 90s is that the FDA allowed particular types of treatments to be approved through an accelerated approval process.

In this process, drugs only needed to show that they were safe and that early indications were that the drug had an effect on the disease. In addition, patients on the early trial had to have gone through all approved treatments for the disease. They did not need to do the large and expensive drug trials in order to be approved. The FDA, however, severely restricted this special treatment only to drugs that were for patients that had few other options and faced likely death. Many drugs for HIV/AIDS and late-stage cancers were approved under this process including a drug called bevacizumab (or trade name Avastin®) for breast cancer. My own research shows that HIV/AIDS drugs got through the development process much quicker than the average drug and were much cheaper to develop.*** A plausible explanation is that the FDA’s accelerated approval process reduced the burden on the drug sponsors to develop HIV/AIDS drugs.

When the FDA approved trastuzumab in 1998 it did so on the basis of a small early phase safety trial and upon early results from a single later phase trial. It also received commitments from the drug sponsor that more trials would be conducted to test the safety and effectiveness of the drug. The FDA had similar commitments from the sponsor of bevacizumab. However, in the case of bevacizumab, when those follow up trials came back showing minimal or no effect of bevacizumab for breast cancer, the FDA withdrew its approval for treatment of breast cancer with bevacizumab. This was the first time the FDA had subsequently withdrawn approval for a drug that had been approved under the accelerated system.

Two years ago the FDA denied accelerated approval for T-DM1 after the completion of an early phase trial. While the data for the trial showed that T-DM1 shrunk tumors in 1 of 3 patients, the original trial design did not meet the standard for accelerated approval because patients on the trial had not exhausted all available treatments irrespective of the patient’s “HER2” status. Due to this denial, the drug’s sponsor had to wait for the data provided by the EMILIA trial and two other large trials. My own research suggests that drug sponsors spend $27m per year on average taking drugs through these large late stage human clinical trials.**** The FDA’s denial of accelerated approval for T-DM1 has likely increased the time to market by at least two years and increased the out of pocket cost to the sponsor by over $60m (although some of this out of pocket cost would have been incurred regardless of the FDA’s decision).

Perhaps the standard for accelerated approval should be evaluated with respect to targeted therapies. Should patients be required to exhaust all treatments if a newly developed treatment is targeted to a specific patient population? Discussions between FDA and sponsors are confidential, making it difficult to evaluate specific FDA decisions. This is a question that might be most appropriately addressed at an FDA Oncology Drug Advisory Committee meeting.

I think EMILIA has taught us much about hope for curing some forms of late-stage cancers, the ability of researchers to achieve amazing feats of bio-engineering, hope for a new stable of more effective and less toxic cancer drugs as well as the new economics of drug development.


* Chris does not represent the views of the Federal Trade Commission or any individual commissioner.
** J Clin Oncol 30, 2012 (suppl; abstr LBA1) (http://abstract.asco.org/AbstView_114_98675.html)
*** Estimating the Cost of New Drug Development: Is it really $802m? with Van Brantner, Health Affairs, March/April: 420-428, 2006.
**** Spending on New Drug Development, with Van Brantner, Health Economics, 19(2):130-141, 2010.

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