American Association for Cancer Research

Clinical Trials and Special Patient Populations

New cancer drugs and special populations

We are in a brave new world where there are a lot of new medications for cancer. We have traditionally used chemotherapy, which damages the DNA and causes a lot of side effects. Now we understand cancer biology a lot better, so we know that there are some key proteins that might drive a tumor to grow and if we can block these proteins, then we can shut down the tumor growth.

For example, there is a protein called epidermal growth factor receptor, or EGFR, which sits in the cell membrane. When the right chemicals bind to it, the receptor is activated and it sends signals for the tumor cells to grow. Normal cells have some of these receptors, and they work like a switch—the growth signal turns on and off. However, many tumor cells have numerous receptors that stimulate them to grow. In addition, in tumor cells, these receptors may be activated all the time—the switch is stuck in the on position—and so tumor cells grow continuously.

Iressa We now have these new drugs called EGFR inhibitors. I will talk a lot about gefitinib, also called Iressa. There’s another one called Tarceva. These drugs block the activation of these receptors so that tumor growth can be blocked.

We know that these epidermal growth factor receptors are common in a lot of tumor types, such as brain, head and neck, lung, kidney, colorectal, bladder, and in women, ovarian and cervical cancers.

TarcevaWhen pathologists examine these tumors, they can use a chemical stain to look for the protein. This is what they see: If you have the protein in the tumor, it stains dark. When tumor cells stain really dark, you figure that in that tumor, the protein is very important. The thinking is that if you use one of these drugs—the EGFR inhibitors, Iressa or Tarceva—in a tumor where the protein is very important, you will get good results. You will shrink the tumor.


Before Gefitinib

Lungs of a patient before treatment with Iressa (gefitinib).

When we started testing these drugs, Iressa and Tarceva, we saw that they didn’t work in a lot of patients. In this country, we could see tumor shrinkage in about one out of 10 lung cancer patients. But then we saw a phenomenon that Dr. Tom Lynch at Massachusetts General Hospital in Boston called the “Lazarus response.” Lazarus was brought back from the dead in the Bible. In a similar manner, there was the occasional patient who came to the clinic in a wheelchair on oxygen, and after taking this pill once a day for a couple of months, will now come into the clinic walking, with clear lungs on the CT scan.


After Gefitinib

Lungs of the same patient after treatment with Iressa (gefitinib).

These cases were dramatic, but few and far between—maybe one out of 10 people. When the Iressa results were sent to FDA for approval, further examination showed that certain populations benefited more than others. Eighteen percent of women had their tumors shrink compared to 5 percent of men. In those who had never smoked, tumors shrunk in 29 percent of patients compared to 5 percent of smokers. In other studies, it became clear that the benefit in Japanese patients compared to North American patients was a ratio of 3-to-1.

What researchers later found was that there was a mutation—a change in the patients’ DNA code—in the EGFR gene in some tumors. The tumors that have these mutations are very sensitive to the drugs Iressa and Tarceva. That’s probably because these tumors are growing by using this EGFR pathway. Therefore, if we block the pathway using one of these drugs, the cells die quickly.

A lot of different investigators went back and looked at those folks who have had dramatic responses to these drugs and looked at their tumors to see whether there was a mutation. What they found was that about seven out of 10 of those patients’ tumors had that mutation. In addition, because the responses were higher in Japanese people, women, and nonsmokers, a number of scientists asked the question “How many of these special populations have tumors with the mutation?”

Dr. Adi Gazdar and his colleagues from the University of Texas in Dallas did a number of studies. They looked at 160 tumor samples and evaluated the presence of mutations. Twenty percent of never-smokers had the mutation in their tumors, compared to 7 percent of former smokers and 3 percent of current smokers. If you remember the numbers of patients in these groups who had their tumors shrink after taking Iressa, it tracks the presence of mutations quite closely. The number of women who never smoked who had the mutations in their tumors was also higher than for men.

And now, let’s look at geography. Dr. Gazdar and his group did a comparison of about 600 tumors from different parts of the world, looking for the presence of that mutation. Let’s take a never-smoker from a particular country and let’s see what we find.

In the U.S., about 30 percent of nonsmokers’ tumors have the mutation. In Australia, the numbers are quite close, with maybe 32 or 35 percent of nonsmokers with the mutation. But look at Taiwan, Japan, Hong Kong—the mutations are present in 60, 70 and 80 percent of non-smokers, respectively, and there are similar data coming out of Singapore, Korea and China. It looks like, for reasons we don’t understand, there is a high proportion of the mutation in non-smokers from Asia—much higher than in Europe or North America. I was at a meeting with a Japanese colleague who was telling me that in their studies in nonsmokers, Iressa is working in 70 percent of patients. And patients who were previously dying in an average of four months are now alive two and a half to three years, taking this drug.

Here in the U.S., the data I have described are based on the Caucasian population. We don’t have a clue about what happens in other ethnic groups such as Hispanics and African-Americans. So we have a drug whose use appears to be particularly pertinent to what we are talking about—the importance of doing studies in special populations—and yet we don’t have any information about its use in our special populations. The outcome of African-American males, when they have lung cancer, is much worse than any other group in this country. We have drugs, Iressa (which was initially granted accelerated approval for lung cancer, but is now only available to patients already receiving the drug because it failed to demonstrate a survival benefit) and Tarceva, which is approved for lung cancer. But we don’t know what these drugs do in African-American men. Nobody has looked at it. And if you look at the North American studies, there is very little information about ethnicity. Now, because of the importance of geography, some researchers are going back to those North America studies and trying to tease out the number of Asians who were on those studies to try to explain the results.

I think these epidermal growth factor receptor inhibitors—Iressa and Tarceva—highlight the importance of doing studies in special populations. We have drugs that clearly have different effectiveness in different groups of people. But we don’t really know the groups of people we’ve treated so far.