Laura Esserman, MD, Director of the Carol Franc Buck Breast Care Center at the University of California Medical School is determined to revolutionize how cancer drugs are developed. “The record for producing new cancer drugs is abysmal,” she says. “Fully 60 percent to 70 percent of late-stage cancer trials fail.” And among the 30 percent that don’t fail, many are marginally useful or less effective than existing drugs. Yet the cost of developing those drugs is staggering. It can take 10 years, a billion dollars and thousands of women as subjects. Esserman and Donald A. Berry, a biostatistician at M.D. Anderson Cancer Center in Houston, designed the I-Spy-2 Phase II clinical trial, now underway, to reverse this record and get effective drugs onto the market quicker, for less money, and with fewer subjects.
To do that, they joined forces with a large group of researchers and some unlikely partners, including several pharmaceutical companies, the National Cancer Institute, Safeway Foundation, Quantum Leap Foundation, and the U.S. Food and Drug Administration, to topple some old ideas about conducting clinical trials.
Narrowing Down the Test Population
The current practice of testing a drug on any and all breast cancer patients is often ineffective because breast cancer is not a single disease and a drug that is effective in one patient may not work in another. I-Spy-2 is designed to learn which drugs work on breast cancers with specific characteristics. “For every drug that goes through the trial, we’re trying to come up with a set of gene-based and molecular markers that we think will predict response,” Esserman says. “And we’re working with the FDA to make sure that these markers are useful for deciding on treatments beyond our trials.”
“We already know that targeted treatments work,” she continues. For example, some cancers are estrogen receptor positive (ER-positive), and some are estrogen receptor negative (ER-negative). An ER-positive cancer cell reacts to the presence of estrogen by ramping up and growing like crazy. An ER-negative cancer cell is more or less indifferent to the presence of estrogen. Some very good drugs have been developed to treat ER-positive cancers, including tamoxifen, taxol, aromatase inhibitors, anything that impedes the impact of estrogen on the cells. “More women with stage I and II and probably stage III breast cancer are surviving because of chemo-therapy and tamoxifen,” says Columbia University’s Barron H. Lerner, MD, author of The Breast Cancer Wars: Hope, Fear, and the Pursuit of a Cure in Twentieth-Century America.
Testing Several Drugs at Once
Instead of testing one drug in each clinical trial, I-Spy-2 tests multiple drugs at once — up to five at any given time, with the goal of assessing as many as 12 before the trial is over. Each patient in the trial will get the standard of care required of her cancer—chemotherapy at the beginning of the treatment and surgery to remove the tumor at the end. In addition, each of five groups of patients, whose members have been screened for particular biological markers on their cancers, will be given one of the novel drugs in combination with taxol. The patients’ tumors are monitored with MRIs to see which respond best to the drugs being given. After a period of time, the drugs that are determined to be effective will be moved on to Phase III trials. Those that prove ineffective will be dropped and new ones will be introduced. “All of which means the trial is adaptive,” Esserman says. “If we start to see that Drug A works well for the hormone receptor subtypes, for example, the next patient like that that comes into the trial is more likely to get that drug. As a result, the trial starts to learn what works and what doesn’t.” After six months, the tumor, if any remains, is removed and evaluated. “In a traditional clinical trial, the results aren’t compiled until the trial is over, years after it began, but we collect data on the drug’s effectiveness and evaluate it all along,” Esserman says.
Choosing Subjects Who Might Benefit Most
Traditionally, clinical trials have started with the sickest patients, those whose cancer has metastasized, which means it has spread from the breast to other parts of the body. The survival rate for these metastatic cancer patients is about 20 percent at five years, and at this stage, no treatment is likely to change the prognosis significantly. So the measure of success in these trials is not a cure or survival but extending a patient’s life by a few extra—very precious—weeks or months. If the drug being tested does prove to extend life for these patients, it must be re-tested on early stage patients whose lives might be saved. This stage of testing could take many years more.
I-Spy-2 patients have biologically high-risk tumors—minimum size is 2.5 cm—but their cancer has not metastasized. “If the goal is to make sure people don’t die of this disease, you want to make sure you’re giving these agents at a time when you might be able to cure someone and improve their care,” Esserman says. “Our subjects are people at the highest risk who are most in need of having their outcomes improved.”
Putting Drug Treatment First
In I-Spy-2, drug treatment comes before surgery. In some ways, the current treatments are backwards if your goal is to stop the cancer from spreading. After all, metastatic disease is the real killer, and surgery isn’t very useful in stopping it. “Once the microscopic cells have sloughed off from the lesion in your breast and begun their migration to another organ, like the liver or the lung, it doesn’t matter what operation I do, it’s not going to save your life,” Esserman says. “What saves your life is if you happen to be the person whose migrating tumor cells will be destroyed by the drug therapies we have.” Not all drugs are equally effective on all cancers, and if you operate and take the tumor out, you don’t have any way to tell if the drug is working, except if the cancer does spread or recurs. Give the drugs first and you can monitor the tumor itself. “We’ve known for some time that scheduling surgery before or after chemo does not affect long-term outcomes,” Dr. Esserman says. “By holding off on the surgery, we can determine if the drug is having an effect on the tumor itself. We don’t have to wait years to see if the cancer returns to learn if the drug was effective.”
“Maybe some day, we’ll evaluate a tumor based on an array of 500 genes and every patient will be given a specific pill that will deliver just the right amount of the exact drug based on her biomarkers,” Berry says. “We’re not trying to do that with I-Spy-2, and obviously it’s enormously difficult, but we’re moving in that direction.”
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