Clinical Trials Game-Changer?

As a test run, in 2002, Esserman initiated I-SPY 1, which showed that a breast tumor’s response to neoadjuvant chemotherapy was a very good predictor of long-term, disease-free survival; the study also showed that the change in tumor size, as measured on MRI, was a good predictor of a patient’s treatment response. These findings validated the I-SPY framework, and made possible the March 2010 launch of I-SPY 2, which is testing multiple drugs and multiple biomarkers at 20 locations around the country.

In late 2006, BATTLE 1 began enrolling patients with metastatic non–small cell lung cancer whose disease had progressed during other treatments. To enter the trial, every participant had to have a new tumor biopsy, which allowed the researchers to determine the tumor’s current molecular signature—and to assign patients to the treatments that had been hypothesized to be most effective in tumors with specific biomarkers.

“We didn’t want to test drug A versus drug B, or A plus B versus C or D,” explains BATTLE founder Edward S. Kim, a medical oncologist at the University of Texas M. D. Anderson Cancer Center in Houston. “BATTLE was never meant to be a drug approval trial,” he says. “It was designed to change the way we approach research.”

And it did. The BATTLE 1 trial looked at four different therapies and evaluated 11 biomarkers. The findings, which were published in Cancer Discovery in June 2011, showed that lung cancer patients with a mutant KRAS gene appeared to do best when taking the drug Nexavar (sorafenib)—and that lung cancer patients were willing to enroll in a trial that required a new tumor biopsy. Those results set the stage for BATTLE 2, a phase II trial initiated in June 2011 that is testing two new investigational therapies in patients who have already received other treatments, and BATTLE 3, also known as BATTLE-FL (for “first line”), which is enrolling newly diagnosed patients.

Both pharmaceutical companies and the FDA are getting behind these trials. BATTLE was initially funded by a Department of Defense grant and now has pharmaceutical company backing. Meanwhile, I-SPY has the support of the Biomarkers Consortium, a partnership established in 2006 by the Foundation for the National Institutes of Health that includes the FDA, the National Institutes of Health and major pharmaceutical companies. This partnership helped Esserman gain FDA approval to change drugs or evaluate new biomarkers in the I-SPY 2 study without stopping the study, writing a new protocol and waiting for approval.

The information that can be gleaned from studies like I-SPY and BATTLE has the potential to make phase III trials faster and less expensive. That’s because if a phase II trial can identify biomarkers that predict which patients will see a large benefit, “then you can have a more targeted phase III study,” says Kim.

Whether phase II trials like I-SPY and BATTLE will be replicated for other types of cancer remains to be seen. But there is little doubt that we will see more trials that study biomarkers and new drugs simultaneously. This is part of the reason pharmaceutical companies have jumped in to provide financial support for the two new BATTLE trials. It’s also why the FDA is looking at how and when results from I-SPY 2 might be used to grant a drug accelerated approval.

In the end, though, it all comes back to the patients—who keep hearing about targeted therapies and personalized cancer care and wonder what that means for them. “At the end of the day,” says Esserman, “I put myself in the shoes of the people I’m taking care of. And we need to be able to tell them as quickly and efficiently as possible which new drugs are effective and which patients should take them.”

Adds Kure, the California breast cancer patient: “Past trials have gotten us to this point. Hopefully, the information they gain from me in this trial will make it easier for someone else who has to go through this tomorrow.”

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