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Novel cancer drug stalls tumor growth

It took a while to get “just right,” but the drug T-DM1 both fights breast cancer and delivers fewer side effects, said Dr. Kimberly Blackwell, director of the Breast Cancer Clinical Program and a professor of medicine at the Duke Cancer Institute.

In a Phase III clinical trial, advanced-stage breast cancer patients who were randomly assigned to receive T-DM1 saw their cancer growth delayed longer than patients in the control group that received standard drug regimens. The new drug combines antibodies with toxins to selectively target tumor cells without the slew of side-effects associated with chemotherapy.

“It’s not just about the drug not hurting patients, it’s about the drug not hurting patients and helping them live longer—that’s the success story,” Blackwell said.

In the trial, women with metastatic breast cancer—cancer that is spreading to other areas of the body—were randomly assigned two different treatments: T-DM1 or the standard drug regimen of capecitabine and lapatinib. The study found that women who were given T-DM1 had no cancer growth for a median of 9.6 months, whereas women who received the other treatment saw no cancer growth for a median of 6.4 months.

In addition to the drug’s ability to slow the growth of cancer, most women taking it did not experience hair loss, nausea and diarrhea, which are associated with typical chemotherapy, Blackwell said.

“[Blackwell] took patients that had relapsed in other therapies and not only saw tumor response but a prolongation of life,” DCI Executive Director Dr. Michael Kastan said. “It’s a great technical breakthrough and I am confident we will see other successes.”

Referred to as an antibody-drug conjugate, T-DM1 is a combination of the antibody trastuzumab—the T in the name—and the toxin DM1. The antibody latches onto the protein HER2, which is found on the surface of breast cancer tumors, Blackwell said. When this happens, the toxin is delivered to the cancerous cell.

One in five women with breast cancer have tumors with high levels of HER2 proteins, she added. The antibody acts as a carrier pigeon that delivers the DM1, which then can prevent cancerous cells from growing and spreading, Blackwell said.

“It’s about delivery as opposed to how many cells you can kill,” she noted. “I can dump toxins on cancer cells in a lab all day, but the problem is fighting the cancer in a way that spares [healthy] tissue.”

‘A long time coming’

Data supporting the use of antibody-drug conjugates that target the HER2 proteins found on breast cancer tumors was first found in 1998, Blackwell said.

It was not until 2009 that people tried finding toxins and antibody combinations that would allow the treatment to be used without chemotherapy, she said. This venture, however, would prove to be difficult.

“It’s like goldilocks and the three bears—you can’t have a toxin that holds too tightly to the antibody or that gets released too soon,” Blackwell said. “You want it to be just right so that the toxin is delivered directly to the tumor.”

When data showed that T-DM1 was effective in both treating the cancer and reducing side effects in 2010, researchers had finally made a breakthrough, she said.

Kastan noted that this discovery required precise chemical accuracy and several trials.

“The combination of the tumor type [they chose to target] with the antibody and toxin, as well as the chemical linkage between the two, requires sophisticated chemistry and a lot of time,” he said. “These trials have been arduous.... It’s been a long time coming.”

Adding to the arsenal

T-DM1 will act as the forerunner for a new class of treatment that combines two types of drugs to fight cancer, said Dr. Joseph Moore, medical director of the Duke Raleigh Cancer Center.

“Basically, what you’re trying to do is get a synergy of powerful treatment with fewer effects,” he said. “T-DM1 is a real addition [and] there will be many more to come.”

The drug adds to the wealth of progress that has been made in detecting and treating cancer since he started tackling the disease as a fellow in 1975, Moore said. Not every patient is cured, but chances of success have risen greatly since then.

Kastan noted that the breakthrough changes the way cancer will be treated by physicians in the future.

“We were limited the last 40 years because we only had a handful of drugs to use,” he said. “In the next 20 to 30 years we will have a lot more drugs and they will have to be tested, but they will be smarter and more effective at what they do.”

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