The battle toward personalized lung cancer therapy

After combination chemotherapy for lung cancer took his hair, Jerry Stutts and his wife Nancy decided it was time to let the grandkids know what was under that cap he always wore. 

“We were worried that the younger ones might be afraid,” Stutts says. 

So Nancy shaved the tufts of hair that remained and drew a large smiley face that covered the top of Jerry’s head to ease the shock when he finally doffed his cap.

After dinner on a Sunday afternoon, the cap came off for the five grandchildren, ages 9 months to 8 years old. 

“They all got so tickled,” Nancy says.

When the chemotherapy stopped working in mid-2008, the retired farmer from Bonita, La., went on the second-line therapy Tarceva®. 

The drug failed to control his cancer and made him feel miserable — a queasy stomach, nerve pain in his fingers and a general weak and wobbly feeling. Stutts thought it was somehow his fault that the Tarceva® wasn’t working. “I was starting to get a complex about my body — was it only me?” he says. 

"What’s actually wrong with all second-line lung cancer treatments is that they only work for about 10 percent of patients," says Edward Kim, M.D., assistant professor in MD Anderson’s Department of Thoracic/ Head and Neck Oncology. “Right now, no one knows which 10 percent that is for any of these drugs. There are no predictive tumor biomarkers to guide this decision, so essentially you’re selecting a drug based on possible side effects.”

Breast cancer, on the other hand, has several biomarkers that indicate which drug should be administered. Patients whose tumors overexpress a protein called HER2, for example, are treated with the drug Herceptin®. 

Kim is principal investigator for an innovative set of clinical trials designed to match drugs to the molecular aspects of a patient’s tumor. The trial is called BATTLE, for Biomarker-based Approaches of Targeted Therapy for Lung Cancer Elimination. The effort is funded by the U.S. Department of Defense and began enrolling patients in November 2006.

“The idea is to learn from the tumor’s biology how best to treat a patient’s lung cancer,” Kim says. 

Stutts joined the trial in September 2008 and was randomized to Nexavar®, a drug approved by the U.S. Food and Drug Administration for liver and kidney cancer. Research shows it’s also active against lung cancer. 

Stutts’ cancer has not progressed for three months. And there have been no side effects other than mild fatigue and nerve pain in his hands, but those have been with him since chemotherapy began more than a year ago.

“Stable disease is a good thing,” Kim says. “You aren’t killing off all of the cancer, but you’re stopping its growth. It’s all about getting your hands around cancer and not letting go.” 

All patients in BATTLE have late-stage lung cancer that has persisted, grown or returned. Some have been through two or three different treatment regimens. 

BATTLE’s first step is a fine-needle biopsy of the patient’s tumor. This is unique in that patients usually don’t have additional biopsies beyond initial diagnosis. 

“We believe the tumor after first- and secondline chemotherapy treatment is not the same as it was before treatment began,” Kim says. 

Drugs being evaluated in BATTLE are Tarceva®, Zactima®, Nexavar® and a combination drug called Targretin®. Patients early in the trial were assigned to one of 20 slots — four drugs against four groups of potential biomarkers and a group with no biomarkers. 

Patients were placed in the 20 groups based on earlier research to determine which of the biomarkers each drug was likely to target. The four no-biomarker groups will help the researchers identify new biomarkers after the trial closes. 

After the first 97 patients enrolled, a second unique feature of BATTLE began. In a process called adaptive randomization, subsequent patients are assigned to a drug based on information gained from the early patients. The statistical design is a well-established way of testing biomarkers in cancer. This aspect of the trial continues, with each patient adding more information for assigning those to come. 

If one drug fails to help anyone, that particular arm of the study can be closed to new patients. The percentage of patients assigned to one treatment arm might increase while others decrease. If the first drug is not working, a patient can choose to drop out of that trial, have a new biopsy and enter one of the others. 

So far, none of the four options has been closed and 237 patients have enrolled over two years. The study will close at 250 patients, probably in late summer 2009. 

The researchers know which drugs patients receive but are blinded as to the biomarker profiles that led to their assignments to those drugs. When the trial is unblinded, the research team can analyze how the original biomarkers worked and identify new ones that emerged during the trial. 

The team collects patients’ initial biopsies to compare them to their BATTLE biopsies to learn how lung cancer changes as treatment proceeds, Kim says. 

Study participants get a CT scan every eight weeks to evaluate their tumors. 

After BATTLE ends, a follow-up trial using the same design will test drugs in combination with standard chemotherapy as first-line treatment. 

Other research institutions are investigating lung cancer biomarkers, says Kim, but they don’t perform new biopsies and their studies are small, with about 20 patients. MD Anderson’s many patients allow for more powerful clinical trials. 

Jerry Stutts came to MD Anderson from Louisiana after a persistent cough led eventually to a diagnosis of non-small cell lung cancer. 

Stutts farmed full time from 1972 to 2002 before easing out of the operation and finally into full retirement last year. Sons Jason, 36, and Justin, 31, run the farm now, focusing on row crops such as rice, cotton and soybeans.

“My sons do real well — they love to farm, and they were ready for their dad to get out,” Stutts deadpans. 

“Mr. Stutts has a dry sense of humor,” Kim says, noting the good-natured bantering that goes on between the two. A prolonged friendly dispute, for example, over whether Kim really goes home and cooks dinner for his family was settled when Stutts talked by phone with Kim’s wife and got the answer for himself. 

Such friendliness on the part of Kim and other MD Anderson staff helps patients and families adjust to such a large institution, Nancy Stutts says. 

“Everyone at MD Anderson is so compassionate and courteous,” she says. “And they really know what they’re doing.” 

In the meantime Nancy and Jerry, that smiley face now replaced by a full head of hair, know they’re in good hands.