Pairing the targeted therapy Tarceva with the anti-inflammatory drug Celebrex increased response rates in lung cancer patients by about three-fold, said Dr. Karen Reckamp, an assistant professor of hematology/oncology and lead author of the study. The research appears in the June 1 issue of Clinical Cancer Research, the peer-reviewed journal of the American Association of Cancer Research.
Previous laboratory studies at UCLA showed that a cell signaling pathway known as COX-2 may be linked to resistance to drugs like Tarceva, which block tumor cell growth by targeting the protein EGFR, or epidermal growth factor receptor. Researchers theorized that giving Tarceva with Celebrex, a COX-2 inhibitor, would help battle resistance and prove to be an affective combination against lung cancer.
Typically, about 10 percent of lung cancer patients respond to Tarceva. In Reckamp's study of the combination therapy, about 33 percent of patients responded.
"Tarceva alone is a great drug and has a lot of clinical benefits, but for a small proportion of patients," Reckamp said. "With this drug combination, we saw an increase in response rates, indicating we are overcoming some resistance. We also may be beginning to understand the mechanisms of that resistance."
Volunteers in the Phase I study, patients with advanced lung cancer that had failed to respond to all conventional therapies, took several Celebrex pills and one Tarceva pill each day. After eight weeks, researchers looked at response rates. Patients were able to stay on the study as long as they didn't experience tumor growth. The longest duration of response was 93 weeks, Reckamp said, about three to four times longer than the average duration of response for a patient with advanced lung cancer.
The study was part of the Specialized Program of Research Excellence (SPORE) in lung cancer at UCLA's Jonsson Cancer, a program funded by the National Cancer Institute at top research institutions nationwide to find better and more effective ways to prevent, detect and treat lung cancer.
"This trial is an important early step in utilizing combination targeted therapies in lung cancer," said Dr. Steven Dubinett, director of UCLA's lung cancer SPORE and a professor of pulmonary and critical care medicine. "Dr. Reckamp's trial is the first to study increasing doses of a COX-2 inhibitor in lung cancer in an attempt to define an optimal biological dose. Larger trials of combination therapies utilizing this dose will now be required."
The biology of an individual's tumor determines whether they will respond to Tarceva. Because researchers don't yet fully understand what biologic characteristics determine response, they can't test patients first to determine who should be given the drug. Since 90 percent of patients don't respond to Tarceva, the drug was not an option for them. Reckamp said a portion of those may now be able to take Tarceva combined with Celebrex.
Because they target what is broken in a cancer cell and leave the healthy cells alone, therapies like Tarceva cause fewer side effects than conventional therapies such as chemotherapy, which targets all fast growing cells and often results in debilitating side effects. Reckamp characterized the side effects seen with the combination therapy as minor.
The next step is a larger Phase II study to confirm the efficacy of the combination therapy and further probe the mechanisms of Tarceva resistance, Reckamp said. That study is expected to begin at UCLA in the fall.
Reckamp's study was the first to determine the safest and most effective dose of Celebrex to use in lung cancer. Previously, doses were based on studies done in colon cancer patients.
"I think the results of this early phase study are promising and I anticipate we'll have a better understanding of Tarceva resistance in the near future," she said.
Lung cancer is the most common cause of cancer-related death in both men and women and accounts for about 29 percent of all cancer deaths. This year alone, 174,470 people will be diagnosed with lung cancer in the United States. Of those, 162,460 will die, according to the American Cancer Society.
Only about 15 percent of people who get lung cancer reach five-year survival. Those with advanced disease usually survive less than a year.
"It's crucial that we develop better treatments for this disease," Reckamp said.