Researchers Focus On Lung Cancer
Researchers at the University of Colorado Cancer Center have created new criteria for selecting patients for targeted therapies that may revolutionize the standard of care for non-small cell lung cancer.
When Dr. Marileila Varella-Garcia got an email in 2004, she opened the attached spreadsheet and turned immediately to the survival curves.
“I was expecting the results I saw, but you never really know before you see the curves,” said Varella-Garcia, professor of Medical Oncology at the University of Colorado Denver School of Medicine (UCD SOM). She is one the world’s pioneer of using a technology called fluorescence in situ hybridization (FISH) to look at gene amplification in solid tumors.
The spreadsheet held statistical analysis of years of work by a collaborative team of lung cancer researchers at the University of Colorado Cancer Center. The project hypothesized that non-small cell lung cancer (NSCLC) tumors that have multiple copies of the EGFR gene identify patients who will benefit from EGFR inhibiting drugs. About 159,000 Americans are diagnosed with NSCLC each year, and about 50 percent are EGFR+. Most lung cancers are diagnosed after the tumor has spread throughout the lungs and to other parts of the body. Median life expectancy for patients diagnosed with Stage IV NSCLC is nine to 12 months.
The Colorado team includes Drs. Varella-Garcia, Fred Hirsch, Paul Bunn, Wilbur Franklin and Federico Cappuzzo, an Italian scientist who did a post-doctoral fellowship in Hirsch’s lab. The researchers knew from previous studies here and around the world that NSCLC tumors carrying extra copies of the EGFR gene indicate a poor prognosis for NSCLC patients. EGFR+ lung tumors are more aggressively invasive than EGFR- lungtumors. The group’s goal: to identify biomarkers which could predict sensitivity for EGFR inhibitors.
The 2004 study results, based on tissue samples from Cappuzzo’s patient cohort in an Italian study of the EGFR inhibitor Iressa (gefitinib), showed that Iressa blocks the gene activation in EGFR+ tumors, which slows or stops tumor invasion and metastasis. However, Iressa didn’t pan out in the United States after a large, randomized study could not demonstrate a significant survival benefit with the drug, which was then disapproved by FDA. But another similar drug, Tarceva (erlotinib), demonstrated a significant survival benefit in advanced lung cancer. It was approved by FDA in 2004.
Knowing that EGFR inhibitors improve survival and stop cancer progression in advanced NSCLC is only helpful if you know exactly which patients to give the drugs to. Tarceva, Iressa and Cetuximab, another EGFR inhibitor, are expensive, and they are not free from side effects. Further studies at UCCC and elsewhere showed that while the drugs helped some people, they did not help others.
“We needed a tool to tell us which patients to put on these drugs,” said Hirsch, professor of Medical Oncology and Pathology at UCD SOM. “We believed that EGFR FISH was that tool.”
In 2007, the UCCC team announced that they had a valid test, based on Varella-Garcia’s EGFR FISH probes, Franklin’s and Hirsch’s immunohistochemistry work and Franklin’s gene mutation analysis, that would predict which patients would benefit from EGFR inhibitors.
More importantly, the group invented a scoring system for these tests that is likely to become the gold standard for identifying patients who will benefit from EGFR inhibitors as first-line therapy. In two Phase II clinical trials, the UCCC team showed that advanced NSCLC EGFR+ patients have double the median life span—about 15 months—as EGFR- patients after being treated with Tarceva or cetuximab and chemotherapy, compared to EGFR- patients treated on that protocol. What’s more, the combination therapy stopped tumor growth and invasion and even shrank the tumors.
“When we give patients the right drugs for their exact tumor type, we can help them live a longer, more comfortable life with the disease,” said Bunn, professor of Medical Oncology at UCD SOM and principal investigator of UCCC’s Lung Cancer Specialized Program of Excellence grant, which helped fund much of the work behind this discovery. For the past year, he has been screening NSCLC patients’ tumors, and if EGFR+, he puts patients on combination therapy.
One patient, Dr. Yang Chen, was diagnosed with advanced EGFR+ NSCLC in February 2008. Bunn, his medical oncologist, put him on combination therapy, followed by radiation and surgery. One year later—well past the typical median life expectancy for someone with this diagnosis—his cancer is in remission and he is back at work at University of Colorado Hospital.
“My case was very unique though, because my body responded quickly to the targeted drug therapies,” Chen told the Boulder Daily Camera in a Dec. 9, 2008 article. “After only my second full chemotherapy cycle, a scan showed all my hot spots were no longer hot, meaning my cancer was being effectively (destroyed).”
Will other patients see the same success as Chen? The scoring system must be tested in Phase III trials. Hirsch is an architect of the MARVEL trial—the first Phase III clinical trial ever to determine if biomarkers can help guide therapies for lung cancer—and an upcoming Southwest Oncology Group trial, both of which will enroll 1,200 to 1,500 patients. UCD’s Colorado Molecular Correlates lab, developed and run by Franklin, will be responsible for EGFR screening for every patient tumor, further cementing the UCCC’s status as the nation’s expert in this field.
If the EGFR FISH tool is validated in the trials, its use could revolutionize treatment for NSCLC patients around the globe. Most commercial labs can conduct FISH assays today; technicians would need only be trained on the Colorado scoring system. “The results of this study could very well change the way lung cancer patients are treated in the future, similar to how screening for HER2 changed how patients with HER2+ breast cancer tumors are treated,” Hirsch said. HER2 is the only other gene that has been proven as an effective biomarker to select patients for treatment with the anti-HER2 drug Herceptin (trastuzumab).
Back in 2004, the Colorado team had hoped that the EGFR FISH project would result in a tool that could be used worldwide against the lung cancer problem.
“The move from basic science to clinical application is a complex and lengthy process,” Varella-Garcia said. “Thousands of scientific hypotheses are tested before the generation of a laboratory test with clinical impact. It is quite uncommon for one group to take an idea from the laboratory to the clinical market. We are all quite excited that we have created something that will significantly help patients with advanced lung cancer live longer and with better quality of life.”