Genetic marker may predict cancer response to immunotherapy drug
CHICAGO, IL—In a report of a proof-of-principle study of patients with colon and other cancers for whom standard therapies failed, researchers found that mistakes in mismatch repair genes may accurately predict who will respond to certain immunotherapy drugs known as PD-1 inhibitors. Such drugs aim to disarm systems developed by cancer cells to evade detection and destruction by immune system cells.
Results of the trial with pembrolizumab (Keytruda) were presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting, and published in the New England Journal of Medicine (2015; doi:10.1056/NEJMoa1500596).
"This study gives us a solid clue about how immunotherapy may work in cancer and how to guide immunotherapy treatment decisions based on the genetic signatures of a cancer rather than class of cells or organ of origin," said senior author Luis Diaz Jr, MD, an oncologist at the Johns Hopkins Kimmel Cancer Center and a member of the Ludwig Center at Johns Hopkins in Baltimore, Maryland.
"Defects in mismatch repair genes are found in a small percentage of many cancer types, and this type of biomarker for immunotherapy response could apply to tumors containing errors in other DNA repair genes, as well," said Dung Le, MD, also of Johns Hopkins. "Using a predictive biomarker can help us direct the use of immunotherapy drugs to patients who are more likely to respond, avoiding giving people expensive and time-consuming treatments that are not likely to work or delaying the use of other treatments."
For the study, scientists enrolled and treated 48 patients with cancer.
In one group of 13 patients with advanced colon and rectal cancers and mismatch repair gene defects, eight had partial responses to pembrolizumab, meaning their cancers shrunk by at least 30% in diameter. Four patients had prolonged disease stability, and one patient experienced disease progression.
In another group of patients with colon and rectal cancer who had no defects in mismatch repair genes, all 25 failed to respond.
In a third group of 10 patients with a variety of other cancers that tested positive for mismatch repair gene defects (four with pancreatic/bile duct cancers, two with uterine cancers, two with small bowel cancers, one with stomach cancer and one with prostate cancer), one patient with uterine cancer had a complete response, meaning there was no radiographic evidence of their cancer, five had partial responses, one had stable disease, and three patients' cancers progressed.
All patients had received and were no longer responding to previous therapies.
Since pembrolizumab can cost more than $100,000 per year, choosing patients most likely to benefit also takes on financial urgency.
Median overall and disease progression-free survival in the colon cancer group with mismatch repair-defect group have not been reached yet, since several patients in this group have continued to respond to the immunotherapy drug for more than 12 months. Median follow-up for this group is 36 weeks (ranging from 5 to 55 weeks).
In the group of patients with colon cancer who lack the mismatch repair errors, median overall survival was 7.6 months, and median disease progression was 2.3 months. These patients were followed for up to 42 weeks. In the third group of patients with mistakes in mismatch repair genes, median overall survival has not been reached, and their median disease progression-free survival was 5.4 months after being followed for up to 42 weeks.