Genetic glitch can predict response to new class of cancer drugs
Patients with colon and other cancers who have a specific defect in genes needed for DNA repair are far more likely to respond to a new class of drugs such as Merck & Co’s Keytruda, which enlist the immune system to attack tumors, a new study has shown.
The small study, financed not by Big Pharma but by swimmers who raised charitable donations, tested Keytruda in patients with advanced colon and rectal cancers and found 92 percent of patients with the genetic defect had their disease controlled compared with 16 percent who did not carry the defect.
The findings, announced on Friday at the American Society of Clinical Oncology (ASCO) meeting in Chicago, point to a new way to predict who will respond to the treatments, which are known as PD-1 inhibitors and can cost $150,000 a year.
“Conservatively speaking, we think this would help 2 to 3 percent of all cancer patients,” said Dr. Luis Diaz of the Ludwig Center at Johns Hopkins Kimmel Cancer Center in Baltimore, whose study was also published online in the New England Journal of Medicine.
“These are patients with metastatic disease that wouldn’t have any other alternatives.”
The results come courtesy of some 500 Baltimore swimmers who raised money for the study by taking a chilly dip last fall into a river leading to the Chesapeake Bay.
The study involved patients with defects in the machinery needed for fixing mistakes in DNA. Individuals with these defects develop tumors teeming with mutations, as many as 20 times more than cancer patients with working copies of these repair genes.
Since the immune system is trained to recognize foreign invaders, Hopkins researchers hypothesized that patients with tumors loaded with mutations might have a more robust response to cancer drugs that rev up the immune system, such as Merck’s Keytruda or Bristol-Myers Squibb’s Opdivo.
Diaz said he and Hopkins colleague Dr. Dung Le proposed the trial to several drugmakers who refused to pay for it. Merck donated the study drug but the researchers had to raise money for the trial on their own. They turned to Swim Across America, which raises funds for cancer research.
The scientists have tested Keytruda in 48 patients. Among 13 patients with advanced colon and rectal cancers and DNA repair defects, eight had partial responses, meaning their cancers shrank by at least 30 percent, and four had prolonged stable disease, resulting in a 92 percent disease control rate.
A group of 25 patients with similar cancers who did not have DNA repair defects showed zero response.
In a third group of patients with a variety of other cancers who tested positive for the DNA repair defects, six of 10 responded.
Many of the responses lasted over a year, which is impressive considering the study was done in patients whose “life expectancy was measured in weeks to months,” Le said.
Dr. Lynn Schuchter, an ASCO spokeswoman and a University of Pennsylvania oncologist who was not involved in the trial, said the findings need to be confirmed in a larger study but provide an important explanation of why some patients have remarkable responses to these treatments and others do not.
For Adrienne Skinner of Larchmont, New York, the study was a last-ditch option after she failed to respond to two types of chemotherapy to treat her rare gastrointestinal cancer.
When she started treatment with Keytruda, her cancer had spread to her liver, making it inoperable. She has now been on the therapy for 13 months.
“There is no tumor. I don’t have to have surgery. It’s phenomenal.”