Researchers from Johns Hopkins Kimmel Cancer Center recently presented results from a Phase II clinical trial showing that in patients with colorectal cancers (CRCs) and other cancers for whom standard therapies have failed, it may be possible to accurately predict who will respond to certain immunotherapy drugs known as PD-1 inhibitors, by assessing if these patients have mistakes in so-called mismatch repair (MMR) genes. The study, entitled, “PD-1 blockade in tumors with mismatch repair deficiency,” was presented at the American Society of Clinical Oncology 2015 Annual Meeting and was published in the latest edition of the New England Journal of Medicine.
Background Terminology:
- Mismatch repair genes: MMR genes encode proteins that repair errors in DNA bases that lead to mutations. When these genes are not functioning properly they can lead to cancer-promoting mutations.
- PD-1 inhibitors: this class of drugs blocks the programmed cell death protein 1, thereby activating the immune system to attack tumors.
- Metastasis: The spread of cancer from one part of the body to another. A tumor formed by cells that have spread is called a “metastatic tumor” or a “metastasis.”
Research oncologists have theorized that cancerous tumors with a greater number of mutations are more likely to respond to PD-1 inhibitors and similar immunotherapy drugs. Although, this theory has not been tested in patients with metastatic CRC.
To test the theory that MMR–deficient tumors are more responsive to PD-1 blocking drugs than are MMR–proficient tumors the researchers enrolled 41 patients with previously treated metastatic cancers that was not responding to therapy, and treated them with intravenous pembrolizumab (PD-1 inhibitor) every 14 days. The patients were divided into 3 different groups that included:
- 11 patients with MMR-deficient CRCs
- 21 patients with MMR-proficient CRCs
- 9 patients with MMR-deficient cancers of types other than colorectal
When comparing the survival rate at 20 weeks and the immune response rate for each group the results were as follow:
- The immune response rate for the MMR-deficient CRC group was 40%
- The 20 week survival rate for the MMR-deficient CRC group was 78%
- The immune response rate for the MMR-proficient CRC group was 0%
- The 20 week survival rate for the MMR-proficient CRC group was 11%
- The immune response rate for the MMR-deficient other cancers group was 71%
- The 20 week survival rate for the MMR-deficient other cancers group was 67%
In a University press release Dr. Luis Diaz Jr., MD, an oncologist at the Johns Hopkins Kimmel Cancer Center, a member of the Ludwig Center at Johns Hopkins and senior study author, stated “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.”
“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. 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,” says Dr. Dung Le, MD, an oncologist at the Johns Hopkins Kimmel Cancer Center and study co-author.
Dr. Kenneth W. Kinzler, PhD, co-director of the Ludwig Center at Johns Hopkins and study co-author, expands on his colleagues statements and explains what the next steps are for continuing the research, “It’s rare for patients with colon cancer who have failed all standard therapies to respond and most of them only have a few months to live. While it’s promising to see that patients with mistakes in mismatch repair genes responded more often to immunotherapy than those who did not have these mistakes, we need to test this idea in more patients and potentially earlier on in the sequence of therapies for these advanced cancers.”
