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Mismatch repair deficiency predicts response to pembrolizumab in several cancer types
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CHICAGO — Mismatch repair deficiency may be the first genomic marker to predict how patients with cancer will respond to immune checkpoint blockade with the anti–PD-1 antibody pembrolizumab, according to phase 2 study results presented at the ASCO Annual Meeting.
An analysis that included patients with several cancer types showed those with mismatch repair (MMR)-deficient tumors demonstrated a dramatically higher response rate and significantly longer PFS after treatment with pembrolizumab (Keytruda, Merck) than those who did not have the abnormality, characterized as MMR proficient.
The findings show testing for MMR deficiency could help clinicians identify patients most likely to benefit from pembrolizumab or other anti–PD-1 antibodies, Dung T. Le, MD, assistant professor of oncology at Johns Hopkins Kimmel Cancer Center, and colleagues concluded.
“This is the first study to use genetics in a prospective manner to guide immunotherapy, and it shows mismatch repair-deficient tumors are highly responsive to checkpoint blockade with anti–PD-1,” Le said during a press conference. “These data suggest genomics are more influential than histology for mismatch repair-deficient tumors treated with anti–PD-1.”
The average tumor harbors dozens of somatic mutations, whereas MMR-deficient tumors — identified by an existing commercially available test — can harbor hundreds or thousands of mutations.
Approximately 5% of patients with several cancer types have MMR deficiency. About 20% of sporadic colorectal cancers, and nearly all colorectal cancers associated with Lynch syndrome, are MMR deficient. MMR deficiency also has been reported in several other tumor types, including stomach, prostate, ovarian and endometrial cancers.
As the number of mutations increases, so does the likelihood that the immune system can recognize and destroy a tumor. Consequently, Le and colleagues hypothesized that immune checkpoint blockade would be particularly effective in patients with MMR-deficient tumors.
The analysis included 71 patients divided into three cohorts.
The first cohort included 25 patients with MMR-deficient metastatic colorectal cancer. The second cohort included 25 patients with MMR-proficient metastatic colorectal cancer. The third cohort included 21 patients with MMR-deficient solid tumors other than colorectal cancer.
On average, MMR-deficient tumors harbored 24 times as many mutations as MMR-proficient tumors (approximately 1,700 vs. 70; P = .007).
All patients received IV pembrolizumab 10 mg/kg every 14 days.
Immune-related objective response rate and immune-related PFS at 20 weeks served as co-primary endpoints.
Le presented results for the first 48 patients enrolled.
Among patients with colorectal cancer, those with MMR-deficient tumors demonstrated considerably higher rates of response (62% vs. 0%) and disease control (92% vs. 16%) than those with MMR-proficient tumors. Researchers observed blood marker changes that indicated response in patients with MMR-deficient tumors within a few weeks of treatment initiation.
Patients with MMR-deficient colorectal cancer also achieved longer median PFS (not reached vs. 2.2 months; HR = 0.1; 95% CI, 0.02-0.37) and OS (not reached vs. 5 months; HR = 0.21; 95% CI, 0.04-1) than those with MMR-proficient colorectal cancer. Researchers observed an association between higher total somatic mutation load and PFS (P = .02).
In the cohort of patients with MMR-deficient solid tumors other than colorectal cancer, researchers reported a 60% objective response rate and a 70% disease control rate. The researchers observed responses in patients with advanced endometrial cancer, stomach, small bowel and bile duct cancers, suggesting this approach could have “broad applicability,” Le said.
The responses also appeared durable, as several have lasted more than 1 year, Le said.
Researchers reported 20-week median immune-related PFS rates of 78% among those with MMR-deficient colorectal cancer, 67% for other types of MMR-deficient solid tumors, and 11% among those with MMR-proficient colorectal cancer.
A prospective study in a larger group of patients is necessary to confirm these findings. However, the possibility of achieving durable responses with manageable toxicity may support use of this approach as part of upfront treatment, Le said.
“This study is really about bridging immunotherapy and genomics for the benefit of patients, and it has implications for a broad range of cancers,” Le said in a press release. “Opening the door to this effective new therapy would be a breakthrough for this subset of patients with metastatic colon cancer and other hard-to-treat cancers.” – by Mark Leiser
For more information:
Le DT, et al. Abstract LBA100. Presented at: ASCO Annual Meeting; May 29-June 2, 2015; Chicago.
Disclosure: The researchers report research funding from, honoraria from and employment relationships with Merck. See the study for a full list of all researchers’ relevant financial disclosures.
Perspective
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Richard Kim, MD
Immunotherapy is one of the hot topics in oncology. Unfortunately other than gastric cancer, immunotherapy has not worked well in other gastrointestinal cancers. Le and colleagues attempted to evaluate to see if mismatch repair (MMR) deficiency can potentially be a biomarker in predicting response to anti–PD-1 drugs. Targeting these subset populations makes senses as these patients tend to have more somatic mutations eliciting a strong immune response from the host.
The study using pembrolizumab (Keytruda, Merck) included three cohorts: MMR-deficient colon cancer vs. MMR-proficient colon cancer vs. MMR-deficient non-colorectal tumors. The results were fascinating as patients with MMR deficiencies had a response rate of 62% compared with 0% in MMR-proficient arm. The responses also were seen in MMR-deficient endometrial, gastric and biliary cancers. Further, these patients had durable response with many patients responding to treatment longer than 12 months.
This is the first study to demonstrate MMR as a biomarker which can help us predict which patients will benefit from immunotherapy. This is just the start. We’ve now proven the concept that immunotherapy works in patients with mismatched repair deficiency tumors. This study should be validated in a larger study and potentially even moved up to the first or second line since this study was mostly conducted in a refractory setting. Further, we also know that tumors can eventually develop resistance to anti–PD-1 drugs. So, the next step would be to potentially combine with other immunotherapy drugs such as anti–CTLA-4 or with anti-angiogenic drugs to see if the combination can offer more potent tumor activity.
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Lynn M. Schuchter, MD, FASCO
The presence of 1,700 mutations is like putting a red flag on a cancer cell and saying to the immune system, “Here I am.” It really allows the immune system to recognize these cancer cells as foreign. We have heard about many of the advances in immunotherapy in melanoma and kidney cancer, but it is really exciting to hear about the use of these treatments to stimulate the immune system across a broad array of cancer types, including solid tumors that traditionally have been quite refractory to treatment, as well as cancers that we haven’t thought would respond to the immune system. We know every patient who receives immunotherapy is not going to respond, so it is very important to precisely define which patients is going to benefit and which patients should not be exposed to these treatments, which do have the potential for side effects.
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