First cancer treatment for any solid tumor with MSI-H or dMMR approved

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May 24, 2917 – The American Food & Drug Administration (FDA) just approved a major extension of the clinical indications for Pembrolizumab (Keytruda). For the first time,  a cancer treatment has been approved for any solid tumor, irrespective of the tumor’s original location, as long as the targeted tumor is carrying a specific genetic feature (i.e., biomarker).

 

Thus, Pembrolizumab (Keytruda) is now indicated for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that have been identified as

Immunohistochemical and MSI Molecular Testing in a Colorectal Cancer.

having a biomarker referred to as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). This indication covers patients with solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options and patients with colorectal cancer that has progressed following treatment with certain chemotherapy drugs (see the newest FDA drug label for details).

This is an important first time for the cancer community, acccording to Richard Pazdur, M.D., acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research and director of the FDA’s Oncology Center of Excellence. Until now and traditionally, the FDA has approved cancer treatments based on where in the body the cancer started, for example, lung or breast cancers. Here, for the first time, FDA has approved a drug based on a tumor’s biomarker without regard to the tumor’s original location.

Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors contain abnormalities that affect the proper repair of DNA inside the cell. Tumors with these biomarkers are most commonly found in colorectal, endometrial and gastrointestinal cancers, but also less commonly appear in cancers arising in the breast, prostate, bladder, thyroid gland and other places. Approximately 5 percent of patients with metastatic colorectal cancer have MSI-H or dMMR tumors.

Pembrolizumab (Keytruda) works by targeting the cellular pathway known as PD-1/PD-L1 (proteins found on the body’s immune cells and some cancer cells). By blocking this pathway (also referred to as immune checkpoint inhibition), Pembrolizumab (Keytruda) may help the body’s immune system fight the cancer cells. The FDA previously approved Pembrolizumab (Keytruda) for the treatment of certain patients with metastatic melanoma, metastatic non-small cell lung cancer, recurrent or metastatic head and neck cancer, refractory classical Hodgkin lymphoma, and urothelial carcinoma.

Pembrolizumab (Keytruda) was approved for this new indication using the Priority Review designation and the Accelerated Approval pathway, under which the FDA may approve drugs for serious conditions where there is unmet medical need and a drug is shown to have certain effects that are reasonably likely to predict a clinical benefit to patients. Further study is required to verify and describe anticipated clinical benefits of Pembrolizumab (Keytruda), and the sponsor is currently conducting these studies in additional patients with MSI-H or dMMR tumors.

The efficacy of Pembrolizumab (Keytruda) for this indication were studied in patients with MSI-H or dMMR solid tumors enrolled in one of five uncontrolled, single-arm clinical trials. In some trials, patients were required to have MSI-H or dMMR cancers, while in other trials, a subgroup of patients were identified as having MSI-H or dMMR cancers by testing tumor samples after treatment began. A total of 15 cancer types were identified among 149 patients enrolled across these five clinical trials. The most common cancers were colorectal, endometrial and other gastrointestinal cancers. The review of Pembrolizumab (Keytruda) for this indication was based on the percentage of patients who experienced complete or partial shrinkage of their tumors (overall response rate) and for how long (durability of response). Of the 149 patients who received Pembrolizumab (Keytruda) in the trials, 39.6 percent had a complete or partial response. For 78 percent of those patients, the response lasted for six months or more.

Common safety issues associated with Pembrolizumab (Keytruda) include fatigue, itchy skin (pruritus), diarrhea, decreased appetite, rash, fever (pyrexia), cough, difficulty breathing (dyspnea), musculoskeletal pain, constipation and nausea. Pembrolizumab (Keytruda) can cause serious conditions known as immune-mediated side effects, including inflammation of healthy organs such as the lungs (pneumonitis), colon (colitis), liver (hepatitis), endocrine glands (endocrinopathies) and kidneys (nephritis). Complications or death related to allogeneic hematopoietic stem cell transplantation after using Pembrolizumab (Keytruda) has occurred.

Moreover, patients who experience severe or life-threatening infusion-related reactions should stop taking Pembrolizumab (Keytruda). Women who are pregnant or breastfeeding should not take Pembrolizumab (Keytruda) because it may cause harm to a developing fetus or newborn baby. The safety and effectiveness of Pembrolizumab (Keytruda) in pediatric patients with MSI-H central nervous system cancers have not been established.

 

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About the Author
Joseph Gut - thasso Ph.D.; Professor in Pharmacology and Toxicology. Senior expert in theragenomic and personalized medicine and individualized drug safety. Senior expert in pharmaco- and toxicogenetics. Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.
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