Spotlight on Immunotherapy: Genetic Makeup of Tumors Informs use of anti-PD-1 drugs for Multiple Cancer Types

By Pooja H. Rambhia, MD Candidate, Case Western Reserve University | 6 October 2017 | News, Science, Treatment


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Imagine the powerlessness one must feel after undergoing rigorous treatment for cancer only to find that your tumor is non-responsive. However – new hope may be on the horizon. In May 2017, the U.S. Food and Drug Administration (FDA) granted accelerated approval to Pembrolizumab for  treatmentof patients whose cancers possess a genetic mutation in the mismatch repair pathway (mismatch repair deficient, or dMMR) or are microsatellite instability-high (MSI-H). This is the first time the agency approved a cancer treatment based on a common biomarker rather than the location in the body where the tumor originated.

Just a few months later, in July, the FDA also approved another anti-PD-1 drug, Nivolumab, for dMMR and MSI-H colon cancer. Each of these treatments first reached the market as melanoma therapies and it is rewarding to witness the increasing use of these life-saving agents in more and more cancer types.

In the FDA’s statement announcing their decision, 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 called it “an important first for the cancer community. Until now, the FDA has approved cancer treatments based on where in the body the cancer started—for example, lung or breast cancers.”

A landmark study, recently published in the journal Science (July 2017), sought to address the underlying genetic landscape of tumors and its impact on immunotherapy response. The ability to predict patient-specific response to immunotherapy would allow doctors to optimize tumor management and avoid putting a patient through a treatment – and its associated side effects - without seeing any benefit. 

This group prospectively evaluated the efficacy of Pembrolizumab, a PD-1 inhibitor, in a range of different cancer subtypes that all possessed a common biomarker, mutations in the mismatch repair pathway. The mismatch repair pathway is important for repairing damaged DNA, and when deficient, can result in the uncontrollable growth of abnormal cells leading to cancer. After taking Pembrolizumab, 77% of patients achieved control of their respective cancers, with their tumors shrinking substantially and stabilizing. Among treated patients, 21% achieved a complete response with resolution of their tumor, and were accordingly taken off treatment within two years. Remarkably, these patients have not experienced recurrence of their cancer. 

How this likely works: It seems that when a patient’s tumor cells are dMMR, they accumulate more mutations resulting in altered proteins that look foreign to one’s immune system which aims itself at deleting the ‘foreign’ cells. MSI-H refers to a specific state of tumor cells that often occurs as a result of dMMR—the genomes of these tumor cells contain mutations specifically in regions called microsatellites, which also leads to greater immune recognition of tumors. But PD-1 receptors on cancer cells allow those cells to evade the immune response that would typically clear the abnormal cells. The impact of this is the cancer is able to effectively hide from a patient’s immune system, and proliferate. Inhibiting this interaction with PD-1 receptors with drugs like Pembrolizumab and Nivolumab, allows the patient’s immune system to see the cancer cell and destroy it. The results of this study are ongoing, but indicate that patients with tumors harboring specific mutations are able to respond to this type of cancer treatment better than others.

This group went on to evaluate how many cancer types possess these specific mutations, and would accordingly benefit from treatment with Pembrolizumab. Over 12 thousand (12,009) cancers representing 32 distinct tumor types were evaluated for deficits in mismatch repair biomarkers. They found that >2% of cancers of the endometrium, stomach, small intestine, colon and rectum, cervix, prostate, bile duct, and liver, as well as neuroendocrine tumors, uterine sarcomas, and thyroid carcinomas, were mismatch repair–deficient. These figures translate to about 60,000 new cancer diagnoses annually. As such, use of Pembrolizumab has the potential to successfully treat a significant number of patients struggling with aggressive, chemo–resistant cancers or tumors so aggressive that they are unable to be surgically removed. The fact that Nivolumab shows activity indMMR and MSI-H colon cancer patients provides added support for the role of PD-1 inhibitors to treat cancers with many mutations. The beauty of dMMR and MSI-H cancers as an indication is that genetic tests for these types of mutations are readily available to physicians, meaning that establishing a new standard of care with regards to cancer treatments is easier to accomplish.

The impact of this trial on the melanoma field is tremendous. In recent years, utility of immunotherapy in treatment of metastatic melanoma has been a very hot topic. Scientists have made major strides in understanding the molecular profile of tumor cells and how the immune system interacts with them. Immunotherapy, including PD-1 inhibitors, have dramatically changed the prognosis for metastatic melanoma patients, with reductions in disease progression, recurrence rates, and tumor size. Merging these therapeutics with heightened knowledge of genetic biomarkers of tumors has thrust immunotherapies into the spotlight, where they can be used to not only treat melanoma patients, but patients with other cancer types as well. As researchers continue to uncover the role of cancer mutations in directing specific therapies, melanoma patients will undoubtedly benefit from such advances. As we continue to see results from this trial, testing for mismatch repair mutations in treatment resistant patients may be considered in order to identify those who may more readily benefit from PD-1 inhibitor therapy.

 


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