A huge paradigm shift in Cancer Treatment: Dr. Nilesh D. Mehta

Cancer

Huge Paradigm shift in Cancer Treatment : Dr. Nilesh D. Mehta

Medical Oncologists have for decades utilized chemotherapy for treating patients with cancer. Depending on the stage and type of cancer being treated, patients experience varying degrees of success. However, there has been some consternation among patients and families about the “C” words – Cancer and Chemotherapy. Doctors try and allay some of the fears about the diagnosis of cancer by focusing on some of the positives that one can think about during these difficult times. Although there have been significant advances in the management of some of the adverse effects of chemotherapy, patients even today shun the idea of taking these treatments. We have come a long way in supportive care treatments to alleviate some of the discomfort patients undergo while on chemotherapy. Why then was an alternative to chemotherapy not discovered?

Back in the 1980s, Dr. Rosenberg at the National Cancer Institute introduced the idea of immunotherapy in the treatment of patients with melanoma. It was an extremely toxic form of therapy using interleukin-2 treatment which resulted in some patients dying but also some patients also enjoyed a long-lasting remission from their cancer. It was a remarkable feat that was achieved decades ago. The focus from “killing all cancer cells” was gradually shifting to “let us trick the cancer cells into dying”. Chemotherapy side effects are well described with patients experiencing hair loss, fatigue, nausea, vomiting, fatigue, bone marrow effects among others. With these biological drugs making headway, the side effect profile shifted to immune related adverse effects. Cancers like melanoma and kidney cancers were among the first of the diseases where non-chemotherapy approaches had shown promise.

Scientists took a huge clue from this and then this journey of targeted drugs with “personalized medicine” began. Pathologists while studying a biopsy sample were sending the cancer specimen for analysis of mutations. If a lung cancer patient had an EGFR mutation, we do not need to start chemotherapy but rather give them a pill once a day to suppress their cancer cells. But, more importantly, we spared them of the toxicity of chemotherapy that has the propensity of “killing” all cells – cancerous and non cancerous – that come in their way. Much akin to a bull dozer going down the street while leveling everything that is underneath. This concept had to change, and it did. Rather than treat the cancer in a generic fashion, why not try and understand the “genetic make-up” of the tumor and then attack it intelligently. That is what has happened over the last decade and a half.

But, with today’s announcement by the FDA, we have taken it up a notch further. Drugs like pembrolizumab ( a check point inhibitor) utilizes patient’s own immune system thus recruiting its own internal defensive forces to fight the cancer cells. This drug has been approved in several cancers including lung, kidney, melanoma, head and neck, Hodgkin’s lymphoma, and urinary bladder. Immense research in the laboratory for years led to the conclusion that we do not need to kill everything in sight to gain success in cancer medicine. Tricking the cancer cells by augmenting our own T lymphocytes can create a similar environment of suppressing the growth of cancer cells.

The U.S. Food and Drug Administration granted accelerated approval on May 23, 2017 to a treatment for patients whose cancers have a specific genetic feature (biomarker). This is the first time the agency has approved a cancer treatment based on a common biomarker rather than the location in the body where the tumor originated. From a practical standpoint what this means is when a biopsy shows cancer cells, the tissue is sent for further analysis to study biomarkers called as microsatellite and mismatch repair testing. This essentially means that the source of the primary tumor becomes somewhat irrelevant but what matters is whether the tumor expresses microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).

Keytruda (pembrolizumab) is indicated for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that have been identified as having a biomarker referred to as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). MSI-H and dMMR tumors contain abnormalities that affect the proper repair of DNA inside the cell. Tumors with these biomarkers are most commonly found in colorectal, uterus, and gastrointestinal cancers, but also less commonly appear in cancers arising in the breast, prostate, bladder, thyroid gland and other places. 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.

“This is an important first for the cancer community,” said 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, the FDA has approved cancer treatments based on where in the body the cancer started—for example, lung or breast cancers. We have now approved a drug based on a tumor’s biomarker without regard to the tumor’s original location.”

This is very exciting news for our patients who may not have responded to their initial therapy and are looking for additional therapy. In the clinical trials performed by the drug company, 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 Keytruda (pembrolizumab) 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 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. While one may not think this treatment as a cure for cancer, we are now seeing for the first time a paradigm shift in our thought process. Let us find out if a cancer patient (whether it be colon cancer, lung cancer or any other cancer) has the abnormalities in their MSI or MMR and then we can offer them pembrolizumab. Role of advanced molecular testing of tumors has now come to the forefront.

Adverse events of pembrolizumab include fatigue, itchy skin, diarrhea, decreased appetite, rash, fever , cough, difficulty breathing, musculoskeletal pain, constipation and nausea. This drug 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). Patients have to be carefully monitored while on these treatments.

Successful research in the laboratory has translated into a promising future for our cancer patients. May 23, 2017 will go down in the history of Oncology developmental therapeutics as a huge day. It appears that finally, chemotherapy will be taking a back seat now that the “driver mutations” and MSI/MMR are being increasingly recognized as targets for our successful therapy. A great day for our patients and their families.

Dr. Nilesh D. Mehta
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