Pembrolizumab is known under the following name: Keytruda.

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1 KEYTRUDA AS A THERAPY FOR MELANOMA IN ADVANCED STAGE OR THAT CANNOT BE EXTIRPATED AND NON-SMALL CELL LUNG CANCER IN ADVANCED STAGE. Section Medicine Subsection Introduction Medicine Original Date February 19, 2016 Revision Date November 04, 2016 "This policy is protected by copyright under federal laws and/or intellectual property laws and State regulations. No part of this publication may be reproduced, stored in a retrieval system, transmitted in any form or by any medium, either electronic, mechanical, photocopy, recording or any other, without the written permission of the health plan." Definition Pembrolizumab is known under the following name: Keytruda. The NCCN in its latest version (2.2016) for Melanoma guidelines details that Keytruda is included as a first line of treatment for patients in advanced stages. Guidelines for Non- Small Cell Lung Cancer, from this same organization in its latest version (4.2016) details that Keytruda is included as subsequent treatment for patients in advanced stages and that the tumor expresses the PD-L1 protein. The organization explained that in recent studies Keytruda shows greater efficacy and better security compared with other treatments. Background The Food and Drug Administration (FDA) granted Keytruda the designation of revolutionary therapy because preliminary clinical studies showed that this drug can offer a substantial improvement of the condition in comparison with the other available therapies. In addition, it received the designation of orphan drug (a drug for the treatment of rare or unusual conditions) and of priority assessment. This category is granted to drugs that, at the time of submitting the application, have the potential to represent a significant Page 1 of 7

2 improvement in safety or efficacy in the treatment of a serious disease. The FDA decided to approve this drug based in the Accelerated Approval Program, which allows to approve a drug to treat a serious or potentially deadly disease based in clinical data that show that there is a therapeutic benefit for the patients. It provides immediate access to these new drugs, while simultaneously the company continues performing clinical studies. Advanced Melanoma Melanoma represents approximately 5% of all new cases of cancer in the United States. It is the most dangerous form of skin cancer that develops by damage in the DNA of the skin cells causing mutations that produce a rapid cell multiplication and the formation of malignant tumors. These tumors are produced in the melanocytes (skin pigment-producing cells, melanin), located in the basal membrane of the epidermis. According to the American Cancer Society, it is estimated that more than 120,000 new cases of melanoma are diagnosed in a year and that about 9,710 patients die annually from this disease. This type of cancer if it is not identified or treated in time it can spread to other cells of the body becoming metastatic melanoma. Advanced Non-Small Cell Lung Cancer Lung cancer is the biggest cause of death by cancer in the United States. About 85-90% of cancerous tumors in the lung are diagnosed as Non-Small Cell lung cancer, due to their size. This is developed by damage to the DNA in the cells of the lining of the bronchi or other structures of the lung such as bronchioles and alveoli. This genetic damage causes mutations in the cells, generates an accelerated cell multiplication and growth of malignant tumors. According to the American Cancer Society, it is estimated that more than 221,200 new cases are diagnosed in a year and that approximately 158,040 patients die because of this disease annually. If this type of cancer is not identified or treated in time it can spread to other cells of the body becoming the metastatic Non-Small Cell lung cancer. Page 2 of 7

3 Regulatory Situation Advanced Melanoma The FDA approved Keytruda to treat melanoma that is advanced or that cannot be extirpated. The efficacy of Keytruda was established in 834 participants of a clinical trial with melanoma patients in advanced or inoperable stage and whose disease progressed after receiving at least 1 previous treatment. Those patients had not received ipilimumab previously. The participants in the study were treated with Keytruda, at a dose of 10 milligrams per kilogram (mg/kg) every 3 weeks, Keytruda 10 milligrams per kilogram (mg/kg) every 2 weeks or ipilimumab 3 milligrams per kilogram (mg/kg) every 3 weeks for 4 doses. Participants receiving the dose of 10 mg/kg every 3 weeks showed a reduction in the size of their tumors in approximately 33% of the cases. This effect lasted at least 1.4 to 8.1 months, and in the majority of patients continued after this period. The safety of Keytruda was evaluated in 411 participants with advanced stage melanoma. The most common side effects reported were fatigue, cough, nausea, diarrhea, constipation, decreased appetite, skin itching, rash and pain in joints (arthralgia). The Keytruda can also cause severe side effects associated with immunological reactions or related to rare damage to healthy organs (such as the lungs, colon, liver, hormoneproducing glands). Advanced Non-Small Cell Lung Cancer The FDA approved Keytruda to treat Non-Small Cell lung cancer in advanced stage in patients who after receiving other treatments their condition has progressed and they express the PD-L1 protein. The efficacy of Keytruda was established in a subset of 61 patients participating in a clinical study suffering from Non-Small Cell lung cancer in advanced stage and whose disease progressed after receiving chemotherapy with a Platinum or any targeted therapy for certain genetic mutations (ALK or EGFR). In addition, these participants presented tumors positive to the protein PD-L1 based on the result of the diagnostic test approved by the FDA (22C3 pharmdx). The participants were treated with Keytruda with a higher Page 3 of 7

4 dosage than the one recommended, 10 milligrams per kilogram (mg/kg) every 2-3 weeks. Approximately 41% of participants noted a reduction in the size of their tumors. This effect lasted at least 2.1 to 9.1 months. The safety of Keytruda was evaluated in 550 participants with Non-Small Cell lung cancer in advanced stage. The most common side effects reported were fatigue, cough, decrease in appetite and lack of air. The Keytruda can also cause severe side effects associated with immunological reactions or related to rare damage to healthy organs (such as the lungs, colon, hormone-producing glands). Policy A. Keytruda is indicated to treat advanced, metastatic and inoperable melanoma and Non-Small Cell lung cancer in advanced stage that progresses after having received other treatments and presents tumors that express the PD-L1 protein. 1. The FDA approved dose is 2 mg/kg in intravenous infusion (IV) for 30 minutes. It should be given once every three weeks. The treatment must continue until the progression of the disease occurs or unacceptable toxicity. 2. In pharmacokinetic studies no difference was found in creatinine clearance (CrCl) of patients with mild, moderate or severe renal dysfunction, (egfr 15 ml/min to 89 ml/min) compared with patients of normal renal function (egfr 90 ml/min); patients with egfr < 15 ml/min were not studied. Therefore, no adjustment of dosage in patients with renal dysfunction is required. B. The decision to treat a patient with Keytruda should be based on the following criteria: 1. It must be prescribed by a hematologist or oncologist. 2. Diagnosis of advanced or that cannot be extirpated melanoma or Non-Small Cell lung cancer in advanced stage that progresses after having received other treatments and presents tumor(s) that express the PD-L1 protein. 3. Patient 18 years or older Page 4 of 7

5 4. Required information: a) Patient s weight b) Evidence of having received chemotherapy with a platinum (cisplatin or carboplatin) c) It presents evidence of having obtained a positive result to the expression of the PD-L1 protein (determined by the test approved by the FDA). C. The admission of the patient to the hospital with the single and only purpose of administering Keytruda requires individual pre-authorization for treatment in essence of service. The request must include the following documentation: 1. Insured s contract number. 2. It must be prescribed by a hematologist or oncologist. 3. ICD-9 or ICD-10 diagnostic code. 4. Medical necessity documentation. a. Evidence of at least one metastasis 5. Number of milligrams to be administered (2 mg/kg) D. If a patient, with the diagnosis approved for payment by this policy, is admitted to the hospital, and as part of the treatment requires the use of Keytruda, Triple-S will cover the treatment after the requirements previously exposed are met. E. Triple-S only pays the dose every 3 weeks of the medication. F. Triple-S will not consider for payment the use of Keytruda under the following circumstances: a. The patient presents hypersensitivity to the product or any of its components. b. Patient does not comply with any of the above mentioned criteria. Page 5 of 7

6 Codes Melanoma Code Number Description ICD Malignant melanoma of the skin ICD 10 C43 Malignant melanoma of the skin ICD Non-Small Cell Lung Cancer ICD 10 C34 Non-Small Cell Lung Cancer HCPCS J9271 Injection, pembrolizumab 1 mg Limitation According to those established in policy. Pre-Auto Required Ángela Hernández, MD Associate Medical Director Benjamín Santiago, MD Executive Medical Director References 1. American Cancer Society. Cancer Facts & Figures Accessed January 11, Codes ICD-9 and ICD-10 for malignant melanoma: ICD-9-CM to ICD-10-CM Based on FY2014 ICD-9-CM codes Recovered from: 3. Facts & Comparisons eanswers Keytruda Monograph. Last modification October Wolters Kluwer Health, Inc. Recovered from: Page 6 of 7

7 apping=-1&fromtop=true#firstmatch 4. Facts & Comparisons eanswers Keytruda Monograph. Last modification October Recovered from: Keytruda (pembrolizumab) [prescribing information]. Whitehouse Station, NJ: Merck; September Merck Sharp and Dohme Co Highlights of Prescribing Information. Recovered from: 7. National Comprehensive Cancer Network (NCCN) Guidelines Melanoma Version Available at: Accessed on January, National Comprehensive Cancer Network (NCCN) Guidelines Non-Small Cell Lung Cancer Version Available at: Accessed on January, Skin Cancer Foundation Melanoma. Recovered from: UptoDate Pembrolizumab Drug Information. 11. U.S Food and Drug Administration FDA approves Keytruda for advanced melanoma. First PD-1 blocking drug to receive agency approval. Recovered from: U.S Food and Drug Administration FDA approves Keytruda for advanced non-small cell lung cancer. First drug approved in lung cancer for patients whose tumors express PD-L1. Recovered from: Page 7 of 7