Summary of the Risk Management Plan (RMP) V. 1.6, July 2017 for BAVENCIO Avelumab 200 mg/10 ml Concentrate for Solution for Infusion Marketing Authorisation Number 66380 Marketing Authorisation Holder: Merck (Schweiz) AG, Zug Disclaimer: The Risk Management Plan (RMP) is a comprehensive document submitted a spart oft he application dossier for market approval of a medicine. The RMP summary contains information on the medicine s safety profile and explains the measures that are taken in order to further investigate and follow the risks as well as to prevent or minimise them. The RMP summary of Bavencio is a concise document and does not claim to be exhaustive. As the RMP is an international document, the summary might differ from the Arzneimittelinformation/Information sur le médicament approved and published in Switzerland, e.g. by mentioning risks occurring in populations or indications not included in the Swiss authorization. Please note that the reference document which is valid and relevant for the effective and safe use of Bavencio in Switzerland is the Arzneimittelinformation/Information sur le medicament (see www.swissmedic.ch) approved and authorized by Swissmedic. Merck (Schweiz) AG is fully responsible for the accuracy and correctness of the content of the published summary RMP of Bavencio.
VI.2 VI.2.1 Elements for a Public Summary Overview of Disease Epidemiology Merkel cell carcinoma (MCC, also known as cutaneous neuro-endocrine carcinoma) is a rare type of skin cancer that starts in neuro-endocrine cells called Merkel cells. MCC usually appears as a painless tumor on the head and neck, but can also be found on the arms and legs, and sometimes on other parts of the body. In Europe, MCC accounts for less than 1% of all skin malignancies and about 4.0 per 100,000 people are affected by MCC in Europe. MCC predominantly affects the white population, affects men more often than women and occurs more frequently in elderly individuals and those with immunodeficiency. Additional risk factors include previous cancer disease, Merkel cell polyomavirus infection, and ultraviolet light exposure. MCC is a debilitating and life-threatening disease because it grows rapidly and spreads (metastasizes) quickly to other parts of the body. Once this cancer has spread, it has very poor long-term survival. VI.2.2 Summary of Treatment Benefits Bavencio contains the active substance avelumab. The medicine has been shown to be effective in treating adult patients with progressing spreading Merkel Cell Carcinoma (MCC). In an ongoing study including two parts, patients received Bavencio at a dose of 10 milligram per kilogram (mg/kg) every two weeks until cancer progression or the occurrence of side effects. The study looked at how the patient s cancer responded to treatment and how long responses persisted. The first part of the study (part A) included 88 patients who were previously treated with at least one other anti-cancer drug (chemotherapy). Twenty-nine out of 88 patients (33.0 %) responded to Bavencio treatment with improvement of their disease (tumor size decreased). This response was durable and was still present after 6 months in 93 % of patients who had a response to treatment and after 12 months in 71 % of patients who had a response to treatment. The second part of the study (part B) will include 112 subjects who were not previously treated with any chemotherapy for their metastatic cancer. Results from 29 subjects show that 62.5% of subjects responded to Bavencio treatment (their disease improved). The study is ongoing and data with longer follow-up will be reported in the future. 1
VI.2.3 Unknowns Relating to Treatment Benefits In both supporting studies the majority of patients were adult or elderly white Caucasians. Avelumab was not studied in special patients with autoimmune disease, infections with HIV, hepatitis B or hepatitis C, organ transplant recipients, or pregnant or lactating patients. VI.2.4 Summary of Safety Concerns Important identified risks of the lung (pneumonitis) of the liver (hepatitis) In the supporting clinical trials, 1.2% (21/1738) of the patients developed inflammation of the lung (pneumonitis). Pneumonitis can be serious, lifethreatening and can have a fatal outcome. Signs and symptoms may include new or worsening cough and, breathing difficulties. In the supporting clinical trials 0.9% (16/1738) of the patients developed inflammation of the liver (hepatitis). Hepatitis can be serious, lifethreatening and can have a fatal outcome. Signs and symptoms may include yellowing of the skin or in the whites of the eyes, severe nausea, or vomiting, pain on the right side of the stomach area (abdomen), drowsiness, tiredness, dark urine (tea colored), bleeding or bruising more easily than normal, and feeling less hungry than usual. signs and symptoms of pneumonitis and may delay or completely stop treatment with avelumab depending on the severity of symptoms. Physicians should seek early confirmation of diagnosis. By early recognition and by following recommended treatment guidelines serious complications may be prevented. changes in liver function and signs and symptoms of hepatitis and may delay or completely stop treatment with avelumab depending on the severity of symptoms. By early recognition and by following recommended treatment guidelines serious complications may be prevented. 2
of the large intestine (colitis) Immune-related disorders of hormone producing glands (so-called endocrinopathies, especially of the thyroid, adrenal glands, endocrine pancreas, and pituitary gland) In the supporting clinical trials, 1.5% (26/1738) of the patients developed inflammation of the large intestine (colitis). Colitis can be serious. Signs and symptoms may include diarrhea (loose stools) or more bowel movements than usual, blood in stools or dark, tarry, sticky stools and severe stomach area (abdomen) pain or tenderness. In the supporting clinical trials, 5.6% (98/1738) of the patients developed thyroid disorders, 0.5% (8/1738) adrenal insufficiency, less than 0.1 % (2/1738) type 1 diabetes mellitus and less than 0.1% (1/1738) hypopituitarism. Thyroid disorders, adrenal insufficiency,type 1 diabetes mellitus and hypopituitarism can be serious and lifethreatening. Signs and symptoms of immunerelated disorders of hormone producing glands may include rapid heartbeat, feeling cold, increased sweating, constipation, extreme tiredness, weight gain or weight loss, very low blood pressure, headache, feeling more hungry than usual, increased thirst and urination, dizziness, nausea or vomiting, changes in mood or behavior, such as irritability or forgetfulness and stomach area (abdomen) pain. signs and symptoms of colitis and may delay or completely stop treatment with avelumab depending on the severity of symptoms. Any other causes of colitis should be excluded. By early recognition and by following recommended treatment guidelines serious complications may be prevented. changes in thyroid and other endocrine function and for signs and symptoms of thyroid disorders, adrenal insufficiency, type 1 diabetes mellitus, and pituitary dysfunction, and may delay or completely stop treatment with avelumab depending on the severity of symptoms. By early recognition and by following recommended treatment guidelines serious complications may be prevented. 3
of the muscles (myositis) of the heart (myocarditis) Guillain-Barre Syndrome Uveitis In the supporting clinical trials 0.5% (9/1738) of the patients developed inflammation of the muscles. Myositis can be serious. Signs and symptoms of myositis may include muscle weakness and muscle pain. called immune -related reactions) in In the supporting clinical trials, no patient developed immune-related myocarditis. In other clinical studies in the clinical trial program, single cases have been reported. Myocarditis can be serious, lifethreatening and can have a fatal outcome. Signs and symptoms of myocarditis may include trouble breathing, dizziness or fainting, fever, chest pain and chest tightness or flu-like symptoms. In the supporting clinical trials a single subject experienced Guillain-Barre Syndrome. Guillain-Barre Syndrome can be serious. In the avelumab supporting clinical trials a single subject experienced Uveitis. Uveitis can be serious. Uveitis is an inflammation of eye. signs and symptoms of myositis and may delay or completely stop treatment with avelumab depending on the severity of symptoms. By early recognition and by following recommended treatment guidelines further exacerbations may be prevented. signs and symptoms of myocarditis with subsequent cardiologic consultation and laboratory investigations to ensure the initiation of appropriate treatment measures at an early stage. Avelumab should be delayed for new-onset moderate or severe cardiac signs or symptoms and corticoids should be administered. Avelumab has to be completely stopped for immune-related myocarditis. By early recognition and by following recommended treatment guidelines serious complications may be prevented. signs and symptoms of Guillain-Barre Syndrome and may initiate appropriate diagnostic and therapeutic measures in case of suspicion of the syndrome. signs and symptoms of uveitis and may initiate appropriate diagnostic and therapeutic measures in case of suspicion of uveitis. 4
of the kidney (nephritis) and renal dysfunction Severe reactions related to the administration of avelumab (infusion-related reactions) Important potential risks To date, in the supporting clinical studies, a single patient suffered immune-related inflammation of the kidney or renal dysfunction. Signs and symptoms of kidney (nephritis) and renal dysfunction may include abnormal kidney function tests, urinate less than usual, blood in your urine, or swelling in your ankles reactions during administration. In the supporting clinical trials, 0.7% (12/1738) of the patients developed severe reactions during the infusion. Infusion-related reactions can be serious and life-threatening. Signs and symptoms of severe reactions during infusion may include chills or shaking, rash, hives, flushing, shortness of breath, low blood pressure, dizziness, fever, back or neck pain and abdominal pain. signs and symptoms of nephritis and renal dysfunction and may initiate appropriate diagnostic and therapeutic measures in case of suspicion of nephritis or renal dysfunction. Premedication with an antihistamine and with paracetamol should be considered for the first four infusions. signs and symptoms of infusion-related reactions. Treatment with avelumab should be completely stopped if severe ( Grade 3) infusion-related reactions occur. By early recognition and by following recommended treatment guidelines serious complications may be prevented. Risk Other immune-related events (including immune-related encephalitis, myasthenic syndrome and pancreatitis); Severe cutaneous reactions Development of antibodies against avelumab (immunogenicity) What is known (Including reason why it is considered a potential risk) To date, in the supporting clinical studies, no cases of immune-related encephalitis, myasthenic syndrome and pancreatitis have been reported for avelumab. Severe cutaneous (skin) reactions are a potential class effect of checkpoint inhibitors, the pharmacological class to which avelumab belongs. Severe cutaneous reactions are a diverse group of adverse events. A few events of severe skin reactions (e.g. severe rash) have been observed in relation to avelumab. defense system). Antibodies such as avelumab may induce the immune system to produce antibodies against avelumab. This may be associated with infusion reactions or reduced effectiveness. Up to date in the supporting clinical studies avelumab has shown a low potential to induce the formation of antibodies. 5
Risk Effects on the developing baby (embryofetal toxicity) What is known (Including reason why it is considered a potential risk) To date, there are no cases of avelumab exposure during pregnancy. Based on avelumab s mechanism of action and data of animal models, there is a potential risk that avelumab may cause fetal harm when administered to a pregnant woman. Missing information Risk Safety in patients with Autoimmune disease Safety in patients with HIV, Hepatitis B or C infections Safety in patients with Organ transplants Use during lactation What is known To-date, there is no experience in patients with autoimmune disease. To-date, there is no experience in patients with HIV, hepatitis B or C infections. To date, there is limited experience in avelumab in subjects with prior organ transplantation. It is unknown whether avelumab is secreted in human breast milk. Women should be advised to discontinue breast feeding during treatment with avelumab, and for at least 1 months after the last dose of avelumab Long-term safety The duration of therapy with avelumab in clinical studies ranged up to 138 weeks. Safety and efficacy in immune compromised patients To-date, there is limited experience regarding the efficacy and safety of avelumab in patients with underlying immunosuppressive conditions VI.2.5 Summary of Additional Risk Minimization Measures by Safety Concern All medicines have a SmPC which provides physicians, pharmacists and other health care professionals with details on how to use the medicine, the risks and recommendations for minimising them. An abbreviated version of this in lay language is provided in the form of the Package Leaflet. The measures in these documents are known as routine risk minimisation measures. This medicine has special conditions and restrictions for its safe and effective use (additional risk minimization measures). How they are implemented in each country, however, will depend upon agreement between the marketing authorization holder and the national authorities. These additional risk minimization measures are for the following risks (safety concerns): 1. Immune related adverse reactions 2. Severe infusion related reactions 6
Risk Minimization Measures Objective and rationale Increase the awareness about the identified and potential immune related adverse events associated with avelumab use. Prevent or minimize occurrence of the above-listed risks in patients receiving avelumab and reinforce the dose modifications and treatment guidelines provided in the product labeling. Proposed action: In addition to the mandatory Summary of Product Characteristics (SmPC) and package leaflet (Pl), Merck will produce appropriate educational materials to raise awareness for immune-related adverse reactions Aspects to be emphasized in the educational materials include: The risks associated with avelumab (immune related adverse reactions and IRRs) The importance of monitoring patients for signs and symptoms suggestive of immune related adverse events and IRRs and the actions to take in the case of the occurrence of such events (dose modifications and treatment) The importance of patient counseling in detecting signs and symptoms suggestive of immune related adverse events and reporting them to their healthcare professionals so that appropriate measures can be initiated as soon as possible VI.2.6 Planned Post Authorization Development Plan Study (type and study number) Objectives Efficacy uncertainties addressed Status (planned, started) Date for submission of interim or final reports EMR100070-003 Part B A Phase II, openlabel, multicenter trial to investigate the clinical activity and safety of avelumab (MSB0010718C) in subjects with Merkel cell carcinoma The primary endpoint is durable response, defined as objective response (CR or PR) according to RECIST 1.1, determined by an Independent Endpoint Review Committee, with duration of at least 6 months. Assess the objective response (CR or PR) with duration of at least 6 months in the first line setting in subjects with metastatic Merkel Cell Carcinoma Started Q2 2016 Q1 2020 VI.2.7 Summary of Changes to the Risk Management Plan over Time Not applicable. 7