Public Risk Management Plan (RMP) Summary

Transcription

1 Tecentric (Atezolizumab) 1200 mg/20 ml, Konzentrat zur Herstellung einer Infusionslösung Zul.-Nr Public Risk Management Plan (RMP) Summary Document Version: 2.0 Document Date: Based on EU RMP version 2.0 ( ) Roche Pharma (Schweiz) AG, 4153 Reinach 1/1

2 The Risk Management Plan (RMP) is a comprehensive document submitted as part of the 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 minimize them. The RMP summary of Tecentriq 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 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 Tecentriq in Switzerland is the Arzneimittelinformation (see approved and authorized by Swissmedic. Roche Pharma (Schweiz) AG is fully responsible for the accuracy and correctness of the content of the here published RMP summary of Tecentriq.

3 VI.2 ELEMENTS FOR A PUBLIC SUMMARY VI.2.1. OVERVIEW OF DISEASE EPIDEMIOLOGY Urothelial carcinoma (UC) Tecentriq is used to treat adults with UC, a type of cancer that affects the bladder and urinary system. It is used when the cancer has spread to other parts of the body, returned after previous treatment, or if patients cannot receive cisplatin treatment. Bladder cancer is the ninth most common type of cancer worldwide, and occurs mainly in older adults, with an average age at diagnosis of 73 years. This type of cancer is more common in men, who are four times more likely to be diagnosed with bladder cancer. Smoking is the most important risk factor for bladder cancer, and is associated with about half of the bladder cancers in both men and women. Other risk factors include older age (age > 45 years), exposure to medications such as phenacetin, cyclophosphamide, and chlornaphazine, and exposure to radiation. Non-small cell lung cancer (NSCLC) Tecentriq is used to treat adults with NSCLC, a type of cancer that affects the lung, when it has spread to other parts of the body, or has returned after previous treatment. Patients with NSCLC that is positive for certain tumor mutations (epidermal growth factor receptor [EGFR] or anaplastic lymphoma kinase [ALK] positive) should have received cancer treatment that is specific for these tumor mutations before receiving Tecentriq. Lung cancer is the second most common cancer in men and third most common type of cancer in women, and is the most common cause of cancer death. Lung cancer predominantly occurs in older individuals with an average age at diagnosis of 70 years. While men are more likely to develop lung cancer compared to women, the difference has decreased over time due to an increase in smoking among women. Smoking is the biggest risk factor for the development of lung cancer, with more than 80 percent of lung cancer cases associated with smoking. Other risk factors include second-hand smoke exposure, high levels of air pollution, exposure to cancer causing agents like asbestos, radon, and arsenic, previous tuberculosis infection, family history of lung cancer, and previous chemotherapy treatment for certain cancer types. VI.2.2 SUMMARY OF TREATMENT BENEFITS Tecentriq contains the active substance atezolizumab, which works by using the body s natural immune system to recognize the cancer as foreign, and fight the cancer in a manner similar to an infection. The immune system contains cells called T-cells, which are responsible to detect foreign cells, such as cancer cells, in the body. However, cancer cells can go undetected by the immune system because they have on their surface a protein called PD-L1. When PD-L1 is blocked (by agents such as Tecentriq), T-cells are able to detect the cancer cells as foreign and destroy them. Tecentriq has been shown to be effective in treating 2/20

4 patients with advanced urothelial cancer (UC; bladder cancer or cancer of the urinary tract that has spread to the lymph nodes or other parts of the body) in one main study, and in advanced non-small cell lung cancer (NSCLC; lung cancer that has spread to the lymph nodes or other parts of the body) in one main study. The main study for advanced UC included 310 patients who had received at least one prior treatment, and 119 patients who had not received previous treatment for their cancer. Patients received Tecentriq 1200 mg every three weeks. Approximately 16% of all patients who received at least one prior treatment responded to treatment with Tecentriq, with 65% of them still benefiting after 21.1 months of followup. 37% of patients lived for at least 12 months after starting treatment. The median survival (length of time after start of treatment that half of all patients are alive) among the previously treated UC patients was 7.9 months. In patients who had not been treated previously and who were ineligible to receive cisplatin treatment, 23% responded to treatment with Tecentriq, with 70% continuing to benefit from Tecentriq after 17.2 months of follow-up. 57% of patients lived for at least 12 months after starting treatment. The median survival among these advanced UC patients was 15.9 months. The NSCLC main study OAK enrolled 1225 patients who had received and had disease progression after one or two chemotherapy regimens. In this study, patients were randomized to receive either Tecentriq or docetaxel (a chemotherapy drug commonly used to treat NSCLC). The results from the prespecified primary analysis (using the first randomized 850 patients) provided statistically robust evidence that treatment with Tecentriq prolonged the overall survival (length of time from start of randomization to death) with a 27% relative reduction in the risk of death associated with atezolizumab compared with docetaxel). Half the patients in the atezolizumab arm lived longer than 13.8 months, while half the patients in the docetaxel arm lived longer than 9.6 months. VI.2.3 UNKNOWNS RELATING TO TREATMENT BENEFITS Not enough information is available on the effectiveness or safety of Tecentriq in the following types of patients: Patients who have a history of autoimmune disease (disorder in which a person s immune system [body s own defense system] attacks parts of his or her own body) Patients who have had previous infections Patients who have previously experienced a severe allergic reaction to medicines similar to Tecentriq Patients taking other medicines that work by altering the body s immune response Patients taking other medicines that work against the body s immune response, including corticosteroids Patients receiving any live attenuated (weakened as not to cause an infection) vaccines 3/20

5 Patients with severe liver, kidney, heart, or other organ problems Patients under the age of 18 years (children and adolescents) Patients who are pregnant or breast feeding Patients who receive Tecentriq long-term (more than 1 year) Patients receiving atezolizumab in urothelial carcinoma who are considered unfit for chemotherapy Patients who receive Intra-vesical BCG during or after treatment with atezolizumab. VI.2.4 SUMMARY OF SAFETY CONCERNS IMPORTANT IDENTIFIED RISKS Because Tecentriq acts on the body s defense system, activation of immune cells may cause inflammation and injury to normal tissues (applicable to all identified risks in this table). 4/20

6 Risk What is known Preventability Immune-related hepatitis (inflammation of the liver) Immune-related pneumonitis (inflammation of lung tissues) Immune-related colitis (inflammation of inner lining of the large intestine) In clinical trials, between 1 and 10 in every 100 patients developed non-serious increases in their blood levels of liver enzymes. However, between 1 and 10 in every 1000 patients developed hepatitis. In clinical trials, between 1 and 10 in every 100 patients developed pneumonitis, which was serious in approximately half of these patients. In clinical trials, approximately 1 out of every 100 patients developed colitis, and of these patients, approximately half experienced serious events. Doctors should check patients for signs and symptoms of changes in liver function, and perform laboratory tests needed for checking liver function prior to and after starting therapy with Tecentriq. Patients with abnormal liver function test results prior to beginning therapy with Tecentriq should be properly managed. If a patient develops increased liver enzymes or hepatitis, the doctor may decide to stop Tecentriq temporarily or permanently, and treatment with corticosteroids (medicine used to treat inflammation) may be needed. Patients should inform their doctor if they notice symptoms such as yellowing of skin or eyes, nausea, vomiting, bleeding or bruising, dark urine, or stomach pain. Doctors should check patients for signs and symptoms of pneumonitis. If a patient develops pneumonitis, the doctor may temporarily or permanently discontinue Tecentriq, and treatment with corticosteroids may be needed. Patients should inform their doctor if they notice symptoms such as new or worsening cough, shortness of breath, or chest pain. Doctors should check patients for signs and symptoms of colitis. If a patient develops colitis, the doctor may temporarily or permanently discontinue Tecentriq, and 5/20

7 Immune-related pancreatitis (inflammation of the pancreas) Immune-related endocrinopathies (inflammation of endocrine glands): Type 1 diabetes mellitus (insufficient production of insulin by pancreas) Hypothyroidism (underactive thyroid gland) Hyperthyroidism (overactive thyroid gland) Adrenal insufficiency (insufficient hormone production by adrenal gland) Hypophysitis (insufficient hormone production by pituitary gland) In clinical trials, between 1 and 10 in every 1000 patients developed pancreatitis. This figure includes patients with only non-serious increases in blood levels of pancreatic enzymes. In clinical trials, between 1 and 10 in every 100 patients developed hypothyroidism and hyperthyroidism, whereas between 1 and 10 in every 1000 patients developed adrenal insufficiency or diabetes mellitus. Between 1 and 10 in 10,000 patients developed hypophysitis. treatment with corticosteroids may be needed. Patients should inform their doctor if they notice symptoms such as diarrhea, (watery or loose stools), blood or mucus in stools, and stomach or abdominal pain. Doctors should check patients for signs and symptoms of pancreatitis. If a patient develops pancreatitis or has increased levels of pancreatic enzymes, the doctor may temporarily or permanently discontinue Tecentriq, and treatment with corticosteroids may be needed. Patients should inform their doctor if they notice symptoms such as abdominal pain, nausea and vomiting. Doctors should check patients for signs and symptoms of endocrinopathies. If a patient develops diabetes, insulin therapy may be needed, and treatment with Tecentriq may be temporarily stopped until blood sugar levels are controlled. Patients should inform their doctor if they notice symptoms such as feeling more hungry or thirsty than usual, need to urinate more often, weight loss, and feeling tired. Blood tests for thyroid hormones should be checked before and during Tecentriq therapy, and abnormalities properly managed. If a patient develops symptoms of hypothyroidism or hyperthyroidism, Tecentriq may be temporarily stopped and thyroid replacement 6/20

8 Immune related neuropathies (nerve damage): Myasthenia gravis (autoimmune disease marked by muscular weakness) Guillain-Barré syndrome (a rare but serious autoimmune nerve disorder) Immune related meningoencephalitis (inflammation of the membrane around the spinal cord and brain, inflammation of the brain) In clinical trials, between 1 and 10 in every 1,000 patients developed Guillain-Barré syndrome and between 1 and 10 in every 10,000 developed myasthenia gravis. Although rare, these diseases can be lifethreatening. In clinical trials, between 1 and 10 in every 1,000 patients developed serious meningoencephalitis. hormones or other thyroid medication administered. If symptoms of adrenal insufficiency develop, Tecentriq should be temporarily stopped and corticosteroids administered. Patients should inform their doctor if they notice any symptoms such as tiredness, weight loss, weight gain, mood changes, hair loss, constipation, and dizziness. If symptoms of hypophysitis develop, Tecentriq should be temporarily stopped and corticosteroids administered. Patients should inform their doctor if they notice any symptoms such as fatigue and headaches that will not go away. Doctors should check patients for symptoms of muscular weakness and nerve damage. Tecentriq should be stopped permanently if myasthenia gravis or Guillain-Barre syndrome develops, and treatment with corticosteroids may be needed. Patients should inform their doctor if they notice symptoms such as muscle weakness and numbness, or persistent tingling in hands and feet. Doctors should check patients for symptoms and discontinue Tecentriq permanently if patients develop meningoencephalitis. Treatment with corticosteroids should be started. Patients should inform their doctor if they notice symptoms such as neck 7/20

9 Infusion-related reaction (reactions associated with infusion [occurring during or within one day of having the infusion]) Immune-related myocarditis In clinical trials, between 1 and 10 in every 100 patients developed infusion reactions; however these were generally non-serious with only between 1 and 10 in every 1000 patients experiencing serious reactions. In clinical trials, 1 and 10 in every 10,000 patients developed myocarditis. Although rare, this disease can be life-threatening. stiffness, severe headache, fever, chills, vomiting, eye sensitivity to light, confusion or sleepiness. Doctors should check patients for symptoms of infusion related reactions, which may include fever, chills, shortness of breath and flushing. Depending on the severity of the reaction, infusion rates may be reduced or the infusion may be stopped. Tecentriq may need to be permanently stopped if infusion related reactions are severe. Doctors should check patients for symptoms of myocarditis. If a patient develops myocarditis, the doctor may temporarily or permanently discontinue Tecentriq, and treatment with corticosteroids may be needed. Patients should inform their doctor if they notice symptoms such as shortness of breath, decreased exercise tolerance, fatigability, chest pain, swelling of ankles or legs, irregular heart beat or fainting. 8/20

10 IMPORTANT POTENTIAL RISKS Risk Embryofetal toxicity (harm to a developing fetus) Anti-therapeutic antibodies (formation of antibodies against the medicine) Immune-related myositis (inflammation in the muscles) Ocular inflammatory toxicity (eye inflammation) Immune-related nephritis (inflammation of the kidney) Immune-related severe cutaneous adverse reactions (serious skin reactions) What is known (Including reason why it is considered a potential risk) The effect of Tecentriq on pregnant women is unknown. It is possible that Tecentriq could harm unborn babies, including increasing chances of stillbirth and miscarriage. Tecentriq is not recommended during pregnancy unless the potential benefit for the mother outweighs the potential risk to the fetus. If patients could become pregnant, effective contraception should be used while being treated with Tecentriq and up to 5 months after the last dose Therapeutic antibodies such as Tecentriq have a risk of inducing the formation of antibodies against the medicine. Although about 40% of patients have developed these antibodies against Tecentriq in clinical trials, there was no noticeable effect on the medicine s effectiveness or safety. Because Tecentriq activates the immune system, it has a potential to cause inflammation and injury to muscle tissue. Between 1 and 10 in 1000 patients developed myositis in clinical trials; however, there is no conclusive evidence at this time that these were caused by Tecentriq. Because Tecentriq activates the immune system, it has a potential to cause inflammation and injury to eye tissue. Between 1 and 10 in 1000 patients developed ocular inflammatory toxicity in clinical trials; however, there is no conclusive evidence that these were caused by Tecentriq. Because Tecentriq activates the immune system, it has a potential to cause inflammation and injury to tissues of the kidneys. Between 1 and 10 in 10,000 patients developed nephritis in clinical trials; however, there is no conclusive evidence that these were caused by Tecentriq. Because Tecentriq activates the immune system, it has a potential to cause inflammation and injury to tissues of the skin. Between 1 and 10 in 10,000 patients developed serious severe skin reactions in clinical trials; however, there is no conclusive evidence that these were 9/20

11 Immune-related vasculitis (inflammation of the blood vessels) Immune-related hemolytic anemia caused by Tecentriq. Because Tecentriq activates the immune system, it has a potential to cause inflammation and injury to blood vessels. Between 1 and 10 in 1,000 patients developed vasculitis in clinical trials; however, there is no conclusive evidence that these were caused by Tecentriq. Because Tecentriq activates the immune system, it has a potential to cause hemolysis of red blood cells. Between 1 and 10 in 1000 patients developed autoimmune hemolytic anemia in clinical trials; however, there is no conclusive evidence that these were caused by Tecentriq. 10/20

12 MISSING INFORMATION Risk Safety in patients who have a history of autoimmune disease (disorder in which a person s immune system [body s own defense system] attacks parts of his or her own body) Use in patients who also have a viral or bacterial infection Safety in patients who have previously experienced a severe reactions to medicines similar to Tecentriq Safety in patients taking other medicines that work by altering the body s immune response Safety in patients taking other medicines that work against the body s immune response, including corticosteroids Safety in patients receiving any live attenuated (weakened as not to cause an infection) vaccines Safety in patients with severe liver, kidney, heart, or other organ problems Safety in patients under the age of 18 years (children and adolescents) What is known (Including reason why it is considered missing information) Tecentriq was not studied in patients with active autoimmune disease, or who have a history of autoimmune disease. Therefore, there is no information available about the safe use of Tecentriq in patients with autoimmune disease. Care should be taken when administering Tecentriq to these patients. Tecentriq was not studied in patients who have active viral or bacterial infection at the same time as treatment. Therefore there is no information available about the safe use of Tecentriq in these patients. Care should be taken when administering Tecentriq to these patients. Because Tecentriq was not studied in these patients, it is not known if patients who have had severe reactions to medicines like Tecentriq will have a similar reaction to Tecentriq. Care should be taken when administering Tecentriq to these patients. Because Tecentriq also works on the immune system, it was not studied in these patients. Care should be taken when administering Tecentriq to these patients Because Tecentriq was not studied in patients who need to take immune system suppressants, it is not known if these medicines affect how Tecentriq works. Care should be taken when administering Tecentriq to these patients. Tecentriq was not studied in patients receiving any live attenuated vaccines. Care should be taken when administering Tecentriq to these patients. Dose adjustment is not needed in patients with mild liver problems or mild to moderate kidney problems. Tecentriq has not been studied in patients with moderate liver problems, severe kidney problems, or other organ problems. Tecentriq is being studied in children and adolescents, but the results are not yet available. Therefore, the safety and effectiveness of Tecentriq in children and adolescents have not been established. 11/20

13 Safety in patients who are breast feeding Safety in patients who receive Tecentriq longterm Safety profile of atezolizumab in urothelial carcinoma for patients who are considered unfit for chemotherapy Safety profile of atezolizumab in combination with or used sequentially in patients who have been administered intravesical BCG vaccine Tecentriq has not been studied in breastfeeding mothers, and it is unknown whether Tecentriq is present in human milk. A decision must be made whether to discontinue breast-feeding or to discontinue Tecentriq therapy, taking into account the benefit of breast-feeding for the child and the benefit of Tecentriq therapy for the woman. Because only a small proportion of patients have received treatment with Tecentriq for longer than two years, the longterm safety has not been established for this medicine. There is not enough information on patients who are considered unfit to receive chemotherapy. Atezolizumab should be used with caution in these patients after careful consideration of the balance of risks and benefits on an individual basis. Intra-vesical BCG, which is relevant in the treatment of urothelial carcinoma, has not been studied with concomitant or sequential use of atezolizumab, and the safety profile is not known. VI.2.5 SUMMARY OF 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, and the risks and recommendations for minimizing them. An abbreviated version of this in lay language is provided in the form of the package leaflet (PL). The measures in these documents are known as routine risk minimization measures. The SmPC and the Package Leaflet for Tecentriq can be found in Tecentriq s EPAR page. This medicine has special conditions and restrictions for its safe and effective use (additional risk minimization measures). Full details on these conditions and the key elements of any educational material can be found in Annex II of the product information which is published on Tecentriq s EPAR page; 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: Immune-related adverse reactions of immune-related hepatitis, pneumonitis, colitis, pancreatitis, myocarditis, endocrinopathies (including diabetes mellitus, hypothyroidism, hyperthyroidism, hypophysitis 12/20

14 and adrenal insufficiency), neuropathies (including Guillain-Barre syndrome and myasthenic syndrome/myasthenia gravis), meningoencephalitis, and infusion-related reactions. Risk Minimization Measure: Healthcare Provider Brochure and Patient Alert Card Objective and Rationale: Minimize negative outcomes by increasing understanding and awareness of immune-related adverse reactions, and by facilitating early detection and prompt treatment. Description : All healthcare professionals who are expected to prescribe Tecentriq will be provided with a brochure to inform them on how the medicine should be used and how to manage side effects, particularly side effects related to the activity of the immune system Patients will be given an alert card that they should carry with them at all times with information about the risks of the medicine, and instructions on when to contact their doctor if they experience symptoms. 13/20

15 VI.2.6 PLANNED POST-AUTHORIZATION DEVELOPMENT PLAN List of studies in post authorization development plan (studies in PV plan) Study/Activity Type and Title Category (1-3) Objectives Safety concerns addressed Status Date for submission of interim or final reports GO28915 (OAK): A Phase III, Open- Label, Multicenter, Randomized Study to Investigate the Efficacy and Safety of Atezolizumab (Anti-PD-L1 Antibody) Compared with Docetaxel in Patients with Non Small Cell Lung Cancer After Failure with Platinum- Containing Chemotherapy 3 To determine if atezolizumab treatment results in an improved OS compared with docetaxel To evaluate safety and tolerability of atezolizumab compared with docetaxel To evaluate incidence of ATAs against atezolizumab and to explore the potential relationship of the immunogenicity response with pharmacokinetics, safety, and efficacy Anti-therapeutic antibodies Ongoing Final CSR: Q GO29664: A Phase I/II, Multicenter, Open-Label Study of the Safety and Pharmacokinetics of atezolizumab (MPDL3280A) in Pediatric and Young Adult Patients with Previously Treated Solid Tumors 3 To evaluate the safety and tolerability of atezolizumab, focusing on the nature, frequency, and severity of serious and non-serious adverse events, as well as effects on laboratory values, vital signs, or other safety biomarkers Use in pediatric patients Ongoing Final CSR: December 2018 GO29322: A Phase IB Study of the Safety and Pharmacology of atezolizumab Administered with Ipilimumab or Interferon-Alpha in Patients with Locally Advanced or 3 To evaluate the safety and tolerability of atezolizumab and ipilimumab in combination in patients with advanced or melanoma. To evaluate the safety and tolerability Use of atezolizumab with other immunomodulatory drugs Ongoing Final CSR: July 2018

16 Metastatic Solid Tumors WO29635: A Phase IB/II, Open-Label Study of the Safety and Pharmacology of Atezolizumab Administered with or without Bacille Calmette-Guérin in Patients with High Risk Non Muscle- Invasive Bladder Cancer of atezolizumab and interferon alfa-2b in combination in patients with advanced or metastatic RCC or melanoma 3 To evaluate the safety and tolerability of atezolizumab as a single agent and in combination with BCG. To identify the DLTs and to determine the MTD or tolerability at the MAD of BCG in combination with atezolizumab Concomitant or sequential use of atezolizumab with intra-vesical bacillus Calmette-Guérin vaccine Ongoing Final CSR: June 2022 MO39171: Single-Arm Long-Term Safety and Efficacy Study of atezolizumab in previously treated NSCLC Patients MO29983: An Open-Label, Single Arm, Multicenter, Safety Study of atezolizumab in Locally Advanced or Metastatic Urothelial or Non- Urothelial Carcinoma of the Urinary Tract 3 To evaluate the long-term safety of atezolizumab on the bases of the following endpoints: The incidence of all serious adverse events (SAEs) related to atezolizumab treatment and the incidence of serious and nonserious immune-related adverse events (iraes) related to atezolizumab treatment. 3 To evaluate the safety of atezolizumab based on the following endpoints: Nature, severity, duration, frequency and timing of adverse events (AEs) and changes in vital signs, physical findings, and clinical laboratory results during and following atezolizumab administration Long-term atezolizumab use Long-term atezolizumab use Planned Final CSR: May 2022 Ongoing Final CSR: Q /20

17 TBD/Observational Study/TBD Evaluation of the effectiveness of HCP educational materials which aims to facilitate early recognition and intervention of the following important immune-related risks: Pneumonitis, hepatitis, colitis, hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, myocarditis, type 1 diabetes mellitus, neuropathies, meningoencephalitis, pancreatitis, and infusionrelated reactions 3 The overall objective is to evaluate the effectiveness of the HCP brochure designed to mitigate important immunerelated risks in patients receiving atezolizumab in the European Union. Data from HCP surveys and reporting rates for the important identified immune related risks will be collected and analysed to evaluate effectiveness of the HCP brochure. Immune-related adverse events Planned ATAs = anti-therapeutic antibodies; BCG = bacillus Calmette-Guerin; CSR = Clinical Study Report; DLT = dose-limiting toxicity; MAD = maximum administered dose; MTD = maximum tolerated dose; NSCLC = non-small cell lung cancer; OS = overall survival; RCC = renal cell carcinoma Protocol submission: December 2017 Interim report: December 2020 Final Report: December /20

18 Studies which are a condition of the marketing authorization Study/Activity Type and Title Category (1-3) Objectives Efficacy Concerns Addressed 1 Final mature OS data (for Cohort 1) to address uncertainties in relation to efficacy. Status Date for submission of interim or final reports Ongoing Final CSR: Q WO30070 (IMvigor130): A Phase III, Randomized Study of Atezolizumab Alone and in Combination with Chemotherapy Versus Chemotherapy Alone in Participants with Untreated Advanced Urothelial Cancer GO29294 (IMvigor211): A Phase III, Open-Label, Multicenter, Randomized Study to Investigate the Efficacy and Safety of Atezolizumab (MPDL3280A; Anti-PD-L1 Antibody) Compared with Chemotherapy in Patients with 1 To evaluate the efficacy of atezolizumab plus platinumbased chemotherapy compared with placebo plus platinumbased chemotherapy on the basis of PFS and OS To evaluate the efficacy of atezolizumab monotherapy compared with placebo plus platinum-based chemotherapy on the basis of OS To evaluate the safety and tolerability of atezolizumab given as either monotherapy or in combination with platinum based chemotherapy 1 To evaluate the efficacy of atezolizumab treatment compared with chemotherapy treatment with respect to OS To evaluate the safety and tolerability of atezolizumab compared with chemotherapy To Final CSR important to confirm efficacy in untreated UC patients Final CSR is important to address uncertainty on efficacy. Ongoing Final CSR: July 2021 Ongoing Primary CSR: Q Final CSR: May /20

19 Locally Advanced or Metastatic Urothelial Bladder Cancer After Failure with Platinum-Containing Chemotherapy evaluate the incidence of ATAs against atezolizumab and to explore the potential relationship of the immunogenicity response with pharmacokinetics, safety, and efficacy ATA=anti-therapeutic antibody; CSR=Clinical Study Report; DOR=uration of response; PFS=progression-free survival; ORR=overall response rate; OS=overall survival. 18/20

20 VI.2.7 SUMMARY OF CHANGES TO THE RISK MANAGEMENT PLAN OVER TIME Major Changes to the Risk Management Plan over time Version Date (At time of authorization dd/mm/yyyy)* 1.1 Submitted on 15 February 2017 Safety Concerns Immune-related myositis, immunerelated nephritis, immune-related ocular inflammatory toxicity, immune-related severe cutaneous adverse reactions, and immune-related vasculitis added as important potential risks. Use in patients with preexisting viral or bacterial infection added as missing information. Comment Version prepared to add data from the pivotal NSCLC study, OAK (GO28915), and to address the Day 120 list of questions received from EMA as part of the E.U. MAA process for atezolizumab in adult patients with locally advanced or metastatic UC after prior platinumcontaining chemotherapy or who are considered cisplatin ineligible, and in adult patients with locally advanced or metastatic NSCLC after prior chemotherapy. 1.2 Submitted on 11 May Submitted on 14 June Submitted on 27 June 2017 Immune related hypophysitis added as an important identified risk. Use of atezolizumab in previously untreated patients with urothelial carcinoma who are considered unfit for chemotherapy. And Concomitant or sequential use of atezolizumab with intravesical bacillus Calmette- Guérin vaccine for the treatment of urothelial carcinoma. Was added as a missing information. No change in safety concerns No change in safety concerns Version prepared to address the Day 180 list of outstanding issues received from the EMA as part of the E.U. MAA process for atezolizumab in adult patients with locally advanced or metastatic UC after prior platinumcontaining chemotherapy or who are considered cisplatin ineligible, and in adult patients with locally advanced or metastatic NSCLC after prior chemotherapy. Also prepared version for adding hypophysitis as an important identified risk. Version prepared to address Day 195 comments received from EMA for the E.U. MAA Version prepared to add additional comments received from EMA for the E.U. MAA (Added additional Category 1

21 1.5* Submitted on 14 July 2017 (received CHMP positive opinion on 19 July 2017) 2.0 Submitted on 29 September 2017 Missing information use in pregnancy and lactation amended to use during lactation Immune-related myocarditis added as important identified risk and autoimmune haemolytic anemia added as potential risk. Educational materials updated. studies as postapproval measures and PASS information to PV plan). Version prepared to address additional comments received from EMA for the E.U. MAA (Amended safety concern and added final CSR dates to PV plan studies and PAES) Version prepared to add additional safety concerns. * Refers to the version that received CHMP positive opinion. Note, not all versions of the E.U. RMP are approved by the CHMP. 20/20