Summary of the risk management plan (RMP) for Tagrisso (osimertinib)

EMA/2497/2016 Summary of the risk management plan (RMP) for Tagrisso (osimertinib) This is a summary of the risk management plan (RMP) for Tagrisso, which details the measures to be taken in order to ensure that Tagrisso is used as safely as possible. For more information on RMP summaries, see here. This RMP summary should be read in conjunction with the EPAR summary and the product information for Tagrisso, which can be found on Tagrisso s EPAR page. Overview of disease epidemiology Tagrisso is a cancer medicine used to treat a type of lung cancer called non-small cell lung cancer. Approximately 85% to 90% of all lung cancers are non-small cell lung cancers (NSCLC). Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer-related deaths worldwide. NSCLC is more common in the developed world (Europe, North America and Eastern Asia) and has been reported to occur in around 80 men in every 100,000 per year and around 50 women in every 100, 000 per year. Tagrisso is used in patients with NSCLC with a specific mutation ( T790M ) in the EGFR gene. These mutations have been found in 10% to 20% of white patients and in 30% to 60% of patients with NSCLC who are of East Asian origin. These mutations are more frequently seen in patients who have already been treated with medicines called EGFR tyrosine kinase inhibitors. Most diagnoses of lung cancer are in patients aged over 50 years. The most important risk factors for the development of NSCLC with a T790M mutation in the EGFR gene are prior treatment with an EGFR tyrosine kinase inhibitor, female sex, not smoking and being of East Asian origin. Summary of treatment benefits Tagrisso contains the active substance osimertinib. It has been investigated in two main studies involving 411 patients who had the T790M mutation and in whom the disease progressed despite previous treatment with EGFR tyrosine kinase inhibitors. In both studies, which were still ongoing at the time of Tagrisso s initial evaluation, the medicine was not compared with any other treatment. The main measure of effectiveness was the proportion of patients who responded to treatment (objective response rate) and whose tumour shrank, which was assessed using body scans and standardised criteria for solid tumours. Combining both studies, the overall response rate at the time of analysis was 66% (263 out of 398 patients) and preliminary data suggest that the average length of response was 8.5 months. Page 1/13

Unknowns relating to treatment benefits The safety and effectiveness of Tagrisso has not been studied in patients under 18 years. In addition, as very few patients studied had significant liver or kidney problems, the safety and effectiveness of Tagrisso in these patients not yet fully established. Animal studies have shown that Tagrisso adversely affects the survival and the development of the fetus. Pregnant or breastfeeding women were therefore excluded from clinical trials. Women should not breastfeed or become pregnant whilst taking Tagrisso. Summary of safety concerns Important identified risks Risk What is known Preventability Serious inflammation of the lungs called interstitial lung disease (ILD) Problems with the electrical activity of the heart (QT prolongation) ILD is difficult to diagnose, but if left untreated, it can be life threatening or fatal. In clinical studies of Tagrisso, 2.7% of patients have reported ILD-or ILD-like events, some of which have been fatal (4 out of 1,221 patients). ILD has also been reported with other cancer medicines. No specific risk factors for the development of ILD in Tagrisso - treated patients have yet been identified. Studies have shown that treatment with Tagrisso can have a small effect on the electrical activity of the heart, known as the QT interval. However, the size of the effect is small and is not thought to cause any serious health problems (e.g abnormal heart beat rhythm). Patients and doctors should be aware of the risks of ILD, and the Summary of Product Characteristics (SmPC) and package leaflet (PL) contain information about this possible side effect. Any Tagrisso-treated patient who experiences shortness of breath, cough or fever should be investigated for possible ILD. Treatment with Tagrisso must be interrupted until the symptoms can be investigated. Treatment with Tagrisso must be permanently stopped if ILD is diagnosed. Detection and treatment at an early stage could minimise the effects of ILD. Patients and doctors should be aware of the risks of QT prolongation, especially in patients who may be at an increased risk of developing serious heart problems (e.g. abnormal heart beat rhythm).when possible, Tagrisso should be avoided in patients with congenital long QT syndrome. Appropriate monitoring (such as measuring the elctrical activity of the heart (ECG) and electrolytes) should be done in patients with congestive heart failure, electrolyte abnormalities and when medicines known to prolong the QT interval are given in combination with Tagrisso. Page 2/13

Important potential risks Risk Effects on development and survival of the unborn child What is known There are no data from the use of Tagrisso in pregnant women. Women who are capable of getting pregnant must not become pregnant while taking this medicine and must not start the treatment if they are already pregnant, as Tagrisso could cause harm to the unborn baby (fetus). Animal studies have shown that Tagrisso adversely affects the development and the survival of the fetus. Therefore women of childbearing potential must use effective contraception during treatment with Tagrisso and for at least 2 months after receiving the last dose of Tagrisso. Men must also use effective contraception during treatment with Tagrisso and for 4 months after receiving the last dose of Tagrisso. so that their partners do not become pregnant. Serious skin reactions Severe diarrhoea Eye disorders Liver disorders Patients have reported rash, itching and other similar side effects in clinical trials with Tagrisso. Most of these events tended to be mild or moderate, with only 0.5% of cases considered severe. To date, there have been no reports of certain severe adverse events affecting the skin (e.g. severe blistering, severe exfoliation (flaking of the skin)) that are a concern for other medicines with a similar mechanism of action to Tagrisso. Severe diarrhoea can be a concern for patients taking medicines with a similar mechanism of action to Tagrisso. Diarrhoea has been reported by patients taking Tagrisso, but in most cases it tends to be mild or moderate and does not require any form of treatment. Severe diarrhoea has only been reported in 1% of patients. Patients have reported adverse effects affecting the eye in studies with Tagrisso. These events tended to be mild or moderate in severity.. To date, there have been no reports of certain severe adverse events (e.g. corneal erosion, corneal ulceration), which are a concern for other medicines with a similar mechanism of action to Tagrisso. Changes in the liver function laboratory tests have been reported for patients in clinical trials with Tagrisso. These changes tended to be mild or moderate in nature, and, for a significant number of patients, may be related to the presence of pre-existing lung cancer spreading to the liver. Missing information Risk Long-term exposure to Tagrisso Use in women who are breastfeeding What is known There is limited information on patients who have used Tagrisso treatment for longer than a year, and therefore side effects following long-term treatment with Tagrisso are not known. In the main clinical studies, 23.6% of patients had received Tagrisso treatment for longer than 9 months. Animal studies show that Tagrisso may pass into breast milk. There is no evidence to show that this causes harm to the child but mothers should not Page 3/13

Risk What is known breastfeed while taking Tagrisso. severely reduced kidney function moderately or severely reduced liver function Use in patients capable of only limited self-care or patients who cannot carry out any self-care Use in patients who have lung cancer that has spread to the brain (brain metastases) and who have active symptoms (e.g. headaches, behavioural or personality changes, nausea and vomiting, seizures, etc.) Interaction between Tagrisso and medicines, called non- CYP3A4 mediated PXR substrates that may affect the way Tagrisso or the other medicines work Potential for transporter inhibition (interaction between Tagrisso and medicines that are distributed in the body by transporter proteins that may affect the way Tagrisso or the other medicines work) Potential for P-gp inhibition (Taking Tagrisso with certain other medicines Only a small number of patients with severely reduced kidney function were included in the main clinical trials. The data on these patients is therefore limited. Only a small number of patients with moderately reduced liver function were included in the main clinical trials. The data on these patients is therefore limited. Tagrisso has not been studied in patients who are not able to fully take care of themselves; patients not able to fully take care for themselves, patients who are confined to a bed or chair for more than 50% of waking hours or patients who are completely disabled who cannot carry out any self-care and are totally confined to bed or a chair. Patients whose lung cancer had spread to the brain and caused recent symptoms were not included in the main clinical studies. It is therefore not known how these patients will tolerate Tagrisso treatment; however no major difference in the safety and effectiveness of this treatment is expected. It is not known whether medicines called non-cyp3a4 mediated PXR substrates affect the amount of Tagrisso in the body. It is also not known whether Tagrisso affect the amount of these medicines in the body. This in turn may increase the chance of side effects, or affect the effectiveness of these medications. Clinical studies with Tagrisso have shown an interaction is unlikely to occur, however further studies are underway to obtain additional information. It is not known whether taking Tagrisso with medicines that are distributed in the body by transport proteins affect the way Tagrisso or the other medicines work. This in turn may increase the chance of side effects, or affect the effectiveness of these medications. Clinical studies with Tagrisso have shown this is unlikely to occur, however further studies are underway to obtain additional information. It is not known whether taking Tagrisso with other medicines that are distributed in the body by the transporter protein P-gp affect the amount of these medicines. This in turn may increase the chance of side effects, or affect the effectiveness of these medications. Clinical studies with Tagrisso Page 4/13

Risk (those which are distributed in the body by transporter proteins [P-gp] may affect the way Tagrisso or the other medicine works) Absolute bioavailability of Tagrisso (amount of active substance that becomes available in the bloodstream after taking a dose of Tagrisso) Use in elderly patients 75 years or above What is known have shown this is unlikely to occur, however further studies are underway to obtain additional information. The absolute bioavailability of Tagrisso has not yet been determined. Further information is needed to further understand how the body absorbs the medicine and how much active substance becomes available in the bloodstream after taking Tagrisso. There is very limited information available for patients aged 75 years or older who have taken Tagrisso. It is therefore not known how these patients will tolerate Tagrisso treatment; however no major difference in the safety and effectiveness of this treatment is expected. Summary of risk minimisation measures by safety concern All medicines have a summary of product characteristics (SmPC) which provides physicians, pharmacists and other healthcare professionals with details on how to use the medicine, and also describes the risks and recommendations for minimising them. Information for patients is available in lay language in the package leaflet. The measures listed in these documents are known as routine risk minimisation measures. The SmPC and the package leaflet are part of the medicine s product information. The product information for Tagrisso can be found on Tagrisso s EPAR page. This medicine has no additional risk minimisation measures. Planned post-authorisation development plan List of studies in post-authorisation development plan Study/activity D5160C00003 Primary Objective: ILD (AURA3) To assess the efficacy is due in May of AZD9291 compared QT prolongation 2018 (planned) A Phase III, open with platinum-based label, randomised doublet chemotherapy Severe skin reactions study of AZD9291 by assessment of PFS (Tagrisso) vs. (progression-free Severe diarrhoea platinum-based survival). doublet Ocular Toxicity Page 5/13

chemotherapy for patients with locally advanced or metastatic NSCLC (non-small cell Lung Cancer) whose disease has progressed with previous EGFR TKI (tyrosine kinase inhibitor) therapy and whose tumours harbour an EGFR T790M mutation within the EGFR gene. Secondary : To further assess the efficacy of AZD9291 compared with platinum-based doublet chemotherapy in terms of ORR (overall response rate), DoR (duration of response), DCR (disease control rate), tumour shrinkage, and OS (overall survival). To assess the effect of AZD9291 compared to platinum-based doublet chemotherapy on subjects diseaserelated symptoms and HRQoL (health-related quality of life). Hepatotoxicity Long term exposure to AZD9291 To characterise the PK (pharmacokinetics) of AZD9291 and metabolites in subjects receiving AZD9291. Safety objective: To assess the safety and tolerability profile of AZD9291 compared with platinum based doublet chemotherapy. D5165C00001 (CAURAL) A phase III, multicentre, open label, randomized study to assess the efficacy and safety of AZD9291 in Primary Objective: To assess the efficacy of AZD9291 in combination with MEDI4736 versus AZD9291 monotherapy in terms of PFS as 2nd line or ILD QT prolongation Severe skin reactions Severe diarrhoea is due in February 2019 (planned) Page 6/13

combination with MEDI4736 versus AZD9291 monotherapy in patients with locally advanced or metastatic EGFR T790M mutationpositive NSCLC who have received prior EGFR TKI therapy higher treatment for patients who have progressed following an approved EGFR- TKI therapy. Secondary : To further assess the efficacy of AZD9291 in combination with MEDI4736 versus AZD9291 monotherapy in terms of ORR, DoR, DCR, tumour shrinkage, OS and PFS landmark analyses. Ocular Toxicity Hepatotoxicity Long term exposure to AZD9291 To assess the impact of AZD9291 in combination with MEDI4736 versus AZD9291 monotherapy on disease-related symptoms and HRQoL in NSCLC patients. To assess the PK of AZD9291 as a single agent and in combination with MEDI4736. To characterise the PK, immunogenicity and pharmacodynamics of MEDI4736 after single dosing and at steady state after multiple dosing when given intravenously to patients with EGFR mutations (EGFRm) NSCLC in combination with AZD9291. Page 7/13

To assess the safety and tolerability profile of AZD9291 as a single agent and in combination with MEDI4736. D5160C00017 A Phase II, open label, single-arm study to assess the safety and efficacy of AZD9291 in Asia Pacific patients with locally advanced/metastatic NSCLC whose disease has progressed with previous EGFR TKI therapy and whose tumours harbour a EGFR T790M mutation within the EGFR gene. Primary Objective: To assess the efficacy of AZD9291 by assessment of ORR. Secondary : To further assess the efficacy of AZD9291 in terms of PFS, DoR, DCR, tumour shrinkage, and OS. To assess the safety and tolerability profile of AZD9291. To assess the impact of AZD9291 on patients diseaserelated symptoms and HRQoL. ILD QT prolongation Severe skin reactions Severe diarrhoea Ocular toxicity Hepatotoxicity Long term exposure to AZD9291 is due in Nov 2016 (planned) D5160C00022 Open label, multinational, multicenter, real world treatment study of single agent AZD9291 for patients with advanced/ metastatic EGFR T790M mutation positive NSCLC who have received prior therapy with an EGFR TKI. The primary objective of this study is to assess the efficacy and safety of single agent AZD9291 in a real world setting in adult patients with advanced or metastatic, EGFR T790M mutation positive NSCLC, who have received prior EGFR TKI therapy. ILD QT prolongation Severe skin reactions Severe diarrhoea Ocular toxicity Hepatotoxicity Long term exposure to AZD9291 Eastern Cooperative Oncology Group performance status (ECOG PS) 2 is due in May 2019 (planned) Page 8/13

symptomatic brain metastases D5160C00007 (FLAURA) A Phase III, doubleblind, randomised study to assess the efficacy and safety of AZD9291 vs. a SoC EGFR TKI as first-line treatment in patients with EGFRm, locally advanced or metastatic NSCLC. Primary Objective: To assess the efficacy of single agent AZD9291 compared with SoC (standard of care) EGFR TKI therapy as measured by PFS. Secondary objectives: To assess the efficacy of AZD9291 compared with SoC EGFR TKI therapy by assessment of PFS in patients with positive (or negative) pretreatment, EGFR T790M (amino acid substitution at position 790 in EGFR, from a threonine to a methionine) mutation; EGFR Ex19del or L858R mutation; or EGFRm (Ex19del or L858R) detectable in plasmaderived ctdna. ILD QT prolongation Severe skin reactions Severe diarrhoea Ocular toxicity Hepatotoxicity Long term exposure to AZD9291 Final CSR (clinical study report) due Jan 2019 (planned) To further assess the efficacy of AZD9291 compared with SoC EGFR TKI therapy. To characterise the PK of AZD9291 and its metabolites (AZ5104 and AZ7550). To assess the impact of AZD9291 compared to SoC EGFR TKI Page 9/13

therapy on patients disease-related symptoms and HRQoL. To assess patient satisfaction with treatment when receiving AZD9291 compared with SoC EGFR TKI therapy. Study D6030C00001 (BLOOM) A Phase I, openlabel, multicentre study to assess the safety, tolerability, pharmacokinetics and preliminary anti-tumour activity of AZD3759 or Tagrisso in patients with EGFRm advanced stage NSCLC Primary Objective: To investigate the safety and tolerability of AZD3759 (both Part A and Part B) when given orally to patients with advanced stage EGFRm NSCLC who have progressed following prior therapy, including Maximum Tolerated Dose determination, if possible (Part A only) ECOG PS 2 symptomatic brain metastases is due in May 2017 Secondary (AZD9291 specific only): To evaluate antitumour efficacy and safety in patients treated with AZD9291 (only for patients with brain metastasis [BM] and/or leptomeningeal metastasis [LM])). To determine the pharmacokinetics of AZD9291 and metabolites in blood and CSF following multiple oral dosing (only for patients with Page 10/13

LM and/or BM). To evaluate the changes from baseline in CNS symptoms (analyzed with European Organization for Research and Treatment of Cancer (EORTC) QLQ-BN20 i QoL assessment) in patients with LM treated with AZD3759/AZD9291. Study D5160C00008 A Phase I, openlabel, nonrandomised study designed to determine the PK profile, safety and tolerability of Tagrisso following a single oral dose in patients with advanced solid tumours and normal hepatic function or mild or moderate hepatic impairment Primary Objective: To characterise the effect of hepatic impairment on the PK of AZD9291 after a single oral dose of 80 mg to patients with advanced solid tumours and mild or moderate hepatic impairment or normal hepatic function. Secondary : To characterise the effect of hepatic impairment on the PK of AZD9291 metabolites AZ5104 and AZ7550 after a single oral dose of 80 mg to patients with advanced solid tumours and mild or moderate hepatic impairment or normal hepatic function. Exposure of AZD9291 in patients with hepatic impairment Hepatotoxicity estimated to be available in November 2018. To investigate the safety and tolerability of single and multiple oral doses of Page 11/13

AZD9291 in advanced solid tumour patients with mild or moderate hepatic impairment and in those with normal hepatic function. D5160C00020 A study to assess the absolute bioavailability of a single oral dose of Tagrisso with respect to an intravenous microdose of Tagrisso in healthy male subjects Primary objective: To assess the absolute bioavailability of AZD9291 in healthy male subjects. Secondary objectives: To evaluate the pharmacokinetic parameters of AZD9291 in plasma following a single oral dose of AZD9291 and a radiolabelled intravenous (IV) microdose of [14C] AZD9291 in healthy male subjects. AZD9291 absolute oral bioavailability estimated to be available in June 2016 Safety : To examine the safety and tolerability of AZD9291. Exploratory objectives: To evaluate the pharmacokinetic parameters of metabolites AZ5104 and AZ7550 in plasma following a single oral dose of AZD9291 and a radiolabelled IV microdose of [14C] AZD9291 in healthy male subjects. To collect and store Page 12/13

deoxyribonucleic acid (DNA) for future pharmacogenetic exploratory research into genes or genetic variation that may influence on PK, metabolism or safety and tolerability to AZD9291. A study of Tagrisso use in patients with severely reduced kidney function Clinical pharmacology reduced-dosing study in patients with severe renal impairment moderate or severe renal impairment Planned to be available in the 4th quarter of 2018. A study assessing the effects of taking Tagrisso with certain other medicines (those which are processed by the body in a certain way [called transporter inhibition ]) Clinical pharmacology study assessing the potential of transporter inhibition Potential for transporter inhibition Planned Not yet decided Study number not yet decided A study assessing the effects of taking Tagrisso with certain other medicines (those which are processed by the body in certain ways [called P-gp inhibition and PXR regulated enzyme ]) Drug-drug interaction study with a substrate for another PXR regulated enzyme (different to CYP3A4), Potential for drugdrug interactions between AZD9291 and non-cyp3a4 mediated PXR substrates Potential for P-gp inhibition Planned to be available in the 4th quarter of 2017. Studies which are a condition of the marketing authorisation Study D5160C00003 is a condition of the EU marketing authorisation. Summary of changes to the risk management plan over time This summary was last updated in 01-2016. Page 13/13