Plain Language Summary of Publication A plain language summary of results from the ADAURA study: osimertinib after surgery for patients who have early-stage EGFR-mutated non-small cell lung cancer Yi-Long Wu1, Masahiro Tsuboi2, Thomas John3, Christian Grohe4, Margarita Majem5, Jonathan W Goldman6, Konstantin Laktionov7, Sang-We Kim8, Terufumi Kato9, Huu-Vinh Vu10, Shun Lu11, Kye-Young Lee12, Charuwan Akewanlop13, Chong-Jen Yu14, Filippo de Marinis15, Laura Bonanno16, Manuel Domine17, Frances A Shepherd18, Lingmin Zeng19, Rachel Hodge20, Ajlan Atasoy21, Yuri Rukazenkov21 & Roy S Herbst*,22 1 Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China; 2­Department of Thoracic Surgery and Oncology, National Cancer Center Hospital East, Kashiwa, Japan; 3Department of Medical Oncology, Austin Health, Melbourne, Australia; 4Department of Respiratory Diseases, Evangelische Lungenklinik, Berlin, Germany; 5Department of Medical ­Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; 6David Geffen School of Medicine at University of California Los Angeles, CA, USA; ⁷Center of Innovative Technologies and Oncology, N.N. Blokhin Russian Cancer Center, Russian Academy of Medical Sciences, Moscow, Russia; ⁸Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea; 9Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama, Japan; 10Department of Thoracic Surgery, Choray Hospital, Ho Chi Minh City, Vietnam; 11Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China; 12Precision Medicine, Lung Cancer Center, Konkuk University Medical Center, Seoul, South Korea; 13Division of Medical Oncology, Faculty of Medicine, Siriraj Hospital, Bangkok, Thailand; 14Department of Internal Medicine, National Taiwan University Hospital Hsinchu Branch and National Taiwan University College of Medicine, Taipei, Taiwan; 15Thoracic Oncology Division, European Institute of Oncology (IEO), IRCCS, Milan, Italy; 16Medical Oncology 2, Istituto Oncologico Veneto IOV IRCCS, Padova, Italy; 17Instituto de Investigacion Sanitaria-Fundación de la Jimenez Diaz, Madrid, Spain; 18Department of Medical Oncology and Hematology, University Health Network, Princess Margaret Hospital and the University of Toronto, Toronto, Ontario, Canada; 19Late Oncology Statistics, AstraZeneca, Gaithersburg, MD, USA; 20Late Oncology Statistics, AstraZeneca, Cambridge, UK; 21Late Oncology Research & Development, AstraZeneca, Cambridge, UK; 22Medical Oncology, Yale School of Medicine and Yale Cancer Center, New Haven, CT, USA First draft submitted: 17 June May 2021; Accepted for publication: 15 September 2021; Published online: 1 November 2021 Summary Here, we summarize the initial results from the ADAURA clinical study How to say (double click to play looking at treatment with osimertinib in patients with a specific type of sound)... non-small cell lung cancer. Osimertinib (TAGRISSO®) is a medication used • Osimertinib: oz-ee-mer-ti-nib to treat a type of NSCLC with a change (mutation) in the EGFR gene, known as EGFR-mutated NSCLC. EGFR stands for ‘epidermal growth factor receptor’. It is a protein present on the surface of both healthy and cancer cells that can regulate how cells grow and divide. Sometimes, certain mutations in EGFR can result in the EGFR protein malfunctioning, which can lead to the formation of cancer, like EGFR-mutated NSCLC. Based on previous clinical studies, osimertinib is already approved for use in patients with EGFR-mutated NSCLC that has spread beyond the lung (metastatic disease). This medication works to stop, prevent, or slow the growth of EGFR-mutated NSCLC tumors, by specifically blocking the activity of EGFR. In the ADAURA clinical study, participants had resectable EGFR-mutated NSCLC, which means they had tumors that can be removed by surgery. Participants took either osimertinib or a placebo (a dummy drug with no active ingredient) after having their tumors removed by surgery. Post-surgery chemotherapy was allowed, but not compulsory (this was decided by the participant and their doctor). To date, the study has shown that osimertinib could be beneficial for patients with resectable EGFR-mutated NSCLC. Participants who took osimertinib have stayed cancer-free for longer than those who took the placebo, regardless of whether or not they received chemotherapy after surgery. Osimertinib treatment also reduced the risk of tumors spreading to the brain and spinal cord, otherwise known as the central nervous system (also called CNS). The side effects experienced by the participants taking osimertinib have been consistent with what we already know. Based on the results from ADAURA, osimertinib has been approved for the treatment of resectable EGFR-mutated NSCLC after tumor removal. The ADAURA study is still ongoing and more results are expected to be released in the future. part of 10.2217/fon-2021-0752 © The Authors Future Oncol. 17(35) 4827–4835  ISSN 1479-6694 4827 Plain Language Summary of Publication Wu, Tsuboi, John et al. Who should read this article? Who sponsored this clinical study? This summary may be helpful for patients with EGFR-mutated The pharmaceutical company AstraZeneca NSCLC and their families, as well as patient advocates, caregivers (the manufacturers of osimertinib) funded and healthcare professionals, including those who are helping and were responsible for conducting this someone to find the best treatment for their diagnosis. ­clinical study. What are the different stages of lung cancer? Lung cancer occurs when there is an abnormal growth of cells (known as a tumor) in the lungs. Numbered stages are often used to categorize lung cancer. The ADAURA clinical study included patients with stage IB, IIA/B or IIIA NSCLC. The stage of disease was determined using the American Joint Committee on Cancer (7th edition) staging categories, which are summarized below. Stages I–IIIA are often referred to as ‘early stage’. Stage IA Stage IB Stage IIA/B Stage IIIA/B Stage IV When When When When the When the cancer is the cancer is the cancer is cancer has grown the cancer has less than 3 cm less than larger than and spread to spread to areas in size and has 5 cm in size 5 cm in size or surrounding that are further not spread and has has spread to areas (e.g., the away (e.g., anywhere else not spread some surrounding lymph nodes), another organ anywhere else areas (e.g., known as of the body), nearby lymph regional known as distant nodes) metastasis metastasis What is EGFR-mutated NSCLC? • However, the cancer can unfortunately still come back • Non-small-cell lung cancer (also known as NSCLC) is the most common type of lung cancer. in around half of patients with stage IB–IIIA NSCLC, even if post-surgery chemotherapy is received. • Around one third (1/3) of patients with NSCLC have tumors that can be removed by surgery (also known as • The cancer may also spread to other parts of the body, such as the brain and spinal cord, otherwise known as ‘resectable’ NSCLC). the central nervous system (also called CNS). Almost half of patients with NSCLC • After surgery, chemotherapy is often recommended for patients with stage II–IIIA resected NSCLC and develop brain metastases, which can have a big impact on patient quality of sometimes recommended for patients with stage IB. life. 4828  Future Oncol. (2021) 17(35) future science group Results from ADAURA: osimertinib in resected EGFR-mutated NSCLC Plain Language Summary of Publication What is EGFR-mutated NSCLC? (continued) EGFR 10–20% • New and improved therapies, such as personalized • Almost half of all patients with NSCLC of Asian ethnicity and (targeted) treatment, are therefore needed for patients around 10–20% of patients in other parts of the world have with resectable NSCLC. tumors with a mutation in the EGFR gene, which is known as EGFR-mutated NSCLC. This type of lung cancer can be • EGFR stands for ‘epidermal growth factor receptor’. It is a protein present on the cell surface that can control how identified by testing for changes in genes or the activity of proteins, known as biomarkers (including EGFR mutation), cells grow and divide. by testing either blood or a sample of the tumor. • Some patients with NSCLC have a mutation in the gene for EGFR. This can • Common types of EGFR mutation include exon 19 deletion and L858R substitution, which each account for around cause lung cancer tumors to grow more 45% of all EGFR mutations. quickly, due to a change in how the EGFR protein functions. What is osimertinib? The medication being studied in the ADAURA clinical study is osimertinib. It is taken by mouth (tablet) at a dose of 80 mg once per day, to treat resectable EGFR-mutated NSCLC. Unlike chemotherapy, osimertinib is a personalized treatment option, targeted specifically for patients with EGFR mutations. Osimertinib belongs to a group of EGFR-targeted medicines known as EGFR-tyrosine kinase inhibitors, or EGFR-TKIs. Osimertinib is a next generation treatment that works by blocking the activity of EGFR. Over time, this can slow, prevent, or stop the growth of NSCLC tumors. Osimertinib is currently recommended for the treatment of EGFR-mutated NSCLC that has spread to other parts of the body (metastatic disease). In December 2020, osimertinib was approved for the treatment of resectable EGFR-mutated NSCLC after tumor removal (early-stage disease), based on results from the ADAURA clinical study. future science group Future Oncol. (2021) 17(35) 4829 Plain Language Summary of Publication Wu, Tsuboi, John et al. What was the ADAURA clinical study designed to look at? • The aim of the ADAURA clinical study was to see how long participants in the study with resectable EGFR-mutated NSCLC would remain alive and cancer-free with osimertinib treatment (known as cancer-free survival), after having their tumors completely removed by surgery. • Post-surgery chemotherapy was allowed, but not mandatory (this was decided by the participant and their doctor). • The study compared results in participants who received osimertinib versus participants who took a placebo (a dummy drug with no active ingredient). Cancer-free survival was assessed in participants with resectable EGFR-mutated NSCLC (stage IB, II or IIIA). The safety of the treatment was also assessed. • The ADAURA clinical study is still ongoing and more results are expected to be released in the future. • Here, we summarize results from the study’s primary data analysis. • The primary analysis was completed earlier than planned due to results that were expected to change clinical practice. An Independent Data Monitoring Committee (known as IDMC) recommended that the results be made public. The ADAURA clinical study included 682 participants. The study included participants from 231 hospitals and cancer centers across 26 different countries worldwide. Participants were randomly assigned to take either osimertinib or a placebo. Neither the participant nor their doctor knew which treatment they were taking. 4830  Future Oncol. (2021) 17(35) future science group A plain language summary of results from the ADAURA study Plain Language Summary of Publication What was the ADAURA clinical study designed to look at? (continued) The characteristics of participants included in each treatment group were similar: Osimertinib Placebo All patients Female (%) 68% 72% 70% Approximately two thirds (2/3) of participants were female. Average 63 62 62 age (range) (30–86) (31–82) (30–86) The participants were aged 30–86 years. The average age was 62 years. Smoking history Yes 32% 25% 29% Approximately two thirds (2/3) of participants had no history of smoking. No 68% 75% 72% Race Asian 36% 36% 36% Approximately two thirds (2/3) of Non-Asian 64% 64% 64% participants were Asian. Treatment was planned to continue for 3 years, unless the cancer came back, or the participant decided to stop treatment for other reasons Randomization 1:1 Osimertinib 80 mg once per day 339 participants 682 participants Placebo 343 participants *In randomized clinical studies, unequal patient numbers can sometimes occur between treatment groups due to random variation during the allocation process. future science group Future Oncol. (2021) 17(35) 4831 Plain Language Summary of Publication Wu, Tsuboi, John et al. What were the overall results of the study? To date, the participants who took osimertinib had longer cancer-free survival than those who took placebo. In participants with resectable stage II–IIIA NSCLC, there was an 83% reduction in the risk of the cancer returning or death in participants who took osimertinib compared to placebo. In participants with resectable stage IB–IIIA NSCLC, 89% of those who took osimertinib were alive and cancer-free at 2 years, compared with 52% of participants who took placebo. 90% of participants who took osimertinib 44% of participantswho took a placebo were alive and cancer-free at 2 years were alive and cancer-free at 2 years In participants with resectable stage II–IIIA NSCLC, 90% of those who took osimertinib were alive and cancer-free at 2 years, compared with 44% of participants who took placebo. In participants with resectable stage IB–IIIA NSCLC, there was an 80% reduction in the risk of the cancer returning or death in participants who took osimertinib compared to placebo. 89% of participants who took osimertinib 52% of participants who took a placebo were alive and cancer-free at 2 years were alive and cancer-free at 2 years 4832 Future Oncol. (2021) 17(35) future science group Results from ADAURA: osimertinib in resected EGFR-mutated NSCLC Plain Language Summary of Publication What were the overall results of the study? (continued) 60% of participants who took osimertinib, and 60% of those who took placebo, received chemotherapy before their treatment began Among all participants who received chemotherapy, 89% of those who took osimertinib were alive and cancer-free at 2 years, compared with 49% of participants who took placebo. Among all participants who did not receive chemotherapy, 89% of those who took osimertinib were alive and cancer-free at 2 years, compared with 58% of participants who took placebo. Osimertinib treatment also reduced the risk of 89% of participants who took osimertinib were alive and tumors spreading to the CNS. cancer-free at 2 years, regardless of whether or not • Among all participants with resectable NSCLC, only 1% of those who took osimertinib had cancer they received chemotherapy after surgery 89% 89% that came back and spread to the CNS, compared with 10% of participants who took placebo. • This meant there was an 82% reduction in the risk 58% of CNS-related cancer or death in participants who 49% took osimertinib. The chance of participants who took osimertinib remaining free of CNS-related cancer at 2 years was Received chemotherapy Did not 98%. In participants who took placebo, the chance receive chemotherapy of remaining free of CNS-related cancer at 2 years was 85%. Osimertinib Placebo What were the most common side effects? The most common side effects (of any severity) experienced by participants are shown in the figure. Diarrhea Nail effects 46% 20% 25% 1% Osimertinib group Placebo group Osimertinib group Placebo group (participants %) (participants %) (participants %) (participants %) Dry skin Itching skin 23% 6% 19% 9% Osimertinib group Placebo group Osimertinib group Placebo group future science group (participants %) (participants %) www.futuremedicine.com (participants %) (participants %)  Plain Language Summary of Publication Wu, Tsuboi, John et al. What were the most common side effects? (continued) • Side effects of grade 3 or higher (for example, those considered medically important, requiring hospitalization or significant treatment) were reported in 20% of participants who took osimertinib and 13% of participants who took placebo. • 15% of participants who took osimertinib and 1% of participants who took placebo had their dose reduced to 40 mg (decided by their doctor). • The number of participants who stopped treatment due to side effects was low (11% of participants who took osimertinib and 3% of participants who took placebo). • The side effects observed were consistent with what we already know about osimertinib. Participants who Participants who reported had their dose reduced to 40 mg Participants who stopped side effects of grade 3 or higher* (%) (decided by their doctor) (%) treatment due to side effects (%) 20% 13% 15% 11% 3% 1% Grade 3 or higher Dose reduced Stopped treatment Osimertinib Placebo *For example, those considered medically important, requiring hospitalization or significant treatment What do the results of this study mean? • longer To date, this study has shown that participants who took osimertinib after having their tumors removed by surgery had cancer-free survival compared with participants who took placebo. • The cancer-free benefit with osimertinib was seen regardless of whether participants received chemotherapy after their surgery or not. • The number of participants who stopped treatment due to side effects was low. The side effects observed were consistent with what we already know about osimertinib. • The ADAURA study is still ongoing and more results are expected to be released in the future. Educational resources Learn about the European Society for Medical Oncology (ESMO) clinical practice guidelines for the treatment of non-small cell lung cancer. These guidelines assist physicians in determining the best treatment for their patients. Read the guidelines for patients at: https://www.esmo.org/for-patients/patient-guides/non-small-cell-lung-cancer 4834 Future Oncol. (2021) 17(35) future science group Results from ADAURA: osimertinib in resected EGFR-mutated NSCLC Plain Language Summary of Publication Where can I find more information? The full title of the original publication in the New England Journal of Medicine is: ‘Osimertinib in Resected EGFR-Mutated Non-Small-Cell Lung Cancer’ You can read the original article at: www.nejm.org/doi/full/10.1056/NEJMoa2027071 You can read more about the ADAURA study on the following websites: • Type the study number, NCT02511106, into the search bar of the ClinicalTrials.gov website at www.clinicaltrials.gov • Type the EudraCT identifier 2015-000662-65 into the search field at www.clinicaltrialsregister.eu/ctr-search • Ifstaffyouatareyouror study were a study participant and have questions about the results of this study, please speak with the doctor or center. • Patients should ask their healthcare providers for more information about the benefits and risks of any treatment. • More information about clinical trials in general can be found at: https://www.clinicaltrials.gov/ct2/about-studies/learn Financial & competing interests disclosure Disclosure forms provided by the authors are available with the full text of the original article at NEJM.org. The authors would like to acknowledge Rachel Gater, PhD of Ashfield MedComms, an Ashfield Health Company, part of UDG Healthcare plc for medical writing support that was funded by AstraZeneca in accordance with Good Publications Practice (GPP3) guidelines (http://www.ismpp.org/gpp3). Acknowledgments AstraZeneca would like to thank all of the patients who participated in this clinical study, their families and all of the study center staff members who contributed. The authors would also like to thank Dann Wonser, Diane Legg, Joanne Kiers and John Cannings for reviewing this article and providing valuable contributions to the development of this plain language summary publication. future science group Future Oncol. (2021) 17(35) 4835