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Osimertinib Versus Erlotinib Or Gefitinib in Patients with EGFR-Mutated Advanced Non-Smal

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Osimertinib Versus Erlotinib Or Gefitinib in Patients with EGFR-Mutated Advanced Non-Smal European Journal of Cancer 125 (2020) 49e57 Available online at www.sciencedirect.com ScienceDirect journal homepage: www.ejcancer.com Original Research Patient-reported outcomes from FLAURA: Osimertinib versus erlotinib or gefitinib in patients with EGFR- mutated advanced non-small-cell lung cancer Natasha B. Leighl a, Nina Karaseva b, Kazuhiko Nakagawa c, Byoung-Chul Cho d, Jhanelle E. Gray e, Tina Hovey f, Andrew Walding g, Anna Ryde´n h, Silvia Novello i,* a Princess Margaret Cancer Centre, Toronto, ON, Canada b City Clinical Oncology Dispensary, St. Petersburg, Russia c Department of Medical Oncology, Kindai University Faculty of Medicine, Osakasayama, Japan d Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea e Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA f PHASTAR, London, UK g AstraZeneca R&D, Cambridge, UK h AstraZeneca Gothenburg, Mo¨lndal, Sweden i Department of Oncology, University of Turin, Azienda Ospedaliero-Universitaria San Luigi Gonzaga, Turin, Italy Received 25 October 2019; accepted 6 November 2019 Available online 12 December 2019 KEYWORDS Abstract Background: In the FLAURA trial, osimertinib demonstrated superior EORTC QLQ-C30; progression-free survival and a favorable toxicity profile to erlotinib or gefitinib as initial ther- EORTC QLQ-LC13; apy in patients with EGFR-mutated advanced non-small-cell lung cancer. Patient-reported Non-small-cell lung outcomes from FLAURA are discussed here. cancer; Methods: Patients (N Z 556) completed the EORTC QLQ-LC13 weekly for 6 weeks, then Osimertinib; every 3 weeks, and the QLQ-C30 every 6 weeks. Prespecified key symptoms were cough, Patient-reported dyspnea, chest pain, appetite loss, and fatigue. Score changes from baseline to randomized outcomes treatment discontinuation were assessed using a mixed-effects model. A 10-point change was considered clinically relevant. Odds of improvement and time to deterioration were inves- tigated. QLQ-C30 functioning scores were assessed post hoc. Results: Questionnaire completion rates were >70% at most time points. Baseline mean scores were similar in the osimertinib and erlotinib/gefitinib arms. Scores improved in both arms, but none reached clinical relevance at 5% significance level. A statistically significant difference * Corresponding author: Department of Oncology, University of Turin, Azienda Ospedaliero-Universitaria San Luigi Gonzaga, Regione Gon- zole, 10, 10043, Orbassano, Turin, Italy. E-mail address: [email protected] (S. Novello). https://doi.org/10.1016/j.ejca.2019.11.006 0959-8049/ª 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). 50 N.B. Leighl et al. / European Journal of Cancer 125 (2020) 49e57 favoring osimertinib for chest pain was not clinically relevant (À6.84 vs À3.88; p Z 0.021). Odds of improvement and time to deterioration were similar between treatments. In post hoc analyses, improvements favored osimertinib for emotional functioning (8.79 vs 4.91; p Z 0.004) and social functioning (7.66 vs 1.74; p < 0.001). Cognitive functioning remained stable with osimertinib but deteriorated with erlotinib/gefitinib (0.03 vs À3.91; p Z 0.005). Conclusions: Key symptoms improved from baseline in both treatment arms in FLAURA. Key symptom improvements that were both statistically significant and clinically relevant were not observed in favor of either treatment arm. Clinical trial registration: NCT02296125 ª 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 1. Introduction permanent treatment discontinuation (13% vs 18%) [16]. Based on these results, osimertinib was approved as For patients with advanced non-small-cell lung cancer first-line treatment for patients with EGFRm advanced (NSCLC) and sensitizing epidermal growth factor NSCLC and is recommended by National Comprehen- receptor mutations (EGFRm), the introduction of sive Cancer Network guidelines as the preferred first-line targeted therapy with EGFRetyrosine kinase in- treatment for patients with EGFRm advanced or met- hibitors (TKIs) has markedly improved clinical out- astatic NSCLC [19]. comes [1e7]. PROs were part of secondary outcome measures in Symptom management is crucial in the treatment of the FLAURA trial and were assessed prospectively patients with advanced NSCLC. Cough, dyspnea, using the European Organisation for Research and chest pain, fatigue, and appetite loss are key patient- Treatment of Cancer (EORTC) Quality of Life Ques- reported symptoms and have a marked negative tionnaire Lung Cancer 13 items (QLQ-LC13) and impact on health-related quality of life (HRQoL) [8,9]. Quality of Life Questionnaire Core 30 items (QLQ- Patients with advanced NSCLC who received first- C30). The aim of the current analysis was to evaluate the line treatment with erlotinib, gefitinib, or afatinib symptom burden in the FLAURA trial, in patients in experienced improvements in symptoms and HRQoL the osimertinib arm compared with those in the erloti- compared with patients who received chemotherapy nib/gefitinib arm. [10e12]. In the LUX-Lung 7 trial that compared first- line afatinib and gefitinib, similar improvements in patient-reported outcomes (PROs) were observed in both treatment arms [13]. In the ARCHER 1050 trial, 2. Methods progression-free survival (PFS) and overall survival (OS) were longer with dacomitinib than with gefitinib 2.1. Study design and patients in the first-line treatment of patients with NSCLC, but improvements in global HRQoL were seen only with FLAURA (NCT02296125) was a multinational, phase gefitinib [6,14]. 3, double-blind, double-dummy, randomized trial [16]. Osimertinib is an oral, irreversible, central nervous The methods and primary efficacy results have been system (CNS)-active, third-generation EGFR-TKI with reported in detail [16]. In brief, eligible patients had preclinical and clinical evidence of potent activity locally advanced or metastatic EGFRm (exon 19 dele- against EGFRm NSCLC and the T790M resistance tion or L858R) NSCLC and were eligible for first-line mutation, the most common cause of resistance to early- therapy with an EGFR-TKI. Patients were random- generation EGFR-TKIs [15e18]. The greater selectivity ized 1:1 to receive oral osimertinib 80 mg once daily for mutated EGFR and relative sparing of wild-type (n Z 279) or either oral gefitinib 250 mg once daily or EGFR also mean that osimertinib is associated with oral erlotinib 150 mg once daily (n Z 277). The cut-off less toxicity than earlier EGFR-TKIs [16]. In the phase 3 date for the current analysis was 12 June 2017. FLAURA trial of first-line treatment, osimertinib FLAURA was conducted in accordance with the significantly improved PFS compared with erlotinib or Declaration of Helsinki and is consistent with the gefitinib (18.9 months vs 10.2 months; hazard ratio International Conference on Harmonisation and [HR]: 0.46; 95% confidence interval [CI]: 0.37e0.57; Good Clinical Practice, applicable regulatory re- p < 0.001) [16]. Rates for adverse events were lower with quirements, and the AstraZeneca Bioethics Policy. osimertinib than with erlotinib/gefitinib for grade 3 The study was approved by the institutional review (34% vs 45%) and for adverse events leading to board and/or independent ethics committee associated with each study center. All patients provided written N.B. Leighl et al. / European Journal of Cancer 125 (2020) 49e57 51 informed consent before any study-specific procedures Table 1 were performed. EORTC QLQ-LC13 and QLQ-C30 scores at baseline. QLQ-LC13 Osimertinib, Erlotinib/ 2.2. Questionnaires mean (SD) gefitinib, mean (SD) Patients completed the questionnaires using electronic Scale/items Cougha 32.8 (27.2) 33.5 (28.8) devices. The EORTC QLQ-LC13 was completed at Hemoptysis 3.9 (14.3) 2.9 (10.7) baseline, then every week for 6 weeks, followed by every Dyspneaa 22.5 (23.1) 25.0 (22.8) 3 weeks. The EORTC QLQ-C30 was completed at Sore mouth 4.4 (13.2) 5.2 (14.4) baseline and then every 6 weeks. The EORTC QLQ- Dysphagia 5.0 (14.0) 5.3 (13.9) LC13 is a 13-item lung-cancer-specific questionnaire Peripheral neuropathy 6.6 (15.5) 10.1 (20.1) Alopecia 5.1 (15.0) 6.4 (16.4) that measures disease-related symptoms and treatment- Chest paina 19.5 (25.3) 20.8 (25.7) related side effects [20]. The EORTC QLQ-C30 is a 30- Pain in arm or shoulder 17.6 (24.4) 19.1 (26.3) item cancer questionnaire that measures symptoms and Pain in other parts 23.3 (25.7) 22.4 (25.7) functional aspects commonly related to cancer [21]. An Pain medication/help 60.1 (25.4) 62.6 (25.3) outcome variable consisting of a score from 0 to 100 was QLQ-C30 Symptom scale/items derived from each of the symptom scales and items in Fatiguea 32.2 (24.9) 35.8 (26.2) the two questionnaires [20,21]. A higher score on the Nausea and vomiting 7.3 (14.9) 7.2 (13.6) symptom scale represents more/worse symptoms [20,21]. Pain 25.8 (27.5) 27.2 (27.8) Higher functional scores represent a higher (“better”) Dyspnea 24.4 (28.4) 25.2 (27.8) HRQoL or level of functioning [20,21]. For both ques- Insomnia 25.6 (27.9) 30.2 (28.4) Appetite lossa 22.7 (28.5) 25.6 (29.9) tionnaires, a difference in score of at least 10 points was Constipation 13.3 (23.0) 16.2 (25.2) considered clinically relevant, corresponding to at least a Diarrhea 5.4 (14.6) 5.7 (15.1) moderate change in HRQoL [22]. Financial difficulties 15.4 (24.3) 16.5 (26.7) The prespecified key symptoms of importance in Global health status/QoL 62.5 (23.2) 58.8 (22.8) advanced NSCLC were cough, dyspnea, chest pain, Functional scales Physical functioning 79.6 (21.6) 75.7 (21.0) appetite loss, and fatigue [8,9].
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