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Routine-Dose and High-Dose Icotinib in Advanced Non-Small Cell Lung Cancer Patients Harboring EGFR Exon 21 L858R Mutation: the Randomized, Phase II, INCREASE Trial

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Routine-Dose and High-Dose Icotinib in Advanced Non-Small Cell Lung Cancer Patients Harboring EGFR Exon 21 L858R Mutation: the Randomized, Phase II, INCREASE Trial Author Manuscript Published OnlineFirst on February 14, 2020; DOI: 10.1158/1078-0432.CCR-19-3064 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Routine-dose and High-dose Icotinib in Advanced Non-Small Cell Lung Cancer Patients harboring EGFR Exon 21 L858R Mutation: the Randomized, Phase II, INCREASE Trial Running title: High-dose Icotinib in Advanced Non-Small Cell Lung Cancer Xi Li1,✝, Li Zhang2,✝, Da Jiang3, Yan Wang4, Aimin Zang5, Cuimin Ding6, Min Zhao7, Wuyun Su8, Yan Zhang9, Diansheng Zhong10, Jin Wu11, Cuiying Zhang12, Guangyu An13, Xingsheng Hu4, Gang Cheng14, Huaqing Wang15, Yongqun Li16, Xiaohui He4, Junli Liu17, Li Liang18, Lieming Ding19, Li * Mao19, Shucai Zhang1 1Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China; 2Respiratory Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College Hospital, Beijing, China; 3Department of Medical Oncology, The Forth Hospital of Hebei Medical University, Tumor Hospital of Hebei Province, Shijiazhuang, China; 4State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; 5Hebei Key Laboratory of Cancer Radiotherapy and Chemotherapy, Department of Medical Oncology, Affiliated Hospital of Hebei University, Baoding, China; 6Department of Respiratory Medicine, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China; 7Department of Oncology, Hebei Chest Hospital, Shijiazhuang, Hebei, China; 8Department of Medical Oncology, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China; 9Department of Oncology, Affiliated People’s Hospital of Hebei Medical University, Shijiazhuang, China; 10Department of Oncology, Tianjin Medical University General Hospital, Tianjin, China; 11Department of Head and Neck and Genito-Urinary Oncology, Harbin Medical University Cancer Hospital, Harbin, China; 12Department of Medical Oncology, People's Hospital of Inner Mongolia Autonomous Region, Hohhot, China; Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 14, 2020; DOI: 10.1158/1078-0432.CCR-19-3064 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 13Department of Medical Oncology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China; 14Department of Oncology, Beijing Hospital, National Center of Gerontology, Beijing, China; 15Department of Respiratory Medicine, Tianjin People‘s Hospital, Tianjin, China; 16Respiratory Department, Sixth Medical Center of PLA General Hospital, Beijing, China; 17Department of Medical Oncology, Xingtai People's Hospital of Hebei Medical University, Xingtai, China; 18Department of Oncology, Peking University Third Hospital, Beijing, China; 19Betta Pharmaceutical Co., Ltd., Hangzhou, China. ✝: These authors contributed equally. *Corresponding author: Prof. Shucai Zhang, Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, No. 97 Ma Chang, Tongzhou District, Beijing, 101149, China; Tel: +86-010-89509304; Email: [email protected] Financial support: This work was supported by Betta pharmaceuticals Co., Ltd.,. Conflict of Interests: Li Mao and Lieming Ding are employees of Betta Pharmaceuticals which provided partial funding for the study. Other authors declared no conflict of interests. Word count: 4147 Tables/figures: 3 figures, 3 tables, 1 supplemental figures. Statement of translational relevance Non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon 21 L858R mutation is considered less sensitive to EGFR tyrosine kinase inhibitors, and new strategies are anticipated to improve the efficacy of targeted therapies among this patient population. This multicenter phase II randomized clinical trial provides an analysis of progression-free survival (PFS) in treatment-naïve EGFR-mutant NSCLC patients on high-dose Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 14, 2020; DOI: 10.1158/1078-0432.CCR-19-3064 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. icotinib (250mg, thrice daily), as compared with routine-dose icotinib (125mg, thrice daily). Increasing the dose of icotinib significantly prolonged the median PFS (mPFS) in patients with exon 21 L858R mutation from 9.2 months to 12.9 months, which was comparable to the mPFS in patients harboring exon 19 deletion and receiving routine-dose icotinib. This study indicates that high-dose icotinib could be a better therapeutic option for patients with EGFR exon 21 L858R mutation, which is less responsive to EGFR TKIs than exon 19 deletion during rountine use of icotinib. Abstracts Background: Our primary purpose is to explore safety and efficacy of high-dose icotinib in comparison with routine-dose icotinib in non-small cell lung cancer (NSCLC) patients harboring 21-L858R mutation. Patients and Methods: Treatment-naïve, EGFR-mutant (21-L858R or exon 19 deletion at 2:1) NSCLC patients were enrolled. Patients with 21-L858R mutation were randomized to receive routine-dose icotinib (125mg, thrice daily; L858R-RD) or high-dose icotinib (250mg, thrice daily; L858R-HD) , whereas patients with exon 19 deletion received only routine-dose icotinib (19-Del-RD) until progression, death, or unacceptable toxicity. The primary endpoint was median progression-free survival (mPFS), assessed by an independent review committee (IRC). Results: From May, 2015 to November, 2017, 253 patients (86 in L858R-RD; 90 in L858R-HD; 77 in 19-Del-RD) were enrolled. The mPFS in L858R-HD group was similar to that in 19-Del- RD group (12.9 months and 12.5 months, respectively), and was significantly longer than that in L858R-RD group (12.9 months vs. 9.2 months, hazard ratio [HR]: 0.75; 95% confidence interval [CI]: 0.53 to 1.05). A longer but statistically non-significant mPFS was observed between 19- Del-RD and L858R-RD groups (12.5 months vs. 9.2 months, HR: 0.80; 95% CI: 0.57 to 1.13). A higher objective response rate (ORR) was observed in L858R-HD group compared to L858R-RD Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 14, 2020; DOI: 10.1158/1078-0432.CCR-19-3064 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. group (73% vs. 48%), also between 19-Del-RD and L858R-RD groups (75% vs. 48%). Similar incidences of grade 3/4 toxicities were observed among the three treatment groups. Conclusion: High-dose icotinib improved mPFS and ORR in NSCLC patients harboring 21- L858R mutation with acceptable tolerability, which could be a new therapeutic option for this patient population. Keyword: icotinib, high dose, EGFR mutation, exon 21 L858R Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 14, 2020; DOI: 10.1158/1078-0432.CCR-19-3064 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Introduction Lung cancer, mainly non-small cell lung cancer (NSCLC), remains the most commonly diagnosed cancer and the leading cause of cancer mortality worldwide, with an estimated 2.1 million new cases and 1.8 million deaths in 2018 [1]. Epidermal growth factor receptor (EGFR) signaling pathway plays an important role in regulating tumorigenesis and cell survival in cancer development and progression [2], and NSCLC harboring EGFR mutations is a subtype of lung cancer with sensitivity to treatment with small molecule EGFR tyrosine kinase inhibitors (EGFR TKIs). The frequency of EGFR mutations varies among regions worldwide, occurring in approximately 50% of Asian NSCLC patients and about 10% of Caucasian NSCLC patients [3]. Exon 19 deletion (19-Del) mutation and L858R mutation in exon 21 (21-L858R) are the two most frequent types of EGFR mutations, which have become the most important determining factors of clinical response to EGFR TKIs [4-6]. Although these two common mutations could predict clinical benefits from EGFR TKIs, possible differential sensitivities to EGFR TKIs based on EGFR mutation types were investigated in retrospective studies and subgroup analysis, and lower efficacy of EGFR TKIs in patients with 21-L858R mutation than those with 19-Del mutation was reported [7-11]. So far, EGFR mutations have been extensively studied. Icotinib is a highly specific and selective EGFR-TKI, which is only approved in China for treatment of NSCLC. It has proven non-inferior efficacy to gefitinib as second-/third-line treatment in patients with advanced NSCLC, and superior efficacy as first-line treatment versus chemotherapy in EGFR-mutant NSCLC patients [12-14]. A randomized study also found that icotinib significantly improved intracranial progression-free survival (PFS) when compared with whole-brain irradiation (WBI) in patients with brain metastases and EGFR mutations [15]. However, many questions remain Downloaded
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