Lung Cancer 86 (2014) 207–212
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
A single-arm, multicenter, safety-monitoring, phase IV study of icotinib in treating advanced non-small cell lung cancer (NSCLC) Xingsheng Hu a,1 , Baohui Han b,1 , Aiqin Gu b , Yiping Zhang c , Shun Chang Jiao d , Chang-li Wang e , Jintao He f , Xueke Jia g , Li Zhang h , Jiewen Peng i , Meina Wu j , Kejing Ying k , Junye Wang l , Kewei Ma m , Shucai Zhang n , Changxuan You o , Fenlai Tan p , Yinxiang Wang p , Lieming Ding p , Yan Sun a,∗ a Department of Medical Oncology, Cancer Institute/Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China b Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China c Department of Chemotherapy, Zhejiang Cancer Hospital, Key Laboratory Diagnosis and Treatment Technology on Thoracic Oncology, Hangzhou, China d General Hospital of People’s Liberation Army, Beijing, China e Department of Lung Cancer, Cancer Institute and Hospital, Tianjin Medical University, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China f Sichuan Cancer Hospital and Institute, Chengdu, China g Baoding Hengxing Medicine Integrative Hospital, Baoding, China h Department of Respiratory Medicine, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China i Department of Medical Oncology, Zhongshan City Pepole’s Hospital, Zhongshan, China j Department of Thoracic Medical Oncology Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing, China k Zhejiang Sir Run Run Shaw Hospital, Department of Medicine, Zhejiang University, Hangzhou, China l State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China m Cancer Center of the First Hospital of Jilin University, Changchun, China n Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China o Department of Medical Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China p Betta Pharmaceuticals Co., Ltd, Hangzhou, China
a r t i c l e
i n f o
Article history: Received 3 June 2014 Received in revised form 14 August 2014 Accepted 22 August 2014 Keywords: Non-small-cell lung cancer Icotinib EGFR TKIs Phase IV real-world study safety efficacy
a b s t r a c t Background: The phase 3 ICOGEN trial established the non-inferiority of icotinib to gefitinib in terms of progression-free survival (PFS) in non-small cell lung cancer (NSCLC) patients, and this led to the approval of icotinib for NSCLC by the China Food and Drug Administration. A phase 4 study was conducted to assess the safety and efficacy of icotinib in a broad range of patients with advanced NSCLC across China. Methods: This study retrospectively analyzed data from unresectable, recurrent, and/or advanced NSCLC patients who received oral icotinib 125 mg three times per day. The primary endpoint was safety. The secondary endpoints included objective response rate (ORR) and disease control rate (DCR), which were investigated overall and in subgroups such as patients with an EGFR mutation and elderly patients. Results: Between August, 2011 and August, 2012, a total of 6087 advanced NSCLC patients were registered in this study, of which 5549 were evaluable for safety and tumor response. The median age was 63 years (range 21–95 years), and 1571 (28.3%) patients were over the age of 70. The majority of patients were non-smokers, and had adenocarcinoma and stage IV disease. The overall incidence of adverse drug reactions (ADRs) of any grade was 31.5%. The most common ADRs included rash (17.4%) and diarrhea (8.5%), and three patients experienced interstitial lung disease (ILD). The ORR and DCR were 30.0% and 80.6%, respectively, for the overall population, and 33.4% and 81.2%, 30.3% and 80.3%, and 30.4% and 89.3%, for first-line, second-line, and third-line or multiple line subsets, respectively. In 665 EGFR-mutated patients who were evaluable for tumor response, the ORR and DCR were 49.2% (327/665) and 92.3% (614/665), respectively.
∗ Corresponding author. Tel.: +86 21 25070357/10 67781331x8519; fax: +86 10 67734107. E-mail address: [email protected] (Y. Sun). 1 These authors contributed equally to this work. http://dx.doi.org/10.1016/j.lungcan.2014.08.014 0169-5002/© 2014 Elsevier Ireland Ltd. All rights reserved.
208
X. Hu et al. / Lung Cancer 86 (2014) 207–212
Conclusions: The data from over 6000 patients was consistent with the results of the ICOGEN study. Icotinib demonstrated a favorable toxicity profile and efficacy in the routine clinical setting. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
2.2. Assessments
Lung cancer is one of the most common malignancies, accounting for millions of deaths worldwide, yet its treatment remains a challenge for the medical world [1]. Non-small cell lung cancer (NSCLC) comprises about 85% of lung cancer [2]. Most NSCLC patients are at an advanced stage when diagnosed, leaving systemic chemotherapy as the only treatment option. Systemic chemotherapy prolongs survival compared with best supportive care alone; however, the standard of care chemotherapy is associated with side effects, especially in elderly patients and those with a poor performance status [3]. The discovery and development of targeted agents have had a major impact on the treatment of NSCLC. Several small-molecular targeted agents have been approved for the treatment of lung cancer since 2002: gefitinib, erlotinib, icotinib, crizotinib, and afatinib, and all of them have greatly improved the survival of NSCLC patients as compared to chemotherapy. Icotinib (Commana, Betta Pharmaceuticals Co., Ltd, Hangzhou, China) is a highly potent, orally active, epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor (TKI) [4]. Icotinib displayed a favorable toxicity profile in phase 1 studies [5,6]. In a phase 2 study, icotinib provided a PFS of 4.6 months for pretreated NSCLC patients [7], and the tolerable and effective range of icotinib was 100–625 mg three times per day [8]. These results were subsequently confirmed in further studies [9,10]. In the phase 3 ICOGEN study, icotinib yielded a non-inferior PFS when compared to another EGFR-TKI, gefitinib (4.6 [3.5–6.3] months vs. 3.4 [2.3–3.8] months; p = 0.13), in patients with advanced NSCLC, who had progressed after receiving at least one line of chemotherapy [9]. Moreover, the incidence rates of adverse reactions (60.5% vs. 70.4%; p = 0.045) and drug-related diarrhea (18.5% vs. 27.6%; p = 0.03) in the icotinib arm were significantly lower than those in the gefitinib arm, and no treatment-related deaths nor interstitial lung disease (ILD) were reported in either groups [9]. Based on this study, icotinib was approved by the China Food and Drug Administration as second- or third-line treatment for advanced NSCLC. Since icotinib is an investigational new drug, further assessment of its safety and efficacy in a broad range of patients is warranted. With this in mind, we examined our data retrospectively to assess the real-world utilization of icotinib in NSCLC patients.
Safety and tolerability assessments were conducted in patients who received at least one dose of icotinib. Safety data included drug-related adverse events (adverse reactions, ADRs); and clinically significant abnormal complete blood count and liver function laboratory. ADRs were graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 3.0 (CTCAEv3) and were coded by the Medical Dictionary for Regulatory Activities (MedDRA) version 12.1. Icotinib-related serious adverse events (SAEs) and treatment withdrawal were also recorded. Tolerability in elderly patients was also included as a safety concern. Physician-based tumor response data were collected for efficacy assessment, in patients who received at least one cycle 4-week cycle of icotinib treatment. Efficacy was assessed by tumor response and defined as the sum of complete remission (CR) or partial response (PR) according to computerized tomography (CT scan). Magnetic resonance imaging (MRI) was utilized to evaluate intracranial lesions. Treating physicians assessed tumor responses with the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Tumor responses were evaluated one month after the first administration of icotinib and then at least every two months. The relationship between efficacy and EGFR mutation was explored in patients who had undergone an EGFR mutation test.
2. Methods
2.3. Statistical analysis Descriptive methods including frequency and percentage were used for analysis. The safety analysis population included patients who received any dose of icotinib, and the intention-to-treat population included patients who received at least one cycle 4-week of icotinib. The primary endpoint was safety, and this was defined by any ADRs after administration of icotinib and laboratory values obtained at each visit. The ADR coding complied with MedDRA (version 12.1). Baseline information included demographic data, vital signs, medical and treatment history, histological type, stage of disease, genetic tests, laboratory tests, tumor response, and the incidence of adverse reactions. The objective response rate (ORR) was defined as the sum of CR and PR, and the disease control rate (DCR) was defined as the sum of CR, PR and stable disease (SD). Logistic regression models were utilized to further explore the relationship between baseline characteristics and tumor response. Subgroup analyses were performed in patients with an identified EGFR status and elderly patients.
2.1. Patients and study design 3. Results This retrospective study analyzed data from patients diagnosed with advanced NSCLC who were prescribed icotinib between August, 2011 and August, 2012. Patients who unresectable, recurrent, and/or advanced NSCLC confirmed by histopathology or cytology were eligible for the study. Icotinib (125 mg tablet, Betta Pharmaceuticals Co., Ltd, Zhejiang, China) was administered orally three times per day on a 4-week cycle until disease progression or occurrence of intolerable toxicity. The primary objective was to assess the safety of icotinib, paying close attention to newly occurring and serious adverse reactions (SAR). The secondary objectives included tumor response and the safety and efficacy of icotinib in elderly patients or those with an EGFR mutation.
3.1. Baseline characteristics From August, 2011 to August, 2012 a total of 6087 patients from 480 hospitals were enrolled in the study. Of these, 5548 were evaluable for safety and tumor response. A total of 538 patients were excluded from the safety and efficacy assessments, including 360 patients who were lost to follow-up, and 109 patients who did not complete at least one course of treatment (Fig. 1). The baseline characteristics are summarized in Table 1. The median age was 63 years (range 21–95 years). The majority of patients had adenocarcinoma (78.6%), and 90.2% had stage IV
X. Hu et al. / Lung Cancer 86 (2014) 207–212
209
Table 1 Baseline patient characteristics. Characteristics
First-line
Age
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
A single-arm, multicenter, safety-monitoring, phase IV study of icotinib in treating advanced non-small cell lung cancer (NSCLC) Xingsheng Hu a,1 , Baohui Han b,1 , Aiqin Gu b , Yiping Zhang c , Shun Chang Jiao d , Chang-li Wang e , Jintao He f , Xueke Jia g , Li Zhang h , Jiewen Peng i , Meina Wu j , Kejing Ying k , Junye Wang l , Kewei Ma m , Shucai Zhang n , Changxuan You o , Fenlai Tan p , Yinxiang Wang p , Lieming Ding p , Yan Sun a,∗ a Department of Medical Oncology, Cancer Institute/Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China b Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China c Department of Chemotherapy, Zhejiang Cancer Hospital, Key Laboratory Diagnosis and Treatment Technology on Thoracic Oncology, Hangzhou, China d General Hospital of People’s Liberation Army, Beijing, China e Department of Lung Cancer, Cancer Institute and Hospital, Tianjin Medical University, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China f Sichuan Cancer Hospital and Institute, Chengdu, China g Baoding Hengxing Medicine Integrative Hospital, Baoding, China h Department of Respiratory Medicine, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China i Department of Medical Oncology, Zhongshan City Pepole’s Hospital, Zhongshan, China j Department of Thoracic Medical Oncology Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing, China k Zhejiang Sir Run Run Shaw Hospital, Department of Medicine, Zhejiang University, Hangzhou, China l State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China m Cancer Center of the First Hospital of Jilin University, Changchun, China n Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China o Department of Medical Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China p Betta Pharmaceuticals Co., Ltd, Hangzhou, China
a r t i c l e
i n f o
Article history: Received 3 June 2014 Received in revised form 14 August 2014 Accepted 22 August 2014 Keywords: Non-small-cell lung cancer Icotinib EGFR TKIs Phase IV real-world study safety efficacy
a b s t r a c t Background: The phase 3 ICOGEN trial established the non-inferiority of icotinib to gefitinib in terms of progression-free survival (PFS) in non-small cell lung cancer (NSCLC) patients, and this led to the approval of icotinib for NSCLC by the China Food and Drug Administration. A phase 4 study was conducted to assess the safety and efficacy of icotinib in a broad range of patients with advanced NSCLC across China. Methods: This study retrospectively analyzed data from unresectable, recurrent, and/or advanced NSCLC patients who received oral icotinib 125 mg three times per day. The primary endpoint was safety. The secondary endpoints included objective response rate (ORR) and disease control rate (DCR), which were investigated overall and in subgroups such as patients with an EGFR mutation and elderly patients. Results: Between August, 2011 and August, 2012, a total of 6087 advanced NSCLC patients were registered in this study, of which 5549 were evaluable for safety and tumor response. The median age was 63 years (range 21–95 years), and 1571 (28.3%) patients were over the age of 70. The majority of patients were non-smokers, and had adenocarcinoma and stage IV disease. The overall incidence of adverse drug reactions (ADRs) of any grade was 31.5%. The most common ADRs included rash (17.4%) and diarrhea (8.5%), and three patients experienced interstitial lung disease (ILD). The ORR and DCR were 30.0% and 80.6%, respectively, for the overall population, and 33.4% and 81.2%, 30.3% and 80.3%, and 30.4% and 89.3%, for first-line, second-line, and third-line or multiple line subsets, respectively. In 665 EGFR-mutated patients who were evaluable for tumor response, the ORR and DCR were 49.2% (327/665) and 92.3% (614/665), respectively.
∗ Corresponding author. Tel.: +86 21 25070357/10 67781331x8519; fax: +86 10 67734107. E-mail address: [email protected] (Y. Sun). 1 These authors contributed equally to this work. http://dx.doi.org/10.1016/j.lungcan.2014.08.014 0169-5002/© 2014 Elsevier Ireland Ltd. All rights reserved.
208
X. Hu et al. / Lung Cancer 86 (2014) 207–212
Conclusions: The data from over 6000 patients was consistent with the results of the ICOGEN study. Icotinib demonstrated a favorable toxicity profile and efficacy in the routine clinical setting. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
2.2. Assessments
Lung cancer is one of the most common malignancies, accounting for millions of deaths worldwide, yet its treatment remains a challenge for the medical world [1]. Non-small cell lung cancer (NSCLC) comprises about 85% of lung cancer [2]. Most NSCLC patients are at an advanced stage when diagnosed, leaving systemic chemotherapy as the only treatment option. Systemic chemotherapy prolongs survival compared with best supportive care alone; however, the standard of care chemotherapy is associated with side effects, especially in elderly patients and those with a poor performance status [3]. The discovery and development of targeted agents have had a major impact on the treatment of NSCLC. Several small-molecular targeted agents have been approved for the treatment of lung cancer since 2002: gefitinib, erlotinib, icotinib, crizotinib, and afatinib, and all of them have greatly improved the survival of NSCLC patients as compared to chemotherapy. Icotinib (Commana, Betta Pharmaceuticals Co., Ltd, Hangzhou, China) is a highly potent, orally active, epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor (TKI) [4]. Icotinib displayed a favorable toxicity profile in phase 1 studies [5,6]. In a phase 2 study, icotinib provided a PFS of 4.6 months for pretreated NSCLC patients [7], and the tolerable and effective range of icotinib was 100–625 mg three times per day [8]. These results were subsequently confirmed in further studies [9,10]. In the phase 3 ICOGEN study, icotinib yielded a non-inferior PFS when compared to another EGFR-TKI, gefitinib (4.6 [3.5–6.3] months vs. 3.4 [2.3–3.8] months; p = 0.13), in patients with advanced NSCLC, who had progressed after receiving at least one line of chemotherapy [9]. Moreover, the incidence rates of adverse reactions (60.5% vs. 70.4%; p = 0.045) and drug-related diarrhea (18.5% vs. 27.6%; p = 0.03) in the icotinib arm were significantly lower than those in the gefitinib arm, and no treatment-related deaths nor interstitial lung disease (ILD) were reported in either groups [9]. Based on this study, icotinib was approved by the China Food and Drug Administration as second- or third-line treatment for advanced NSCLC. Since icotinib is an investigational new drug, further assessment of its safety and efficacy in a broad range of patients is warranted. With this in mind, we examined our data retrospectively to assess the real-world utilization of icotinib in NSCLC patients.
Safety and tolerability assessments were conducted in patients who received at least one dose of icotinib. Safety data included drug-related adverse events (adverse reactions, ADRs); and clinically significant abnormal complete blood count and liver function laboratory. ADRs were graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 3.0 (CTCAEv3) and were coded by the Medical Dictionary for Regulatory Activities (MedDRA) version 12.1. Icotinib-related serious adverse events (SAEs) and treatment withdrawal were also recorded. Tolerability in elderly patients was also included as a safety concern. Physician-based tumor response data were collected for efficacy assessment, in patients who received at least one cycle 4-week cycle of icotinib treatment. Efficacy was assessed by tumor response and defined as the sum of complete remission (CR) or partial response (PR) according to computerized tomography (CT scan). Magnetic resonance imaging (MRI) was utilized to evaluate intracranial lesions. Treating physicians assessed tumor responses with the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Tumor responses were evaluated one month after the first administration of icotinib and then at least every two months. The relationship between efficacy and EGFR mutation was explored in patients who had undergone an EGFR mutation test.
2. Methods
2.3. Statistical analysis Descriptive methods including frequency and percentage were used for analysis. The safety analysis population included patients who received any dose of icotinib, and the intention-to-treat population included patients who received at least one cycle 4-week of icotinib. The primary endpoint was safety, and this was defined by any ADRs after administration of icotinib and laboratory values obtained at each visit. The ADR coding complied with MedDRA (version 12.1). Baseline information included demographic data, vital signs, medical and treatment history, histological type, stage of disease, genetic tests, laboratory tests, tumor response, and the incidence of adverse reactions. The objective response rate (ORR) was defined as the sum of CR and PR, and the disease control rate (DCR) was defined as the sum of CR, PR and stable disease (SD). Logistic regression models were utilized to further explore the relationship between baseline characteristics and tumor response. Subgroup analyses were performed in patients with an identified EGFR status and elderly patients.
2.1. Patients and study design 3. Results This retrospective study analyzed data from patients diagnosed with advanced NSCLC who were prescribed icotinib between August, 2011 and August, 2012. Patients who unresectable, recurrent, and/or advanced NSCLC confirmed by histopathology or cytology were eligible for the study. Icotinib (125 mg tablet, Betta Pharmaceuticals Co., Ltd, Zhejiang, China) was administered orally three times per day on a 4-week cycle until disease progression or occurrence of intolerable toxicity. The primary objective was to assess the safety of icotinib, paying close attention to newly occurring and serious adverse reactions (SAR). The secondary objectives included tumor response and the safety and efficacy of icotinib in elderly patients or those with an EGFR mutation.
3.1. Baseline characteristics From August, 2011 to August, 2012 a total of 6087 patients from 480 hospitals were enrolled in the study. Of these, 5548 were evaluable for safety and tumor response. A total of 538 patients were excluded from the safety and efficacy assessments, including 360 patients who were lost to follow-up, and 109 patients who did not complete at least one course of treatment (Fig. 1). The baseline characteristics are summarized in Table 1. The median age was 63 years (range 21–95 years). The majority of patients had adenocarcinoma (78.6%), and 90.2% had stage IV
X. Hu et al. / Lung Cancer 86 (2014) 207–212
209
Table 1 Baseline patient characteristics. Characteristics
First-line
Age
