Gefitinib Versus Vinorelbine Plus Cisplatin as Adjuvant Treatment for Stage II-IIIA (N1-N2) EGFR-Mutant NSCLC: Final Overall Survival Analysis of CTONG1104 Phase III Trial
Wen-Zhao Zhong, Qun Wang, Wei-Min Mao, Song-Tao Xu, Lin Wu, Yu-Cheng Wei, Yong-Yu Liu, Chun Chen, Ying Cheng, Rong Yin, Fan Yang, Sheng-Xiang Ren, Xiao-Fei Li, Jian Li, Cheng Huang, Zhi-Dong Liu, Shun Xu, Ke-Neng Chen, Shi-Dong Xu, Lun-Xu Liu, Ping Yu, Bu-Hai Wang, Hai-Tao Ma, Jin-Ji Yang, Hong-Hong Yan, Xue-Ning Yang, Si-Yang Liu, Qing Zhou, Yi-Long Wu, Wen-Zhao Zhong, Qun Wang, Wei-Min Mao, Song-Tao Xu, Lin Wu, Yu-Cheng Wei, Yong-Yu Liu, Chun Chen, Ying Cheng, Rong Yin, Fan Yang, Sheng-Xiang Ren, Xiao-Fei Li, Jian Li, Cheng Huang, Zhi-Dong Liu, Shun Xu, Ke-Neng Chen, Shi-Dong Xu, Lun-Xu Liu, Ping Yu, Bu-Hai Wang, Hai-Tao Ma, Jin-Ji Yang, Hong-Hong Yan, Xue-Ning Yang, Si-Yang Liu, Qing Zhou, Yi-Long Wu
Abstract
Purpose: ADJUVANT-CTONG1104 (ClinicalTrials.gov identifier: NCT01405079), a randomized phase III trial, showed that adjuvant gefitinib treatment significantly improved disease-free survival (DFS) versus vinorelbine plus cisplatin (VP) in patients with epidermal growth factor receptor (EGFR) mutation-positive resected stage II-IIIA (N1-N2) non-small-cell lung cancer (NSCLC). Here, we report the final overall survival (OS) results.
Methods: From September 2011 to April 2014, 222 patients from 27 sites were randomly assigned 1:1 to adjuvant gefitinib (n = 111) or VP (n = 111). Patients with resected stage II-IIIA (N1-N2) NSCLC and EGFR-activating mutation were enrolled, receiving gefitinib for 24 months or VP every 3 weeks for four cycles. The primary end point was DFS (intention-to-treat [ITT] population). Secondary end points included OS, 3-, 5-year (y) DFS rates, and 5-year OS rate. Post hoc analysis was conducted for subsequent therapy data.
Results: Median follow-up was 80.0 months. Median OS (ITT) was 75.5 and 62.8 months with gefitinib and VP, respectively (hazard ratio [HR], 0.92; 95% CI, 0.62 to 1.36; P = .674); respective 5-year OS rates were 53.2% and 51.2% (P = .784). Subsequent therapy was administered upon progression in 68.4% and 73.6% of patients receiving gefitinib and VP, respectively. Subsequent targeted therapy contributed most to OS (HR, 0.23; 95% CI, 0.14 to 0.38) compared with no subsequent therapy. Updated 3y DFS rates were 39.6% and 32. 5% with gefitinib and VP (P = .316) and 5y DFS rates were 22. 6% and 23.2% (P = .928), respectively.
Conclusion: Adjuvant therapy with gefitinib in patients with early-stage NSCLC and EGFR mutation demonstrated improved DFS over standard of care chemotherapy. Although this DFS advantage did not translate to a significant OS difference, OS with adjuvant gefitinib was one of the longest observed in this patient group compared with historic data.
Figures
References
- Burdett S Pignon JP Tierney J, et al. : Adjuvant chemotherapy for resected early-stage non-small cell lung cancer. Cochrane Database Syst Rev CD011430, 2015
- Cheng H Li XJ Wang XJ, et al. : A meta-analysis of adjuvant EGFR-TKIs for patients with resected non-small cell lung cancer. Lung Cancer 137:7-13, 2019
- Yuan Y Huang Q Gu C, et al. : Disease-free survival improved by use of adjuvant EGFR tyrosine kinase inhibitors in resectable non-small cell lung cancer: an updated meta-analysis. J Thorac Dis 9:5314-5321, 2017
- Pisters KM Evans WK Azzoli CG, et al. : Cancer Care Ontario and American Society of Clinical Oncology adjuvant chemotherapy and adjuvant radiation therapy for stages I-IIIA resectable non small-cell lung cancer guideline. J Clin Oncol 25:5506-5518, 2007
- Xiu-Yi Zhi Jin-Ming Yu, and Yuan-Kai Shi. Chinese guidelines on the diagnosis and treatment of primary lung cancer (2015 version). Cancer 121:3165-3181, 2015. Cancer 122:162, 2016
- Eberhardt WE De Ruysscher D Weder W, et al. : 2nd ESMO Consensus Conference in Lung Cancer: Locally advanced stage III non-small-cell lung cancer. Ann Oncol 26:1573-1588, 2015
- Ettinger DS Wood DE Aggarwal C, et al. : NCCN guidelines insights: Non-small cell lung cancer, version 1.2020. J Natl Compr Canc Netw 17:1464-1472, 2019
- Kris MG Gaspar LE Chaft JE, et al. : Adjuvant systemic therapy and adjuvant radiation therapy for stage I to IIIA completely resected non-small-cell lung cancers: American Society of Clinical Oncology/Cancer Care Ontario Clinical Practice Guideline Update. J Clin Oncol 35:2960-2974, 2017
- Goldstraw P Chansky K Crowley J, et al. : The IASLC lung cancer staging project: proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer. J Thorac Oncol 11:39-51, 2016
- Colt HG Murgu SD Korst RJ, et al. : Follow-up and surveillance of the patient with lung cancer after curative-intent therapy: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 143:e437S-e454S, 2013
- Deng XF Jiang L Liu QX, et al. : Lymph node micrometastases are associated with disease recurrence and poor survival for early-stage non-small cell lung cancer patients: a meta-analysis. J Cardiothorac Surg 11:28, 2016
- Mok TS Wu YL Thongprasert S, et al. : Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947-957, 2009
- Zhong WZ Wang Q Mao WM, et al. : Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): A randomised, open-label, phase 3 study. Lancet Oncol 19:139-148, 2018
- Yue D Xu S Wang Q, et al. : Erlotinib versus vinorelbine plus cisplatin as adjuvant therapy in Chinese patients with stage IIIA EGFR mutation-positive non-small-cell lung cancer (EVAN): A randomised, open-label, phase 2 trial. Lancet Res Med 6:863-873, 2018
- Pennell NA Neal JW Chaft JE, et al. : SELECT: A phase II trial of adjuvant erlotinib in patients with resected epidermal growth factor receptor-mutant non-small-cell lung cancer. J Clin Oncol 37:97-104, 2019
- Pocock SJ, Simon R: Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Biometrics 31:103-115, 1975
- Gyawali B, Hey SP, Kesselheim AS: Evaluating the evidence behind the surrogate measures included in the FDA's table of surrogate endpoints as supporting approval of cancer drugs. EClinicalMedicine 21:100332, 2020
- Mauguen A Pignon JP Burdett S, et al. : Surrogate endpoints for overall survival in chemotherapy and radiotherapy trials in operable and locally advanced lung cancer: A re-analysis of meta-analyses of individual patients' data. Lancet Oncol 14:619-626, 2013
- Oxnard GR Janjigian YY Arcila ME, et al. : Maintained sensitivity to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer recurring after adjuvant erlotinib or gefitinib. Clin Cancer Res 17:6322-6328, 2011
- Zhou Q Song Y Zhang X, et al. : A multicenter survey of first-line treatment patterns and gene aberration test status of patients with unresectable stage IIIB/IV nonsquamous non-small cell lung cancer in China (CTONG 1506). BMC Cancer 17:462, 2017
- Kelly K Altorki NK Eberhardt WE, et al. : Adjuvant erlotinib versus placebo in patients with stage IB-IIIA non-small-cell lung cancer (RADIANT): A randomized, double-blind, phase III trial. J Clin Oncol 33:4007-4014, 2015
- Zhong WZ Chen KN Chen C, et al. : Erlotinib versus gemcitabine plus cisplatin as neoadjuvant treatment of stage IIIA-N2 EGFR-mutant non–small-cell lung cancer (EMERGING-CTONG 1103): A randomized phase II study. J Clin Oncol 37:2235-2245, 2019
- Wu YL Herbst RS Mann H, et al. : ADAURA: Phase III, double-blind, randomized study of osimertinib versus placebo in egfr mutation-positive early-stage NSCLC after complete surgical resection. Clin Lung Cancer 19:e533-e536, 2018
- Xu ST Xi J-J Zhong WZ, et al. : The unique spatial-temporal treatment failure patterns of adjuvant gefitinib therapy: A post hoc analysis of the ADJUVANT trial (CTONG 1104). J Thorac Oncol 14:503-512, 2019
- Wu YL Tsuboi M He J, et al. : Osimertinib in resected EGFR-mutated non–small-cell lung cancer. N Engl J Med 383:1711-1723, 2020
Source: PubMed