Tyrosine Kinase Inhibitor versus Physician Choice Chemotherapy in Second-Line Epidermal Growth Factor Receptor Mutation Non-Small Cell Lung Cancer: Post hoc Analysis of Randomized Control Trial

Abstract

Background: There is a paucity of prospective data for patients who progressed after first-line tyrosine kinase inhibitor (TKI) or pemetrexed doublet among epidermal growth factor receptor (EGFR) mutation-positive metastatic non-small cell lung cancer (NSCLC). Aim: The aim of the study was to evaluate the outcome of second-line therapy in patients who progressed on TKI or pemetrexed doublet in EGFR mutation-positive NSCLC. Objective: The objective of the study was to calculate response rates, progression-free survival (PFS), and overall survival (OS) of patients receiving second-line therapy in EGFR mutation NSCLC. Materials and Methods: Post hoc analysis of second-line therapy among patients enrolled in randomized control trial comparing TKI versus pemetrexed doublet in EGFR mutation NSCLC. Kaplan–Meir statistics were used for PFS and OS. Impact of variables was measured with Log-rank test. Results: One hundred and eighty-seven patients who progressed on first-line therapy and received second-line agents were analyzed. Male:female: 110 (56.3%):77 (41.2%). One hundred and thirteen patients received gefitinib, while 74 received chemotherapy. Response rate (complete response + partial response) was 53% versus 24% in gefitinib versus chemotherapy group (RECIST v1.1). PFS was 7.4 months versus 4.4 months (P = 0.001), while OS was 14 months versus 9.7 months (P = 0.007), in gefitinib versus chemotherapy group, respectively. Response to TKI significantly improves PFS (10.8 months vs. 3.9 months, P = 0.001) and OS (21.4 months vs. 8.9 months, P = 0.03). Rash, pruritus, dry skin, fatigue, diarrhea, and paronychia were common toxicities of TKI. Conclusion: Second-line TKI improves outcome in EGFR mutation-positive NSCLC who progressed after first-line chemotherapy. Response to therapy, whether with TKI or chemotherapy, favorably impacts outcomes.

Keywords

Gefitinib - pemetrexed - second-line lung cancer

Publication History

Article published online:
17 June 2021

• References

• 1 D’Addario G, Pintilie M, Leighl NB, Feld R, Cerny T, Shepherd FA. et al. Platinum-based versus non-platinum-based chemotherapy in advanced non-small-cell lung cancer: A meta-analysis of the published literature. J Clin Oncol 2005; 23: 2926-36
• 2 Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C. et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 2008; 26: 3543-51
• 3 Lee CK, Brown C, Gralla RJ, Hirsh V, Thongprasert S, Tsai CM. et al. Impact of EGFR inhibitor in non-small cell lung cancer on progression-free and overall survival: A meta-analysis. J Natl Cancer Inst 2013; 105: 595-605
• 4 Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C. et al. Final overall survival results from a randomised, phase III study of erlotinib versus chemotherapy as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer (OPTIMAL, CTONG-0802). Ann Oncol 2015; 26: 1877-83
• 5 Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E. et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): A multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012; 13: 239-46
• 6 Wu YL, Zhou C, Liam CK, Wu G, Liu X, Zhong Z. et al. First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: Analyses from the phase III, randomized, open-label, ENSURE study. Ann Oncol 2015; 26: 1883-9
• 7 Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N. et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361: 947-57
• 8 Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, Sriuranpong V. et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol 2011; 29: 2866-74
• 9 Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J. et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): An open label, randomised phase 3 trial. Lancet Oncol 2010; 11: 121-8
• 10 Inoue A, Kobayashi K, Maemondo M, Sugawara S, Oizumi S, Isobe H. et al. Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naïve non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002). Ann Oncol 2013; 24: 54-9
• 11 Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H. et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010; 362: 2380-8
• 12 Sequist LV, Yang JC, Yamamoto N, O’Byrne K, Hirsh V, Mok T. et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013; 31: 3327-34
• 13 Yang JC, Hirsh V, Schuler M, Yamamoto N, O’Byrne KJ, Mok TS. et al. Symptom control and quality of life in LUX-lung 3: A phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013; 31: 3342-50
• 14 Patil VM, Noronha V, Joshi A, Choughule AB, Bhattacharjee A, Kumar R. et al. Phase III study of gefitinib or pemetrexed with carboplatin in EGFR-mutated advanced lung adenocarcinoma. ESMO Open 2017; 2: e000168
• 15 Chougule A, Prabhash K, Noronha V, Joshi A, Thavamani A, Chandrani P. et al. Frequency of EGFR mutations in 907 lung adenocarcioma patients of Indian ethnicity. PLoS One 2013; 8: e76164
• 16 Noronha V, Prabhash K, Thavamani A, Chougule A, Purandare N, Joshi A. et al. EGFR mutations in Indian lung cancer patients: Clinical correlation and outcome to EGFR targeted therapy. PLoS One 2013; 8: e61561
• 17 Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J. et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004; 22: 1589-97
• 18 Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard JY. et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 trial) [corrected]. J Clin Oncol 2003; 21: 2237-46
• 19 Kris MG, Natale RB, Herbst RS, Lynch Jr. TJ, Prager D, Belani CP. et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: A randomized trial. JAMA 2003; 290: 2149-58
• 20 Cufer T, Vrdoljak E, Gaafar R, Erensoy I, Pemberton K. SIGN Study Group. Phase II, open-label, randomized study (SIGN) of single-agent gefitinib (IRESSA) or docetaxel as second-line therapy in patients with advanced (stage IIIb or IV) non-small-cell lung cancer. Anticancer Drugs 2006; 17: 401-9
• 21 Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL. et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): A randomised phase III trial. Lancet 2008; 372: 1809-18
• 22 Maruyama R, Nishiwaki Y, Tamura T, Yamamoto N, Tsuboi M, Nakagawa K. et al. Phase III study, V-15-32, of gefitinib versus docetaxel in previously treated Japanese patients with non-small-cell lung cancer. J Clin Oncol 2008; 26: 4244-52
• 23 Lee DH, Park K, Kim JH, Lee JS, Shin SW, Kang JH. et al. Randomized phase III trial of gefitinib versus docetaxel in non-small cell lung cancer patients who have previously received platinum-based chemotherapy. Clin Cancer Res 2010; 16: 1307-14
• 24 Douillard JY, Shepherd FA, Hirsh V, Mok T, Socinski MA, Gervais R. et al. Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: Data from the randomized phase III INTEREST trial. J Clin Oncol 2010; 28: 744-52