P76.68 The Impact of Eligibility for Anti-Angiogenic Treatment to the Prognosis of Patients with Non-Small Cell Lung Cancer Harboring EGFR Mutations

Abstract

Previous studies described the efficacy of erlotinib plus angiogenesis inhibitors (bevacizumab/ramucirumab) combination therapy compared with erlotinib monotherapy in epidermal growth factor receptor (EGFR) mutation positive non-small cell lung cancer (NSCLC), regardless of EGFR activating mutation subtype. However, the impact of angiogenesis inhibitors’ eligibility criteria to progression free survival (PFS) and overall survival (OS) is still unclear. Hence, we evaluated the impact of angiogenesis inhibitors’ criteria in patients with NSCLC harboring EGFR activating mutation. We retrospectively collected data of patients with EGFR mutation positive NSCLC who were treated with EGFR tyrosine kinase inhibitor (EGFR-TKI) monotherapy at Shizuoka Cancer Center between 2002 and 2019. Patients whose performance status (PS) was over 3, and those with symptomatic brain metastasis, were excluded from this study. Angiogenesis inhibitors ineligibility was defined as having at least one following conditions; 1) a history of bloody sputum or an exposure of tumor in bronchus, 2) radiologically identified major vessel invasion, 3) a history of cardiovascular disease and 4) history of chemoradiotherapy prior to EGFR-TKI treatment. They were divided into two groups, angiogenesis inhibitors eligible group (AI fit group) and ineligible group (unfit group). A total of 452 patients with NSCLC harboring EGFR activating mutation were included in this study. Among 452 patients, 207 patients had L858R mutation, and 245 patients had exon19 deletion. Median age of all patients was 71 years old (range 31-92), 35.0% were male, 43.1% had history of smoking, and majority of the patients were treated with gefitinib or erlotinib as a first EGFR-TKI (60.3% and 18.8%). AI fit group included 339 patients; 152 patients (44.8%) had L858R and 187 patients (55.2%) had exon19 deletion. In baseline characteristics, patients with PS 2 were more frequently observed in AI unfit group compared with AI fit group. The median PFS of AI fit and unfit group were 12.9 month and 9.6 months (HR 0.72, 95%CI 0.57-0.92, p=0.007), and multivariate analysis indicated PS 2 and AI unfit were associated with shorter PFS. Also, OS was significantly longer in AI fit groups than in unfit group; median OS were 33.0 months and 18.5months, respectively (HR 0.58, 95%CI 0.45-0.74, p<0.001). Multivariate analysis indicated PS 2, AI unfit, EGFR exon 19 deletion, and age ≥75 as significant prognostic factors. Out of four AI eligibility definitions, bloody sputum or exposure of tumor in bronchus were significantly associated with poor PFS (HR 1.43, 95%CI 1.07-1.98 p=0.017) and OS (HR 1.67, 95%CI 1.18-2.36 p=0.004). There was no significant difference in PFS between EGFR mutation subtypes in AI fit group; median PFS were 11.5months in L858R mutation and 13.8months in exon19 deletion (HR 0.85, 95%CI 0.67-1.07 p=0.17). In EGFR mutation positive NSCLC patients, the eligibility of AI was associated with longer PFS and OS, and resulted in insignificance of PFS between L858R and exon19 deletion group. Since these selection bias may have affected previous clinical trials data showing the efficacy of AI plus EGFR-TKI, the results of clinical trials should be carefully considered of its benefits.