Generalization and representativeness of phase III immune checkpoint inhibitor trials in NSCLC

Abstract

Background: Immune checkpoint inhibitors (ICBs) have become standard treatment in platinum-failed non-small cell lung cancer (NSCLC) based on several phase III studies. Recent randomized phase III trials have led to the approval of ICB. However, strict criteria for patient enrollment of phase III trials raise questions regarding generalization in the real world. The aim of this study was to evaluate whether pivotal phase III trials using ICB represent the real world NSCLC patients. Methods: We reviewed the inclusion/exclusion criteria of 3 practice changing phase III trials (CheckMate057, CheckMate017, KEYNOTE-010). Availability of tumor tissue and other exclusion criteria for KEYNOTE-010 were additionally checked. We retrospectively analyzed the database of stage IIIB or IV NSCLC patients diagnosed from 2011 to 2013 at Seoul National University Hospital (cohort 1). We also analyzed the criteria in 53 NSCLC patients who have treated with nivolumab or pembrolizumab as a routine practice (cohort 2). Results: Among the 715 NSCLC patients in cohort 1, 499 (69.9%) were ineligible for 3 trials. Reasons for ineligibility were as follows: no platinum doublet 23.6%, lack of tissue 22.7%, the Eastern Cooperative Oncology Group performance status > 1 14.1%, steroid use 18.2%, active central nervous system metastasis 8.3%, hepatitis B or C virus/ human immunodeficiency virus 8.0% and no measurable lesion 7.3%. EGFR mutation was more common in ineligible group than eligible group (44.7% vs 19.7%, P<0.001) In cohort 2 which comprise 53 patients who received ICB as a routine practice, 67.9% were classified as ineligible group. Treatment outcomes of ICB in cohort 2 seems to be inferior than those of 3 trials: response rate of 11.3%, disease control rate of 26.4%, and median progression-free survival of 1.67 months. Conclusions: Only 30.2% of NSCLC patients were eligible for ICB phase III trial. Although ICB have approved for all platinum-failed NSCLC, the real world efficacy of 60% ineligible patients were still unknown. These findings suggest that a huge gap between the practice changing phase III trials and real world NSCLC patients.