Evaluation of pathological complete response as a surrogate endpoint for overall survival in resectable oesophageal cancer: integrated analysis of individual patient data from phase III trials
Jun Okui, Kengo Nagashima, Satoru Matsuda, Yasunori Sato, Hirofumi Kawakubo, Thomas Ruhstaller, Peter Thuss‐Patience, Magnus Nilsson, Fredrik Klevebro, Lijie Tan, Shaoyuan Zhang, Thomas Aparicio, Guillaume Piessen, Charlène J. van der Zijden, Bianca Mostert, Bas P. L. Wijnhoven, Takahiro Tsushima, Hiroya Takeuchi, Ken Kato, Yuko Kitagawa
Abstract
BACKGROUND: Overall survival (OS) is the standard endpoint for oncological treatment efficacy, but requires long follow-up. The aim of this study was to evaluate pCR as a surrogate for OS in oesophageal cancer. METHODS: An integrated analysis of individual patient data (IPD) from phase III trials comparing perioperative therapies for resectable oesophageal and gastro-oesophageal junction cancer was conducted. Individual-level surrogacy between pCR and OS was assessed using Kendall's rank correlation coefficient (τ). A τ of 0.8 was considered a threshold for a good surrogate. As no method estimating τ between an ordinal endpoint and OS has been reported, a new method was proposed using the inverse-probability-of-censoring weighted estimator adjusted for tied data. RESULTS: Of 22 eligible trials, 10 provided IPD for 1641 patients, including 624 who received neoadjuvant chemotherapy (NAC; 45 (7.2%) achieved pCR) and 1017 who received neoadjuvant chemoradiotherapy (NACRT; 299 (29.4%) achieved pCR). In the NAC subgroup, patients with pCR had an HR for OS of 0.12 (95% c.i. 0.05 to 0.33), the C-index was 0.54 (95% c.i. 0.52 to 0.56), and τ was 0.256. In the NACRT subgroup, the HR was 0.57 (95% c.i. 0.47 to 0.70), the C-index was 0.56 (95% c.i. 0.54 to 0.58), and τ was 0.174. Hypothetical data suggested that achieving strong surrogacy (τ of 0.8) required an HR of 0.09 (95% c.i. 0.07 to 0.11). CONCLUSION: Although pCR was correlated with OS, no evidence of individual-level surrogacy with OS was demonstrated, making it inappropriate to consider pCR as a surrogate endpoint for OS in resectable oesophageal cancer.