Use of intermediate clinical endpoints (ICE) as a primary efficacy endpoint in malignant melanoma.

Abstract

e21075 Background: Melanoma incidence in the US has seen a considerable increase, from 17.8 (1997) to 24.0 (2013) per 100,000, with localized melanoma accounting for 84% of all cases. Early detection and treatment can improve outcomes considerably, resulting in a 99% survival rate. The FDA, within its accelerated approval program, accepts ICE as a primary endpoint, shortening time for patient access to life saving medications. Our objective was to study use of ICE as a primary endpoint for therapies targeting non-metastatic/early-stage malignant melanoma. Methods: A systematic review was conducted in PubMed to identify clinical trials using ICE as a primary endpoint in early stage (non-metastatic, stage I or II) malignant melanoma. An additional search was conducted in clinicaltrials.gov to identify ICE as a primary endpoint in on-going malignant melanoma trials (assess evidence body being built). Searches were limited to the English language, between November 2011 and October 2016. Studies reporting only overall survival (OS) as the primary endpoint were excluded. Results: Of the 226 titles and abstracts screened from PubMed, seven trials were included in the analysis. Of 440 records screened from www.clinicaltrials.gov, one was included, resulting in eight studies of randomized phase 3 trials. Relapse-free survival (RFS) and disease-free survival (DFS) were reported in 3 trials each, and represent the most frequently reported primary ICE (38% each). RFS/DFS is defined as the time from randomization to recurrence of disease or death, and combined, encompass 75% of reported ICE. Other ICE reported were distant metastasis free interval (DMFI, 1 trial) and lymphnode field relapse (1 trial). One trial reported OS as a co-primary endpoint. Conclusions: Definitions of the most observed ICE in malignant melanoma, namely, RFS and DFS, appear to overlap, warranting further investigation into consolidation of outcomes to better assess the value of intermediate endpoints in early stage malignant melanoma. Findings indicate a slow, but growing body of evidence supporting ICE as a primary endpoint in malignant melanoma, bringing focus to prevention or delay of disease progression to alleviate patient burden.