Kelli Snyders1, Doah Cho2, Jun Hee Hong1, Sally Lord2,3, Rebecca Asher2, Ian Marschner2,4, Chee Khoon Lee1,2. 1. Cancer Care Centre, St George Hospital, Kogarah, Australia. 2. National Health and Medical Research Council Clinical Trials Centre, Camperdown, Australia. 3. School of Medicine, The University of Norte Dame, Darlinghurst, Australia. 4. Department of Statistics, Macquarie University, Sydney, Australia.
Abstract
Background: Recent trials of novel agents in 'rare' molecular subtypes of non-small cell lung cancer (NSCLC) have used single-arm trial designs and benchmarked outcomes against historical controls. We assessed the consistency of historical control outcomes using docetaxel data from published NSCLC randomized controlled trials (RCTs).Material and methods: Advanced NSCLC RCTs including a docetaxel monotherapy arm were included. Heterogeneity in tumor objective response rates (ORRs), progression-free survival (PFS) and overall survival (OS), and correlations between outcomes and year of trial commencement were assessed. Results: Among 63 trials (N = 10,633) conducted between 2000 and 2017, ORR ranged from 0% to 26% (I2 = 76.1%, pheterogeneity < .0001). Mean of the median PFS was 3.0 months (range: 1.4-6.4), 3-month PFS ranged from 25% to 85% (I2 = 86.0%, pheterogeneity < .0001). Mean of the median OS was 9.1 months (range: 4.7-22.9), 9-month OS ranged from 23% to 79% (I2 = 83.0%, pheterogeneity < .0001). Each later year of trial commencement was associated with 0.3% (p = .046), 0.5% (p = .11) and 0.9% (p = .001) improvement in ORR, 3-month PFS and 9-month OS rates, respectively.Conclusions: There was significant heterogeneity and an improving trend in docetaxel outcomes across trials conducted over 20 years. Benchmarking biomarker-targeted agents against historical controls may not be a valid approach to replace RCTs. Innovative study designs involving a concurrent control arm should be considered.
Background: Recent trials of novel agents in 'rare' molecular subtypes of non-small cell lung cancer (NSCLC) have used single-arm trial designs and benchmarked outcomes against historical controls. We assessed the consistency of historical control outcomes using docetaxel data from published NSCLC randomized controlled trials (RCTs).Material and methods: Advanced NSCLC RCTs including a docetaxel monotherapy arm were included. Heterogeneity in tumor objective response rates (ORRs), progression-free survival (PFS) and overall survival (OS), and correlations between outcomes and year of trial commencement were assessed. Results: Among 63 trials (N = 10,633) conducted between 2000 and 2017, ORR ranged from 0% to 26% (I2 = 76.1%, pheterogeneity < .0001). Mean of the median PFS was 3.0 months (range: 1.4-6.4), 3-month PFS ranged from 25% to 85% (I2 = 86.0%, pheterogeneity < .0001). Mean of the median OS was 9.1 months (range: 4.7-22.9), 9-month OS ranged from 23% to 79% (I2 = 83.0%, pheterogeneity < .0001). Each later year of trial commencement was associated with 0.3% (p = .046), 0.5% (p = .11) and 0.9% (p = .001) improvement in ORR, 3-month PFS and 9-month OS rates, respectively.Conclusions: There was significant heterogeneity and an improving trend in docetaxel outcomes across trials conducted over 20 years. Benchmarking biomarker-targeted agents against historical controls may not be a valid approach to replace RCTs. Innovative study designs involving a concurrent control arm should be considered.