Benchmarking single-arm studies against historical controls from non-small cell lung cancer trialsan empirical analysis of bias
Publication Details
Snyders, K.,
Cho, D.,
Hong, J.,
Lord, S.,
Asher, R.,
Marschner, i.,
&
Lee, C.
(2020).
Benchmarking single-arm studies against historical controls from non-small cell lung cancer trialsan empirical analysis of bias.
Acta Oncologica, 59 (1), 90-95.
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 (N¼10,633) conducted between 2000 and 2017, ORR ranged from 0% to26% (I2¼76.1%,pheterogeneity<.0001). Mean of the median PFS was 3.0 months (range: 1.4–6.4), 3-month PFS ranged from 25% to 85% (I2¼86.0%,pheterogeneity<.0001). Mean of the median OS was 9.1months (range: 4.7–22.9), 9-month OS ranged from 23% to 79% (I2¼83.0%,pheterogeneity<.0001). Each later year of trial commencement was associated with 0.3% (p¼.046), 0.5% (p¼.11) and 0.9%(p¼.001) 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.
Abbreviations: NSCLC: non-small cell lung cancer; RCTs: randomized controlled trials; ORR: objective response rate; PFS: progression-free survival; OS: overall survival; CIs: confidence intervals; RECIST: Response Evaluation Criteria In Solid Tumors; PFS3: 3-month progression-free survival rate; OS9: 9-month overall survival rate
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