Benchmarking single-arm studies against historical controls from non-small cell lung cancer trials–an empirical analysis of bias

Kelli Snyders, Doah Cho*, Jun Hee Hong, Sally Lord, Rebecca Asher, Ian Marschner, Chee Khoon Lee

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    1 Citation (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)90-95
    Number of pages6
    JournalActa Oncologica
    Volume59
    Issue number1
    DOIs
    Publication statusPublished - 2020

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