Treatment Effect Reanalysis of the Randomized Individual Screening Trial of Innovative Glioblastoma Therapy in Newly Diagnosed Glioblastoma With External Control Data

PURPOSE: -methylguanine-DNA methyltransferase-unmethylated glioblastoma (ClinicalTrials.gov identifier: NCT02977780). To evaluate the validity of using external data sets, we compared treatment effect estimates based on internal INSIGhT control data and matched external control data. METHODS: The three experimental arms of INSIGhT (abemaciclib [n = 72], neratinib [n = 80], and CC-115 [n = 12]) did not improve survival compared with internal controls (standard chemoradiation [n = 70]). We derived external control patient-level data from multiple real-world and clinical trial data sets. We applied propensity score matching and Cox proportional hazards models to estimate treatment effects with external controls. Additionally, using this glioblastoma (GBM) data collection, we specified simulation scenarios to evaluate trial designs that integrate external controls. RESULTS: After matching to external controls, no survival benefit was observed for patients receiving abemaciclib (hazard ratio [HR], 1.00 [95% CI, 0.75 to 1.34]), neratinib (HR, 0.93 [95% CI, 0.70 to 1.24]), or CC-115 (HR, 0.88 [95% CI, 0.41 to 1.88]). Simulations, together with the INSIGhT data and a collection of GBM data sets, allowed us to examine efficiencies and risks of clinical trial designs that leverage external control data. CONCLUSION: The use of carefully matched external controls, to replace or augment the internal controls of INSIGhT, produced treatment effect estimates that were similar to previously published analyses. Single-arm trial designs and hybrid randomized designs incorporating propensity score-matched external control data evaluated treatment effects in the early-phase testing of experimental therapies in newly diagnosed GBM. The validity of this approach and risks of bias depended on the availability of comprehensive and accurate data on all potential confounders, in the absence of unmeasured confounding.

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Journal
Journal of Clinical Oncology
Published
2026-05-22
DOI
https://doi.org/10.1200/jco-25-01586
Primary Topic
Advanced Causal Inference Techniques
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article
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article

Treatment Effect Reanalysis of the Randomized Individual Screening Trial of Innovative Glioblastoma Therapy in Newly Diagnosed Glioblastoma With External Control Data

Keith Lloyd Ligon, Wenya Linda Bi, Ingo K. Mellinghoff, L. Burt Nabors et al.
Journal of Clinical Oncology
Advanced Causal Inference Techniques
article

Treatment Effect Reanalysis of the Randomized Individual Screening Trial of Innovative Glioblastoma Therapy in Newly Diagnosed Glioblastoma With External Control Data

Keith Lloyd Ligon, Wenya Linda Bi, Ingo K. Mellinghoff, L. Burt Nabors, Jaroslaw Hepel, Mary R. Welch, Ayal Aizer, Pier Paolo Peruzzi, Mark R. Gilbert, David M. Meredith, Christine Lu‐Emerson, David A. Reardon, Mei‐Yin C. Polley, Tulika Rudra Gupta, E Galanis, Mehdi Touat, Tracy T. Batchelor, Lorenzo Trippa, Eudocia Q. Lee, Jan Drappatz, L. Nayak, Rameen Beroukhim, Manmeet S. Ahluwalia, Rifaquat Rahman, E Antonio Chiocca, Robert Redd, Sandro Santagata, Heinrich Elinzano, Daphne Haas-Kogan, Omar Arnaout, Shyam Tanguturi, David Schiff, Patrick Y. Wen, J. Ricardo McFaline-Figueroa, Howard Colman, Michael Weller, Ugonma N. Chukwueke, Lisa Doherty, Minesh P. Mehta, Thomas J. Kaley, Isabel Arrillaga-Romany, Yujue Tan
article en

Abstract

PURPOSE: -methylguanine-DNA methyltransferase-unmethylated glioblastoma (ClinicalTrials.gov identifier: NCT02977780). To evaluate the validity of using external data sets, we compared treatment effect estimates based on internal INSIGhT control data and matched external control data. METHODS: The three experimental arms of INSIGhT (abemaciclib [n = 72], neratinib [n = 80], and CC-115 [n = 12]) did not improve survival compared with internal controls (standard chemoradiation [n = 70]). We derived external control patient-level data from multiple real-world and clinical trial data sets. We applied propensity score matching and Cox proportional hazards models to estimate treatment effects with external controls. Additionally, using this glioblastoma (GBM) data collection, we specified simulation scenarios to evaluate trial designs that integrate external controls. RESULTS: After matching to external controls, no survival benefit was observed for patients receiving abemaciclib (hazard ratio [HR], 1.00 [95% CI, 0.75 to 1.34]), neratinib (HR, 0.93 [95% CI, 0.70 to 1.24]), or CC-115 (HR, 0.88 [95% CI, 0.41 to 1.88]). Simulations, together with the INSIGhT data and a collection of GBM data sets, allowed us to examine efficiencies and risks of clinical trial designs that leverage external control data. CONCLUSION: The use of carefully matched external controls, to replace or augment the internal controls of INSIGhT, produced treatment effect estimates that were similar to previously published analyses. Single-arm trial designs and hybrid randomized designs incorporating propensity score-matched external control data evaluated treatment effects in the early-phase testing of experimental therapies in newly diagnosed GBM. The validity of this approach and risks of bias depended on the availability of comprehensive and accurate data on all potential confounders, in the absence of unmeasured confounding.

Journal of Clinical Oncology
Brigham and Women's Hospital (US), Baptist Hospital of Miami (US), Centre National de la Recherche Scientifique (FR), Maine Medical Center (US), Memorial Sloan Kettering Cancer Center (US), Inserm (FR), Chicago Department of Public Health (US), University of Pittsburgh (US), Providence College (US), University of Zurich (CH), University of Utah (US), Rhode Island Hospital (US), Huntsman Cancer Institute (US), Yale Cancer Center (US), University of Alabama at Birmingham (US), Sorbonne Université (FR), University of Chicago (US), Massachusetts General Hospital (US), Baptist Health South Florida (US), University Hospital of Zurich (CH), Center for Neuro-Oncology (US), Dana-Farber Cancer Institute (US), Mayo Clinic in Arizona (US), Global Cancer Institute (US), National Cancer Institute (US), Institut du Cerveau (FR), University of Virginia (US), New York University (US), Columbia University (US)
Good health and well-being
Openalex Percentile: Top 5%
Advanced Causal Inference Techniques
DOISourceOpenAlex
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