Objective response rate targets for recurrent glioblastoma clinical trials based on the historic association between objective response rate and median overall survival

Author:

Ellingson Benjamin M12345ORCID,Wen Patrick Y6,Chang Susan M7,van den Bent Martin8,Vogelbaum Michael A9ORCID,Li Gang10,Li Shanpeng10,Kim Jiyoon10,Youssef Gilbert6,Wick Wolfgang11ORCID,Lassman Andrew B12ORCID,Gilbert Mark R13,de Groot John F7,Weller Michael14ORCID,Galanis Evanthia15ORCID,Cloughesy Timothy F216

Affiliation:

1. UCLA Brain Tumor Imaging Laboratory, Center for Computer Vision and Imaging Biomarkers , Los Angeles, California , USA

2. UCLA Neuro-Oncology Program , Los Angeles, California , USA

3. Department of Radiological Sciences , Los Angeles, California , USA

4. Department of Psychiatry and Biobehavioral Sciences , Los Angeles, California , USA

5. Department of Neurosurgery, David Geffen School of Medicine, University of California Los Angeles , Los Angeles, California , USA

6. Center for Neuro-Oncology, Dana-Farber/Brigham and Women’s Cancer Center, Harvard Medical School , Boston, Massachusetts , USA

7. Division of Neuro-Oncology, University of California San Francisco , San Francisco, California , USA

8. Brain Tumor Center at Erasmus MC Cancer Institute, University Medical Center Rotterdam , Rotterdam , Netherlands

9. Department of NeuroOncology, Moffitt Cancer Center , Tampa, Florida , USA

10. Department of Biostatistics, David Geffen School of Medicine, University of California Los Angeles , Los Angeles, California , USA

11. Neurology Clinic, University of Heidelberg and Clinical Cooperation Unit Neuro-oncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) , Heidelberg , Germany

12. Division of Neuro-Oncology, Department of Neurology, Columbia University Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, New York-Presbyterian Hospital , New York, New York , USA

13. Neuro-Oncology Branch, National Cancer Institute , Bethesda, Maryland , USA

14. Department of Neurology, University Hospital and University of Zurich, Zurich , Switzerland

15. Division of Medical Oncology, Department of Oncology, Mayo Clinic , Rochester, Minnesota , USA

16. Department of Neurology, David Geffen School of Medicine, University of California Los Angeles , Los Angeles, California , USA

Abstract

Abstract Durable objective response rate (ORR) remains a meaningful endpoint in recurrent cancer; however, the target ORR for single-arm recurrent glioblastoma trials has not been based on historic information or tied to patient outcomes. The current study reviewed 68 treatment arms comprising 4793 patients in past trials in recurrent glioblastoma in order to judiciously define target ORRs for use in recurrent glioblastoma trials. ORR was estimated at 6.1% [95% CI 4.23; 8.76%] for cytotoxic chemothera + pies (ORR = 7.59% for lomustine, 7.57% for temozolomide, 0.64% for irinotecan, and 5.32% for other agents), 3.37% for biologic agents, 7.97% for (select) immunotherapies, and 26.8% for anti-angiogenic agents. ORRs were significantly correlated with median overall survival (mOS) across chemotherapy (R2= 0.4078, P < .0001), biologics (R2= 0.4003, P = .0003), and immunotherapy trials (R2= 0.8994, P < .0001), but not anti-angiogenic agents (R2= 0, P = .8937). Pooling data from chemotherapy, biologics, and immunotherapy trials, a meta-analysis indicated a strong correlation between ORR and mOS (R2= 0.3900, P < .0001; mOS [weeks] = 1.4xORR + 24.8). Assuming an ineffective cytotoxic (control) therapy has ORR = 7.6%, the average ORR for lomustine and temozolomide trials, a sample size of ≥40 patients with target ORR>25% is needed to demonstrate statistical significance compared to control with a high level of confidence (P < .01) and adequate power (>80%). Given this historic data and potential biases in patient selection, we recommend that well-controlled, single-arm phase II studies in recurrent glioblastoma should have a target ORR >25% (which translates to a median OS of approximately 15 months) and a sample size of ≥40 patients, in order to convincingly demonstrate antitumor activity. Crucially, this response needs to have sufficient durability, which was not addressed in the current study.

Funder

UCLA SPORE in Brain Cancer

Harvard SPORE in Brain Cancer

Publisher

Oxford University Press (OUP)

Subject

Cancer Research,Neurology (clinical),Oncology

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