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

Benjamin M Ellingson; Patrick Y Wen; Susan M Chang; Martin van den Bent; Michael A Vogelbaum; Gang Li; Shanpeng Li; Jiyoon Kim; Gilbert Youssef; Wolfgang Wick; Andrew B Lassman; Mark R Gilbert; John F de Groot; Michael Weller; Evanthia Galanis; Timothy F Cloughesy

doi:10.1093/neuonc/noad002

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

Neuro Oncol. 2023 Jun 2;25(6):1017-1028. doi: 10.1093/neuonc/noad002.

Authors

Benjamin M Ellingson^{1

2

3

4

5}, Patrick Y Wen⁶, Susan M Chang⁷, Martin van den Bent⁸, Michael A Vogelbaum⁹, Gang Li¹⁰, Shanpeng Li¹⁰, Jiyoon Kim¹⁰, Gilbert Youssef⁶, Wolfgang Wick¹¹, Andrew B Lassman¹², Mark R Gilbert¹³, John F de Groot⁷, Michael Weller¹⁴, Evanthia Galanis¹⁵, Timothy F Cloughesy^{2

16}

Affiliations

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

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.

Keywords: glioblastoma; objective response rate; overall survival; recurrent GBM.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Angiogenesis Inhibitors / therapeutic use
Antineoplastic Agents* / therapeutic use
Brain Neoplasms* / pathology
Glioblastoma* / pathology
Humans
Lomustine / therapeutic use
Neoplasm Recurrence, Local / drug therapy
Neoplasm Recurrence, Local / pathology
Temozolomide / therapeutic use

Substances

Temozolomide
Antineoplastic Agents
Lomustine
Angiogenesis Inhibitors

Abstract

Publication types

MeSH terms

Substances

Grants and funding