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

doi:10.1093/neuonc/noad002

Meta-Analysis

. 2023 Jun 2;25(6):1017-1028.

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

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.

PMID: 36617262
PMCID: PMC10237425
DOI: 10.1093/neuonc/noad002

Meta-Analysis

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 et al. Neuro Oncol. 2023.

. 2023 Jun 2;25(6):1017-1028.

doi: 10.1093/neuonc/noad002.

Authors

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.

PMID: 36617262
PMCID: PMC10237425
DOI: 10.1093/neuonc/noad002

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.

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Conflict of interest statement

BME is a Paid Consultant and Advisor for Siemens; Medicenna; MedQIA; Imaging Endpoints; Agios Pharmaceuticals; Neosoma; Janssen; Kazia; VBL; Oncoceutics; Boston Biomedical Inc; ImmunoGenesis; and Ellipses Pharma. BME has received grant funding from Siemens, Agios, and Janssen. T.F.C. is cofounder, major stock holder, consultant and board member of Katmai Pharmaceuticals, member of the board for the 501c3 Global Coalition for Adaptive Research, holds stock option of Notable Labs, holds stock in Chimerix and receives milestone payments and possible future royalties, member of the scientific advisory board for Break Through Cancer, member of the scientific advisory board for Cure Brain Cancer Foundation, has provided paid consulting services to GCAR; Gan & Lee; BrainStorm; Katmai; Sapience; Inovio; Vigeo Therapeutics; DNATrix; Tyme; SDP; Novartis; Roche; Kintara; Bayer; Merck; Boehinger Ingelheim; VBL; Amgen; Kiyatec; Odonate Therapeutics QED; Medefield; Pascal Biosciences; Bayer; Tocagen; Karyopharm; GW Pharma; Abbvie; VBI; Deciphera; VBL; Agios; Genocea; Celgene; Puma; Lilly; BMS; Cortice; Wellcome Trust; Novocure; Novogen; Boston Biomedical; Sunovion; Human Longevity; Insys; ProNai; Pfizer; Notable labs; Medqia Trizel; Medscape and has contracts with UCLA for the Brain Tumor Program with Oncovir; Merck; Oncoceutics; Novartis; Amgen; Abbvie; DNAtrix; Beigene; BMS; AstraZeneca; Kazia; Agios; Boston Biomedical; Deciphera; Tocagen; Orbus; AstraZenica; Karyopharm. M.J.v.d.B. has received honoraria from Carthera; Genenta; Nerviano; Cellgene; Astra Zeneca and Boehringer. H.C. has received in the last year honoraria or consulting fees from Best Doctors/Teladoc; Orbus Therapeutics; Adastra Pharmaceuticals; Bristol Meyers Squibb and research funding (instutional contracts) from Orbus; Merck; DNATrix; Abbvie; Beigene; Forma Therapeutics; GCAR; Array BioPharma; Karyopharm Therapeutics; Nuvation Bio; Bayer; Bristol Meyer Squib. W.W. reports to be inventor and patent-holder on “Peptides for use in treating or diagnosing IDH1R132H positive cancers” (EP2800580B1) and “Cancer therapy with an oncolytic virus combined with a checkpoint inhibitor” (US11027013B2). He consulted for Apogenix; Astra Zeneca; Bayer; Enterome; Medac; MSD; and Roche/Genentech with honoraria paid to the Medical Faculty at the University of Heidelberg. MW has received research grants from Apogenix and Quercis, and honoraria for lectures or advisory board participation or consulting from Bayer; Medac; Merck (EMD); Nerviano Medical Sciences; Novartis; Orbus; Philogen and y-Mabs. MAV has patent royalty rights from Infuseon Therapeutics. He has received honoraria from Olympus and Chimerix. His institution has received grant funding from Infuseon Therapeutics; Oncosynergy; and Denovo Pharma for clinical trials for which he is the site primary investigator. EG has received honoraria for advisory board participation from Kiyatec, Inc. (personal compensation) and Karyopharm Therapetuics, Inc. for Data Safety and Monitoring Board participation (compensation to employer). Her institution has received grant funding from Servier Pharmaceuticals LLC (formerly Agios Pharmaceuticals, Inc.), Celgene, MedImmune, Inc. and Tracon Pharmaceuticals.

Figures

**Figure 1.**
Objective response rates (ORRs) for various types of treatments including cytotoxic chemotherapies, biologic-based agents, immunotherapies (select trials), and anti-angiogenic agents. Filled circle under biologic-based agents shows the ORR for a recent trial of dabrafenib and trametinib in BRAF-mutated rGBM. Filled square under “chemotherapies” designates the ORR for NovoTTF-11A.

**Figure 2.**
Correlation between ORR and median overall survival (mOS) for (A) cytotoxic chemotherapies, (B) biologics-based (non-antiangiogenic) agents, (C) immunotherapies (select studies), and (D) anti-angiogenic agents. Note that a strong correlation was observed in all therapeutic categories besides anti-angiogenic agents. (E) Correlation between ORR and mOS for pooled studies in chemotherapies, biologics-based agents, and immunotherapies (46 treatment arms in 3243 rGBM patients). ORR vs mOS in pooled patients split by individual treatment types. showing strong linear correlation (R²*= 0.3900, P < .0001*; *mOS [weeks] = 1.4xORR + 24.8*). (F) ORR vs mOS pooled together along with ORR and mOS in recent study in a recent trial of dabrafenib and trametinib in BRAF-mutated rGBM (filled circle).

**Figure 3.**
Minimum required sample size for (A) a control ORR = 5% (average of all non-antiangiogenic trials); (B) a control ORR = 6.7% (upper 95% confidence interval for all non-antiangiogenic trials); and (C) a control ORR = 7.6% (average from CCNU and TMZ monotherapy trials) assuming a level of significance *P < .01* and power >80%. Results suggest a minimum of 40 patients are required for a target ORR of 25% using an assumed control ORR of 7.6%.

See this image and copyright information in PMC

Comment in

Using historical objective response rates to design single-arm phase II trials in patients with recurrent glioblastoma.
Grossman SA. Grossman SA. Neuro Oncol. 2023 Jun 2;25(6):1029-1030. doi: 10.1093/neuonc/noad046. Neuro Oncol. 2023. PMID: 36881776 Free PMC article. No abstract available.
Reply to Di Nunno et al. concerning objective response rates targets for recurrent glioblastoma clinical trials: Toward surrogate endpoints for phase II trials in patients with recurrent glioblastoma.
Ellingson BM, Wen PY, Cloughesy TF. Ellingson BM, et al. Neuro Oncol. 2023 Aug 3;25(8):1548-1549. doi: 10.1093/neuonc/noad085. Neuro Oncol. 2023. PMID: 37167013 Free PMC article. Clinical Trial. No abstract available.
Letter concerning "Objective response rate targets for recurrent glioblastoma clinical trials based on the historic association between ORR and median overall survival": Toward surrogate endpoints for phase II trials in patients with recurrent glioblastoma.
Di Nunno V, Gatto L, Tosoni A, Bartolini S, Franceschi E. Di Nunno V, et al. Neuro Oncol. 2023 Aug 3;25(8):1546-1547. doi: 10.1093/neuonc/noad071. Neuro Oncol. 2023. PMID: 37171969 Free PMC article. No abstract available.

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References

1. U.S. Department of Health and Human Services, Food and Drug Administration, Oncology Center for Excellence, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics: Guidence for Industry; 2018. Silver Spring, MD; U.S. DHHS FDA. https://www.fda.gov/media/71195/download. Accessed November 1, 2022.
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1. Axelson M, Liu K, Jiang X, et al. . U.S. food and drug administration approval: vismodegib for recurrent, locally advanced, or metastatic basal cell carcinoma. Clin Cancer Res. 2013; 19(9):2289–2293. - PubMed
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[1] U.S. Department of Health and Human Services, Food and Drug Administration, Oncology Center for Excellence, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics: Guidence for Industry; 2018. Silver Spring, MD; U.S. DHHS FDA. https://www.fda.gov/media/71195/download. Accessed November 1, 2022.

[2] U.S. Department of Health and Human Services, Food and Drug Administration, Oncology Center for Excellence, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics: Guidence for Industry; 2018. Silver Spring, MD; U.S. DHHS FDA. https://www.fda.gov/media/71195/download. Accessed November 1, 2022.

[3] Ma P, Mumper RJ. Paclitaxel nano-delivery systems: a comprehensive review. J Nanomed Nanotechnol. 2013; 4(2):1000164. - PMC - PubMed

[4] Ma P, Mumper RJ. Paclitaxel nano-delivery systems: a comprehensive review. J Nanomed Nanotechnol. 2013; 4(2):1000164. - PMC - PubMed

[5] Axelson M, Liu K, Jiang X, et al. . U.S. food and drug administration approval: vismodegib for recurrent, locally advanced, or metastatic basal cell carcinoma. Clin Cancer Res. 2013; 19(9):2289–2293. - PubMed

[6] Axelson M, Liu K, Jiang X, et al. . U.S. food and drug administration approval: vismodegib for recurrent, locally advanced, or metastatic basal cell carcinoma. Clin Cancer Res. 2013; 19(9):2289–2293. - PubMed

[7] Federman N, Brien EW, Narasimhan V, et al. . Giant cell tumor of bone in childhood: clinical aspects and novel therapeutic targets. Paediatr Drugs. 2014; 16(1):21–28. - PubMed

[8] Federman N, Brien EW, Narasimhan V, et al. . Giant cell tumor of bone in childhood: clinical aspects and novel therapeutic targets. Paediatr Drugs. 2014; 16(1):21–28. - PubMed

[9] Wood L. Sunitinib malate for the treatment of renal cell carcinoma. Expert Opin Pharmacother. 2012; 13(9):1323–1336. - PubMed

[10] Wood L. Sunitinib malate for the treatment of renal cell carcinoma. Expert Opin Pharmacother. 2012; 13(9):1323–1336. - PubMed

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

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

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