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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Pages (from-to)1017-1028
Number of pages12
JournalNeuro-Oncology
Volume25
Issue number6
DOIs
Publication statusPublished - 1 Jun 2023

Bibliographical note

Funding Information:
There was no study-specific funding. Outside this work, funding was provided by the National Brain Tumor Society (NBTS), the UCLA SPORE in Brain Cancer (NIH/NCI P50 CA211015) and the Harvard SPORE in Brain Cancer (NIH/NCI P50 CA165962).

Publisher Copyright:
© The Author(s) 2023.

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