TY - JOUR
T1 - Objective response rate targets for recurrent glioblastoma clinical trials based on the historic association between objective response rate and median overall survival
AU - Ellingson, Benjamin M.
AU - Wen, Patrick Y.
AU - Chang, Susan M.
AU - van den Bent, Martin
AU - Vogelbaum, Michael A.
AU - Li, Gang
AU - Li, Shanpeng
AU - Kim, Jiyoon
AU - Youssef, Gilbert
AU - Wick, Wolfgang
AU - Lassman, Andrew B.
AU - Gilbert, Mark R.
AU - de Groot, John F.
AU - Weller, Michael
AU - Galanis, Evanthia
AU - Cloughesy, Timothy F.
N1 - Publisher Copyright:
© The Author(s) 2023.
PY - 2023/6/1
Y1 - 2023/6/1
N2 - 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.
AB - 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.
KW - glioblastoma
KW - objective response rate
KW - overall survival
KW - recurrent GBM
UR - http://www.scopus.com/inward/record.url?scp=85160969073&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85160969073&partnerID=8YFLogxK
U2 - 10.1093/neuonc/noad002
DO - 10.1093/neuonc/noad002
M3 - Review article
C2 - 36617262
AN - SCOPUS:85160969073
SN - 1522-8517
VL - 25
SP - 1017
EP - 1028
JO - Neuro-oncology
JF - Neuro-oncology
IS - 6
ER -