Evaluation bias in objective response rate and disease control rate between blinded independent central review and local assessment: a study-level pooled analysis of phase III randomized control trials in the past seven years

Zhang, Jianrong; Zhang, Yiyin; Tang, Si; Liang, Hengrui; Chen, Difei; Jiang, Long; He, Qihua; Huang, Yu Chen; Wang, Xinyu; Deng, Kexin; Jiang, Shuhan; Zhou, Jun; Xu, Jiaxuan; Chen, Xuanzuo; Liang, Wenhua; He, Jianxing

doi:10.21037/atm.2017.11.24

Cited by 13 publications

(15 citation statements)

References 46 publications

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“…31 However, when these authors carried out a direct comparison of response rates between central and local assessments (data obtained from 28 phase 3 trials on solid tumors), they found significantly lower ORR values associated with blinded independent central review assessment compared to those of local investigators, for both experimental (odds ratio, 0.81; 95%CI, 0.76-0.87) and control arms (odds ratio, 0.79; 95%CI, 0.72-0.85). 32 Taken collectively, our data and those of Zhang et al 32 would suggest that the ORRs assessed by local investigators are significantly higher by about 20% compared to those assessed by blinded reviewers, regardless of whether the ORR assessment was carried out in phase 2 or in phase 3 trials. On the contrary, we and others have shown that no significant discrepancies are observed between the PFSs assessed by local investigators and those assessed by blinded independent central review, both in phase 2 and phase 3 trials (the present findings and Dello Russo et al 1 and Amit et al 2 ).…”

Section: Discussionsupporting

confidence: 70%

Local Investigators Significantly Overestimate Overall Response Rates Compared to Blinded Independent Central Reviews in Phase 2 Oncology Trials

Russo

Cappoli

Pilunni

et al. 2020

The Journal of Clinical Pharma

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The overall response rate (ORR) is a largely adopted outcome measure in early-phase oncology trials. ORR is highly relevant in cancer drug development at the time of deciding whether to move to confirmatory phase 3 trials; moreover, ORR is gaining increasing relevance in fast-track registration procedures. No systematic analysis has been conducted so far to investigate whether a discrepancy exists between ORR assessed by local investigators and those assessed by blinded reviewers in phase 2 oncology trials. In this study, we carried out a search in the clinicaltrials.gov and EudraCT databases, looking at the trials reporting the results of both investigator-assessed and independently-assessed ORR. A discrepancy index was obtained by calculating the ratio of each investigator-assessed ORR on the corresponding independently assessed ORR, so that a discrepancy index >1 indicates that the investigator was "more optimistic," whereas a discrepancy index <1 indicates the opposite. We also analyzed different subgroups (by tumor type, by drug type, by year). Twenty trials met the search criteria; in some cases, >1 comparison was conducted in the trial, so that the total number of comparisons analyzed was 33. The estimated mean discrepancy index was 1.175 (95% confidence interval, 1.083-1.264; n = 33). In conclusion, local investigators significantly overestimate ORR compared to paired blinded reviewers in phase 2 oncology trials. This may represent a risk in drug development, when deciding whether to move to confirmatory, more expensive phase 3 trials. Blinded independent central review should be used in ORR assessment if a more conservative estimate of treatment efficacy is required, as in the case of fast-track drug developments leading to accelerated approvals of cancer therapies.

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Section: Discussionsupporting

confidence: 70%

Local Investigators Significantly Overestimate Overall Response Rates Compared to Blinded Independent Central Reviews in Phase 2 Oncology Trials

Russo

Cappoli

Pilunni

et al. 2020

The Journal of Clinical Pharma

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“…However, these endpoint variables, which are assessed on a continuum, may be considered less clinically robust compared with the binary endpoint of RECIST response for assessing drug activity or lack thereof in a small patient cohort. It is also important to note the lack of a significant correlation when evaluating exposureefficacy using investigator-assessed objective response, which was likely attributable, in part, to discordance between local and central radiology review, as has previously been reported in assessments of RECIST response [16,17]. Despite these limitations, the wide range in the observed AUC avg,ss levels (range, 2328-99,524 ng/mL × h) still allowed detection of a statistically significant correlation between rucaparib exposure and IRR-assessed RECIST response.…”

Section: Discussionmentioning

confidence: 98%

Population exposure-efficacy and exposure-safety analyses for rucaparib in patients with recurrent ovarian carcinoma from Study 10 and ARIEL2

Konecny

Oza

Tinker

et al. 2021

Gynecologic Oncology

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Rucaparib exposure and efficacy/safety relationship were studied using pooled Study 10 and ARIEL2 data.• Rucaparib exposure and response were positively correlated in patients with platinum-sensitive recurrent ovarian carcinoma.• We found no significant association between the model-predicted rucaparib exposure and baseline body weight.• Our analyses support starting rucaparib 600 mg twice daily with subsequent dose modification based on adverse events.

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“…Athymic nude mice were orthotopically injected with 1 × 10 7 MDA-MB-231 cells mixed with Matrigel into the fat pads of the fourth pair of mammary glands. When the tumor sizes reached 100-150 mm 3 , the mice were randomly divided into ve groups (six/group) and i.v. injected with pRNAs (3.3 nmol/mice) twice a week for 3 weeks.…”

Section: Orthotopic Xenograft Breast Tumor Mouse Modelmentioning

confidence: 99%

Development of Targeted Therapy Therapeutics to Sensitize Triple-Negative Breast Cancer Chemosensitivity Utilizing Bacteriophage phi29 Derived Packaging RNA

Zhang

et al. 2020

Preprint

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Background: To date, triple-negative breast cancer (TNBC) treatment options are limited due to it lacks expression of receptors and are only available managed with chemotherapy. What's worse, TNBC is frequently developing resistance to chemotherapy. By using siRNA-based therapeutics, our recent work demonstrated X-box-binding protein 1 (XBP1) was linked to HER2+ breast cancer development and chemoresistance. As is well-known, the instability, off-target effects, net negative charge, and hydrophobicity of siRNA hamper its’ in vivo utilization and clinical transformation. Thus, the development of a siRNA delivery system (DDS) with ultra-stability and specificity is demanded to address the predicament of siRNA delivery.Results: Here, we assembled RNase resistant RNA nanoparticles (NPs) based on the 3WJ of Phi29 DNA packaging motor. To targeted therapy and sensitize TNBC to chemotherapy, the RNA NPs were equipped with epidermal growth factor receptor (EGFR) targeting aptamer and XBP1 siRNA. We found our RNA NPs could deplete XBP1 expression and suppress tumor growth after intravenous administration. Meanwhile, RNA NPs treatment could promote the sensitization of chemotherapy and impair angiogenesis in vivo. Conclusions: The results further demonstrate that our RNA NPs could serve as an effective and promising platform not only for siRNA delivery but also for chemotherapy-resistant TNBC therapy.

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Evaluation bias in objective response rate and disease control rate between blinded independent central review and local assessment: a study-level pooled analysis of phase III randomized control trials in the past seven years

Cited by 13 publications

References 46 publications

Local Investigators Significantly Overestimate Overall Response Rates Compared to Blinded Independent Central Reviews in Phase 2 Oncology Trials

Local Investigators Significantly Overestimate Overall Response Rates Compared to Blinded Independent Central Reviews in Phase 2 Oncology Trials

Population exposure-efficacy and exposure-safety analyses for rucaparib in patients with recurrent ovarian carcinoma from Study 10 and ARIEL2

Development of Targeted Therapy Therapeutics to Sensitize Triple-Negative Breast Cancer Chemosensitivity Utilizing Bacteriophage phi29 Derived Packaging RNA

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