Risk and benefit for umbrella trials in oncology: a systematic review and meta-analysis

Karolina Strzebonska; Mateusz Blukacz; Mateusz T Wasylewski; Maciej Polak; Bishal Gyawali; Marcin Waligora

doi:10.1186/s12916-022-02420-2

Risk and benefit for umbrella trials in oncology: a systematic review and meta-analysis

BMC Med. 2022 Jul 8;20(1):219. doi: 10.1186/s12916-022-02420-2.

Authors

Karolina Strzebonska¹, Mateusz Blukacz^{2

3}, Mateusz T Wasylewski¹, Maciej Polak^{1

4}, Bishal Gyawali⁵, Marcin Waligora⁶

Affiliations

¹ Research Ethics in Medicine Study Group (REMEDY), Faculty of Health Sciences, Jagiellonian University Medical College, Kraków, Poland.
² Institute of Psychology, University of Silesia, Katowice, Poland.
³ Institute of Public Health, Faculty of Health Sciences, Jagiellonian University Medical College, Kraków, Poland.
⁴ Department of Epidemiology and Population Studies, Institute of Public Health, Faculty of Health Sciences, Jagiellonian University Medical College, Kraków, Poland.
⁵ Department of Oncology and the Department of Public Health Sciences, Queen's University, Kingston, Ontario, Canada.
⁶ Research Ethics in Medicine Study Group (REMEDY), Faculty of Health Sciences, Jagiellonian University Medical College, Kraków, Poland. m.waligora@uj.edu.pl.

Abstract

Background: Umbrella clinical trials in precision oncology are designed to tailor therapies to the specific genetic changes within a tumor. Little is known about the risk/benefit ratio for umbrella clinical trials. The aim of our systematic review with meta-analysis was to evaluate the efficacy and safety profiles in cancer umbrella trials testing targeted drugs or a combination of targeted therapy with chemotherapy.

Methods: Our study was prospectively registered in PROSPERO (CRD42020171494). We searched Embase and PubMed for cancer umbrella trials testing targeted agents or a combination of targeted therapies with chemotherapy. We included solid tumor studies published between 1 January 2006 and 7 October 2019. We measured the risk using drug-related grade 3 or higher adverse events (AEs), and the benefit by objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). When possible, data were meta-analyzed.

Results: Of the 6207 records identified, we included 31 sub-trials or arms of nine umbrella trials (N = 1637). The pooled overall ORR was 17.7% (95% confidence interval [CI] 9.5-25.9). The ORR for targeted therapies in the experimental arms was significantly lower than the ORR for a combination of targeted therapy drugs with chemotherapy: 13.3% vs 39.0%; p = 0.005. The median PFS was 2.4 months (95% CI 1.9-2.9), and the median OS was 7.1 months (95% CI 6.1-8.4). The overall drug-related death rate (drug-related grade 5 AEs rate) was 0.8% (95% CI 0.3-1.4), and the average drug-related grade 3/4 AE rate per person was 0.45 (95% CI 0.40-0.50).

Conclusions: Our findings suggest that, on average, one in five cancer patients in umbrella trials published between 1 January 2006 and 7 October 2019 responded to a given therapy, while one in 125 died due to drug toxicity. Our findings do not support the expectation of increased patient benefit in cancer umbrella trials. Further studies should investigate whether umbrella trial design and the precision oncology approach improve patient outcomes.

Keywords: Ethics; Risk-benefit balance; Targeted therapy; Umbrella trial.

Publication types

Meta-Analysis
Systematic Review
Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents* / adverse effects
Humans
Medical Oncology
Neoplasms* / chemically induced
Neoplasms* / drug therapy
Precision Medicine

Substances

Antineoplastic Agents