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

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

Karolina Strzebonska  1 , Mateusz Blukacz  2   3 , Mateusz T Wasylewski  1 , Maciej Polak  1   4 , Bishal Gyawali  5 , Marcin Waligora  6
Affiliations
Meta-Analysis

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

Karolina Strzebonska et al. BMC Med. .

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.

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Conflict of interest statement

Marcin Waligora reports personal fees from the Advisory Bioethics Council (Sanofi) outside the submitted work. Karolina Strzebonska, Mateusz Blukacz, Mateusz T. Wasylewski, Maciej Polak, and Bishal Gyawali declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Structure types of umbrella trials. A An umbrella trial with multiple arms. Accrual to each arm is based on the biomarker test result. B An umbrella trial with multiple sub-studies. Each sub-study has a separate registration number and may include an experimental arm and a control group
Fig. 2
Fig. 2
PRISMA 2020 flow diagram. The number of identified, screened, and included records with the exclusion reasons for potentially eligible reports
Fig. 3
Fig. 3
Forest plot of proportions of objective response rates in experimental sub-trials/arms included in the meta-analysis (random effects). The analysis included data from 21 experimental sub-trials/arms with a total of 185 objective responses among 878 participants evaluated for response. CI, confidence interval
Fig. 4
Fig. 4
Forest plot of proportions of treatment-related grade 5 AEs in experimental sub-trials/arms included in the meta-analysis (random effects). The analysis included data from 15 experimental sub-trials/arms with a total of 9 drug-related deaths among 999 participants evaluated for toxicity. AEs, adverse events; CI, confidence interval
Fig. 5
Fig. 5
Forest plot of proportions of treatment-related grade 3/4 AEs in experimental sub-trials included in the meta-analysis (random effects). The analysis included data from 5 experimental sub-trials/arms with a total of 91 patients that experienced drug-related grade 3/4 AEs. AEs, adverse events; CI, confidence interval
Fig. 6
Fig. 6
Forest plot of proportions of objective response rates in sub-trials/arms included in the meta-analysis (random effects). The analysis included data from 24 sub-trials/arms with a total of 212 objective responses among 1147 participants evaluated for response. CI, confidence interval
Fig. 7
Fig. 7
Forest plot of proportions of treatment-related grade 5 AEs in 17 sub-trials/arms included in the meta-analysis (random effects). The analysis included data from 17 sub-trials/arms with a total of 12 drug-related deaths among 1233 participants evaluated for toxicity. AEs, adverse events; CI, confidence interval
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References

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