Risk and benefit for umbrella trials in oncology: a systematic review and meta-analysis
Karolina Strzebonska1, Mateusz Blukacz2,3, Mateusz T Wasylewski1
1Research Ethics in Medicine Study Group (REMEDY), Faculty of Health Sciences, Jagiellonian University Medical College, Kraków, Poland.
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.
Insights
Precision oncology umbrella trials show a 17.7% objective response rate (ORR). While combinations improved ORR, findings do not strongly support increased patient benefit, with a 0.8% drug-related death rate.
Area of Science:
- Oncology
- Clinical Trials
- Precision Medicine
Background:
- Umbrella clinical trials in precision oncology aim to match therapies with tumor-specific genetic alterations.
- The risk/benefit profile of these trials is not well-established.
- This systematic review and meta-analysis evaluates efficacy and safety in cancer umbrella trials.
Purpose of the Study:
- To systematically review and meta-analyze the efficacy and safety of targeted drugs or combination therapies in cancer umbrella trials.
- To determine the risk/benefit ratio of treatments within these precision oncology studies.
Main Methods:
- Systematic review and meta-analysis of cancer umbrella trials.
- Searched Embase and PubMed for solid tumor trials (Jan 2006-Oct 2019).
- Assessed risk via drug-related grade 3+ adverse events (AEs); benefit via objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).
Main Results:
- Included 31 sub-trials/arms from nine umbrella trials (N=1637).
- Pooled ORR was 17.7%; combination therapy showed higher ORR (39.0%) than targeted monotherapy (13.3%).
- Median PFS: 2.4 months; median OS: 7.1 months; drug-related death rate: 0.8%.
Conclusions:
- On average, 1 in 5 patients responded, and 1 in 125 died from toxicity in trials studied.
- Current findings do not consistently support enhanced patient benefit from umbrella trial designs.
- Further research is needed to confirm if umbrella trials and precision oncology improve patient outcomes.
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