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. 2024 Mar 19;3(1):e000229.
doi: 10.1136/bmjonc-2023-000229. eCollection 2024.

Assessing patient risk, benefit and outcomes in drug development: an observational study of regorafenib clinical trials

Brody Dennis  1 , Chance Bratten  1 , Griffin K Hughes  1 , Andriana M Peña  1 , Ryan McIntire  1 , Chase Ladd  1 , Brooke Gardner  1 , William Nowlin  2 , Reagan Livingston  3 , Jordan Tuia  4 , Alyson Haslam  4 , Vinay Prasad  4 , Matt Vassar  1   5
Affiliations

Assessing patient risk, benefit and outcomes in drug development: an observational study of regorafenib clinical trials

Brody Dennis et al. BMJ Oncol. .

Abstract

Objective: Our objective of this study was to analyse all oncological clinical trials using regorafenib to create a complete risk/benefit profile for the drug.

Background: Creating a novel chemotherapy is costly both in time and capital spent for drug manufacturers. To regenerate what they've spent, drug manufacturers may attempt to repurpose their medications for new indications via clinical trials. To fully understand the risk/benefits in comparison to a drug's efficacy, a pooled analysis must be completed.

Methods: We screened PubMed, Embase, Cochrane (CENTRAL) and ClinicalTrials.gov for trials of regorafenib used to treat solid cancers. Next, we extracted median progression-free survival and overall survival in months, adverse event rates and objective response rate (ORR). Studies were deemed positive, negative or indeterminate based on their pre-specified endpoints and tolerability.

Results: 56 clinical trials were included in our final sample, with 4960 total participants across 13 indications. Most studies (44 of 56; 78.75%) were non-blinded, and a majority were non-randomised (41 of 56; 73.21%). Trials for colorectal cancer started out as positive but became more negative over time. Cumulative risk to patients increased over time while ORR stayed consistently low.

Conclusions: Our findings suggest that since regorafenib's original Food and Drug Administration (FDA) approval, the risk profile for its original indication increased. The amount of non-randomised, single-arm trials in our sample size was concerning, indicating that higher quality research must be conducted. Our results propose that regorafenib's efficacy and safety may be more impactful in cancers other than its FDA approvals.

Keywords: Colorectal cancer; Gastric cancer; Liver cancer.

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Conflict of interest statement

Competing interests: VP reports research funding from Arnold Ventures; royalties from Johns Hopkins Press, Medscape and MedPage; honoraria from GrandRounds/lectures from universities, medical centres, non-profits, professional societies, YouTube and Substack; consulting from UnitedHealthcare and OptumRX; speaking fees from Evicore. Plenary Session podcast has Patreon backers. MV reports receipt of funding from the National Institute on Drug Abuse, the National Institute on Alcohol Abuse and Alcoholism, the U.S. Office of Research Integrity, the Oklahoma Center for Advancement of Science and Technology and internal grants from Oklahoma State University Center for Health Sciences—all outside of the present work. All other authors have nothing to report.

Figures

Figure 1
Figure 1
Flow diagram for study inclusion.
Figure 2
Figure 2
AER for each trial versus the cumulative ORR for each trial per year plotted over time. Δ (AER−ORR) is the absolute difference between the cumulative AER and ORR. AER, adverse event rate; GRID, Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial; ORR, objective response rate.
Figure 3
Figure 3
The cumulative number of patients versus the cumulative number of adverse events (AEs) over time. GRID, Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial; RESORCE, Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial.
Figure 4
Figure 4
Accumulating Evidence and Research Organization diagram for regorafenib clinical trials.
See this image and copyright information in PMC

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