Efficacy, safety and tolerability of drugs studied in phase 3 randomized controlled trials in solid tumors over the last decade

• Main Authors: Domen Ribnikar, Hadar Goldvaser, Zachary W. Veitch, Alberto Ocana, Arnoud J. Templeton, Boštjan Šeruga, Eitan Amir
• Format: Article
• Language: English
• Published: Nature Publishing Group 2021-05-01
• Series: Scientific Reports
• Online Access: https://doi.org/10.1038/s41598-021-90403-3

Abstract Data suggest that for newly approved cancer drugs safety and tolerability are worse than in control arms of registration trials. Less is known about the balance between efficacy and toxicity of drugs studied in unselected phase 3 randomized controlled trials (RCTs) including those not resulting in regulatory approval. We searched Clinicaltrials.gov to identify phase 3 RCTs in patients with advanced breast, colorectal, lung, or prostate cancer completed between January 2005 and October 2016. We extracted efficacy and safety data from publications. For efficacy hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) were extracted. For safety, we computed odds ratios (ORs) and 95% confidence intervals (CIs) for toxic death, treatment discontinuation without progression and commonly reported grade 3/4 adverse events (AEs). Data were then pooled in a meta-analysis. Of 377 RCTs identified initially, 143 RCTs comprising 88,603 patients were included in the analysis. Of these, 79 (57%) trials met their primary endpoint. Compared to control groups, both PFS (HR 0.80; 95% CI 0.78–0.82) and OS (HR 0.87; 95% CI 0.85–0.89) were improved with experimental drugs. Toxic death (OR 1.14; 95% CI 1.03–1.27), treatment discontinuation without progression (OR 1.64; 95% CI 1.56–1.71) and grade 3/4 AEs were also more common with experimental drugs compared to respective control group therapy. Just over half of phase 3 RCTs in common solid tumors met their primary endpoint and in nearly half, experimental therapy had worse safety compared to control arms.