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.
Highlights
Data suggest that for newly approved cancer drugs safety and tolerability are worse than in control arms of registration trials
First we identified the number of patients at risk both, in the experimental and control arms, and collected data on the number of patients with each of the following safety and tolerability outcomes: treatment-related death, treatment discontinuation without disease progression, and 12 commonly reported grade 3/4 adverse events (AEs) including: anemia, neutropenia, thrombocytopenia, diarrhea, vomiting, stomatitis, hypertension, cardiac events, fatigue/asthenia, skin toxicity, dyspnea, neuropathy
The main goal of phase 3 randomized controlled trials (RCTs) is to assess the efficacy of experimental therapy, in the palliative treatment of patients with advanced cancer, where maintaining a good quality of life is crucial, toxicity profile and tolerability of drugs are of considerable importance
Summary
Data suggest that for newly approved cancer drugs safety and tolerability are worse than in control arms of registration trials. 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. It has been demonstrated that newly approved anticancer drugs increase morbidity and treatment-related mortality[5], there are few data about toxicity of experimental cancer drugs in unselected trials including those not resulting in drug registration. We report a meta-analysis of efficacy, safety and tolerability of all phase 3 RCTs in common advanced solid tumors registered on ClinicalTrials.gov. The primary objective of the study was to quantify systematically the trade-off between efficacy and toxicity of experimental cancer therapy relative to control group treatment in unselected phase 3 trials. We hypothesized that a small incremental benefit of experimental cancer drugs would be associated with higher toxicity
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