Background Randomised controlled trials (RCTs) with overall survival (OS) as the primary endpoint remain the gold standard for evaluating the efficacy and safety of new cancer therapies.However, increasing reliance on early or intermediate endpoints such as progression-or recurrence-related time-to-event endpoints (PRTTE) including progression-free survival (PFS) and disease-free survival (DFS) has led to concerns about the strength and clinical relevance of the evidence at the time of approval.We aimed to systematically evaluate the evidence supporting new cancer drugs approved by Swissmedic, focusing on efficacy and safety measures and differences in treatment effects between OS and PRTTE, mainly PFS and DFS, across different cancer types, drug classes, and trial characteristics. MethodsWe identified pivotal clinical trials from the Swissmedic database supporting new active substances and indication extensions between Jan 1, 2001, and Dec 31, 2020.We included RCTs and excluded single-arm, noninferiority studies, and those trials that did not report on the prespecified outcomes of interest (OS, PRTTE, or response rate).Meta-analysis using random-effects models was performed to pool hazard ratios (HRs) for OS and PRTTE, odds ratios (ORs) for response rates, and risk ratios (RRs) for serious adverse events (SAEs).Findings We identified 241 RCTs supporting approvals of 102 cancer drugs.PRTTE endpoints, mainly PFS, were the primary endpoint in 69.2% (167/241) of trials, while OS was the primary endpoint in 30.2% (73/241).Across 194 RCTs reporting OS, PRTTE and SAEs, the newly approved treatment reduced the risk of death by 24% (HR 0.76; 95% CI 0.74-0.77)and risk of the progression or recurrence by 45% (HR 0.55; 95% CI 0.52-0.58)compared with the control arm, with an increased relative risk of SAEs by 26% (RR 1.26; 95% CI 1.21-1.32).Absolute median survival gains were modest (OS 2.42 months; PRTTE (PFS) 3.47 months).In the palliative setting, differences in treatment effect between OS and PRTTE (PFS) varied across solid cancer types and drug classes.Among tumour types, differences between OS and PRTTE were more pronounced in ovarian cancer (OS HR 0.87 vs. PRTTE HR 0.55), whereas in head and neck cancer the estimates were similar (OS HR 0.72 vs. PRTTE HR 0.70).Among drug classes, targeted agents showed more pronounced differences (OS HR 0.74 vs. PRTTE HR 0.48), whereas immune checkpoint inhibitors showed similar effects (OS HR 0.71 vs. PRTTE HR 0.72). InterpretationThe cancer drugs approved by Swissmedic were associated with treatment benefits and modest median survival gains, accompanied by an increased risk of SAEs at the time of approval.The reliance on early endpoints, limited availability of long-term OS data, and the observed differences between PRTTE, mainly PFS/DFS, and OS highlight challenges in interpreting evidence at the time of approval.These findings suggest that treatment effects should be interpreted in the specific clinical and biological context, with enhanced post-approval OS data collection to support the regulatory and clinical assessments.
Rahimzadeh et al. (Thu,) studied this question.
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