Identifying Minimum Threshold Level of Trial Crossover Rates Yielding Nonsignificant Overall Survival Benefit...

Crossover distortion in oncology trials occurs when control-arm patients switch to agent(s) in the experimental arm, potentially attenuating treatment effects in intention-to-treat (ITT) overall survival (OS) analyses. This complicates health technology assessment (HTA) decision-making by masking true treatment benefits. Understanding crossover thresholds compromising ITT OS statistical significance is critical for interpreting trial outcomes.

We aimed to identify minimum threshold beyond which crossover rates are associated with loss of ITT OS statistical significance in advanced/metastatic breast, colorectal, gastrointestinal stromal, lung, prostate, and renal cancers.

A systematic literature review of HTA reports (2013-2024) from NICE-UK, CDA-Canada, HAS-France, G-BA/IQWiG-Germany, PBAC-Australia, AIFA-Italy, AEMPS-Spain, and ICER-US was conducted. Searches were augmented with information from clinical practice guidelines and product labels from regulatory agencies. Submissions reporting crossover rates, with/without crossover-mitigation strategies applied, were analyzed to quantify the relationship between crossover rates and ITT OS statistical significance.

Fifty unique trials from 114 submissions reported crossover rates (NICE = 25, HAS = 19, CDA = 15, PBAC = 13, G-BA/IQWiG = 32, AEMPS = 9, ICER = 1), with crossover-mitigation strategies applied in 26 trials. A hypothesis-generating minimum benchmark of crossover rate (the ratio of control-arm participants switching to agent(s) in the experimental arm) ~42.7% was identified above which ITT OS lost statistical significance. Trials with high crossover rates (42.7%-88%) showed nonsignificant OS improvements, whereas lower rates (<42.5%) demonstrated significant OS benefits. Higher crossover rates were observed in trials with built-in vs natural crossover (52.9% vs 8.1%). In first-line setting, crossover rates >42.5% typically diluted OS benefit. In later-line and refractory diseases, OS significance often persisted beyond 42.7% threshold due to limited confounding by post-progression treatment options and faster death event accrual.

Crossover impact varied by tumor type, treatment line, crossover type, and trial maturity. Crossover >42.7% generally compromised ITT OS significance; however, OS maturity attained in the trial or sustained efficacy of the intervention beyond progression may preserve statistical significance despite high crossover. A crossover rate exceeding 42.7% was associated with nonsignificant ITT OS outcomes in most trials, particularly in first-line settings. OS benefits may persist in later-line settings with fewer post-progression treatment alternatives. This evidence supports contextual interpretation of crossover-affected OS during HTA decision-making.