Time-to-progression ratio as a potential study endpoint in early-phase oncology trials: pooled analysis of phase II trials from the Australian MoST program

Purpose Time-to-progression ratio (TTPr) measures intra-patient treatment benefit by comparing disease control on study treatment with that of the immediately preceding therapy. Its prognostic validity in the immune checkpoint inhibitor (ICI) era remains uncertain.Methods We performed a pooled patient-level analysis of eight phase II trials. Associations between TTPr, TTP on prior therapy (TTP1), and on-study TTP (TTP2/ PFS), objective response rate (ORR), with overall survival (OS) were evaluated using Cox regression. Landmark analyses at 6-months were used to mitigate guarantee-time bias.Results Among 246 evaluable participants, median TTP1 and TTP2 were 3.9 and 2.1 months, respectively, with poor correlation (r = 0.02). TTPr was not associated with OS (TTPr ≥1.3 vs <1.3, HR 0.85, 95% CI 0.57–1.26). In contrast, TTP2 and ORR were strongly prognostic (TTP2 ≥2.1 months vs <2.1 months: HR 0.51, 95% CI 0.35–0.76, p < 0.001); (response vs non-response: HR 0.19, 95% CI 0.07–0.52, p = 0.001) and remained independently associated with OS in multivariable analyses. Findings were consistent across ICI and non-ICI trials.Conclusions TTPr is not a robust prognostic measure in platform trials. Although this raises concern regarding its validity as a surrogate endpoint for OS, formal evaluation requires randomized treatment comparisons.