Future oncology (London, England) · 2026
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.
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Siu Derrick H W, Lin Frank P Y, Thomas David M, Thavaneswaran Subotheni, Espinoza David, Chinchen Sarah, Ballinger Mandy L, Simes R John, Lee Chee Khoon
Аннотация
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.
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.