Trial reportJNCI cancer spectrum2025
INTEGRATE pooled phase 2/3 results are robust to postprogression switching and the winner's curse.
Trial report in JNCI cancer spectrum, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02773524 (A Randomised Phase III Double-Blind Placebo-Controlled Study of Regorafenib in Refractory Advanced Gastro-Oesophageal Cancer), which is not on this map. Not yet cited in PubMed.
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The trial behind it
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A Randomised Phase III Double-Blind Placebo-Controlled Study of Regorafenib in Refractory Advanced Gastro-Oesophageal Cancer (AGOC)
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0 citing papers in PubMed.
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Authors and funding
10 authors.
Funding
Abstract
backgroundThe INTEGRATE phase 3 trial in advanced gastric and esophagogastric junction cancer involved pooling overall survival data with its preceding phase 2 trial, raising concerns about misalignment due to treatment switching in phase 2, or the "winner's curse." We evaluated phase 2 results, adjusted for these opposing effects, against phase 3 according to the prespecified statistical analysis plan.
methodsOverall survival estimates were adjusted for treatment switching using the rank-preserving structural failure time model (RPSFTM) and inverse probability of censoring weights (IPCW) method. A novel shrinkage approach mitigated overestimation from the winner's curse, and Bayesian prediction methods predicted phase 3 outcomes from phase 2 estimates. A simulation study modeled 10 000 seamless phase 2/3 trials to quantify bias in the pooled estimate.
resultsThe observed phase 3 hazard ratio (HR = 0.71, 95% CI = 0.54 to 0.93) for overall survival was more conservative than the adjusted phase 2 estimates (RPSFTM and novel shrinkage approach: HR = 0.61, 95% CI = 0.29 to 1.29; RPSFTM and Bayesian prediction: HR = 0.59, 95% CI = 0.48 to 0.73; IPCW and novel shrinkage approach: HR = 0.55, 95% CI = 0.31 to 0.99; IPCW and Bayesian prediction: HR = 0.58, 95% CI = 0.46 to 0.72). Simulations indicated negligible bias in the pooled log hazard ratio of ‒0.011 and 0.005 under the null and alternative hypotheses, respectively.
conclusionAdjusting phase 2 estimates for both treatment switching and the winner's curse produced point estimates similar to the unadjusted phase 3 results. A prospective plan to pool trial data under a closed testing procedure may be a reasonable strategy when a recruitment shortfall in phase 3 is anticipated, provided that potential sources of misalignment are thoroughly assessed. CLINICAL TRIAL INFORMATION: ACTRN12612000239864 (INTEGRATE I)NCT02773524 (INTEGRATE IIA).
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