{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T11:55:54Z","timestamp":1753876554721,"version":"3.41.2"},"reference-count":16,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T00:00:00Z","timestamp":1748822400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004326","name":"Bayer","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004326","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001111","name":"Cancer Australia","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001111","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"NHMRC","doi-asserted-by":"publisher","award":["1037786","1150467"],"award-info":[{"award-number":["1037786","1150467"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000147","name":"Canadian Cancer Society","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000147","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001349","name":"Singapore National Medical Research Council","doi-asserted-by":"crossref","award":["NMRC\/MOH\/000396"],"award-info":[{"award-number":["NMRC\/MOH\/000396"]}],"id":[{"id":"10.13039\/501100001349","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>The 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 \u201cwinner\u2019s curse.\u201d We evaluated phase 2 results, adjusted for these opposing effects, against phase 3 according to the prespecified statistical analysis plan.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Overall 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\u2019s curse, and Bayesian prediction methods predicted phase 3 outcomes from phase 2 estimates. A simulation study modeled 10\u200a000 seamless phase 2\/3 trials to quantify bias in the pooled estimate.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The observed phase 3 hazard ratio (HR\u2009=\u20090.71, 95% CI\u2009=\u20090.54 to 0.93) for overall survival was more conservative than the adjusted phase 2 estimates (RPSFTM and novel shrinkage approach: HR\u2009=\u20090.61, 95% CI\u2009=\u20090.29 to 1.29; RPSFTM and Bayesian prediction: HR\u2009=\u20090.59, 95% CI\u2009=\u20090.48 to 0.73; IPCW and novel shrinkage approach: HR\u2009=\u20090.55, 95% CI\u2009=\u20090.31 to 0.99; IPCW and Bayesian prediction: HR\u2009=\u20090.58, 95% CI\u2009=\u20090.46 to 0.72). Simulations indicated negligible bias in the pooled log hazard ratio of \u20120.011 and 0.005 under the null and alternative hypotheses, respectively.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Adjusting phase 2 estimates for both treatment switching and the winner\u2019s 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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Clinical trial information<\/jats:title>\n                  <jats:p>ACTRN12612000239864 (INTEGRATE I)<\/jats:p>\n                  <jats:p>NCT02773524 (INTEGRATE IIA)<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jncics\/pkaf053","type":"journal-article","created":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T14:24:23Z","timestamp":1748874263000},"source":"Crossref","is-referenced-by-count":0,"title":["INTEGRATE pooled phase 2\/3 results are robust to postprogression switching and the winner\u2019s curse"],"prefix":"10.1093","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1995-2170","authenticated-orcid":false,"given":"Yu Yang","family":"Soon","sequence":"first","affiliation":[{"name":"NHMRC Clinical Trials Centre, University of Sydney , Sydney, NSW,","place":["Australia"]},{"name":"Department of Radiation Oncology, National University Cancer Institute , Singapore,","place":["Singapore"]},{"name":"Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore , ,","place":["Singapore Singapore"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9028-8682","authenticated-orcid":false,"given":"Katrin","family":"Sjoquist","sequence":"additional","affiliation":[{"name":"NHMRC Clinical Trials Centre, University of Sydney , Sydney, NSW,","place":["Australia"]},{"name":"Cancer Care Centre, St George Hospital , Kogarah, NSW,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6225-1572","authenticated-orcid":false,"given":"Ian C","family":"Marschner","sequence":"additional","affiliation":[{"name":"NHMRC Clinical Trials Centre, University of Sydney , Sydney, NSW,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9397-4976","authenticated-orcid":false,"given":"I Manjula","family":"Schou","sequence":"additional","affiliation":[{"name":"NHMRC Clinical Trials Centre, University of Sydney , Sydney, NSW,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1738-0316","authenticated-orcid":false,"given":"Nick","family":"Pavlakis","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Royal North Shore Hospital , Sydney, NSW,","place":["Australia"]},{"name":"Faculty of Medicine and Health, University of Sydney , Sydney, NSW,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Goldstein","sequence":"additional","affiliation":[{"name":"Nelune Cancer Centre, Prince of Wales Hospital , Sydney, NSW,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5196-3630","authenticated-orcid":false,"given":"Kohei","family":"Shitara","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Oncology, National Cancer Centre Hospital East , Kashiwa City,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3793-8724","authenticated-orcid":false,"given":"Martin R","family":"Stockler","sequence":"additional","affiliation":[{"name":"NHMRC Clinical Trials Centre, University of Sydney , Sydney, NSW,","place":["Australia"]},{"name":"Department of Medical Oncology, Concord Repatriation General Hospital , Sydney, NSW,","place":["Australia"]},{"name":"Department of Medical Oncology, Chris O\u2019Brien Lifehouse , Sydney, NSW,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3740-7563","authenticated-orcid":false,"given":"John","family":"Simes","sequence":"additional","affiliation":[{"name":"NHMRC Clinical Trials Centre, University of Sydney , Sydney, NSW,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5804-2295","authenticated-orcid":false,"given":"Andrew J","family":"Martin","sequence":"additional","affiliation":[{"name":"NHMRC Clinical Trials Centre, University of Sydney , Sydney, NSW,","place":["Australia"]},{"name":"Centre for Clinical Research, ULTRA The University of Queensland Clinical Trials Capability , Herston, Brisbane, 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