{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T19:19:34Z","timestamp":1789154374049,"version":"build-2803163510"},"reference-count":53,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T00:00:00Z","timestamp":1778544000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T00:00:00Z","timestamp":1778544000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT\u2010175217"],"award-info":[{"award-number":["PJT\u2010175217"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2026,10,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Phase 2 (and phase 1 dose expansion, which we label phase 2 for the purposes of this study) cancer trials are the first direct tests of a new drug's efficacy. Because efficacy evidence is lacking, the therapeutic status of drug administration during ethical review is uncertain. We compared the efficacy and safety of cancer monotherapies in phase 2\u00a0with phase 3, where clinical equipoise underwrites a therapeutic status for drug administration. In this systematic review and meta\u2010analysis, we searched Clinicaltrials.gov for phase 2 and 3 investigational monotherapy drug trials in six solid malignancies, with primary completion dates 2015\u20132020, inclusive. Two independent reviewers completed data extraction. Effects were estimated using an inverse\u2010variance weighted random\u2010effects model meta\u2010analysis of proportions using the R package\n                    <jats:italic>meta<\/jats:italic>\n                    . We analyzed 130 phase 2 and 52 phase 3 trial arms, enrolling 6665 and 18,694 patients. The pooled objective response rate was 7% (95% CI 5%\u201311%) in phase 2 versus 24% in phase 3 (95% CI 17%\u201331%;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.0001). The median PFS and OS were shorter in phase 2 compared to phase 3 (3.23 vs. 5.43\u2009months,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.0001; 9.46 vs. 14.44\u2009months,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.0001). The pooled rate of drug\u2010related grade 3\u20134 adverse events was 30% (95% CI 23%\u201337%) in phase 2 and 25% (95% CI 19%\u201332%) in phase 3. Monotherapies delivered in phase 2 cancer trials present diminished risk\u2013benefit compared with phase 3 and align with historic estimates for phase 1. Though there may be exceptions, risks for drug administration in phase 2 should generally be justified by appeals to research rather than therapeutic value.\n                  <\/jats:p>","DOI":"10.1002\/ijc.70538","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T13:36:36Z","timestamp":1778592996000},"page":"2015-2024","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Risk\u2013Benefit of Phase 2 Monotherapy Trials in Adult Solid Cancers: A Systematic Review and Meta\u2010Analysis"],"prefix":"10.1002","volume":"159","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5465-2256","authenticated-orcid":false,"given":"Charlotte","family":"Ouimet","sequence":"first","affiliation":[{"name":"Department of Equity, Ethics and Policy McGill University School of Population and Global Health  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Rosu","sequence":"additional","affiliation":[{"name":"Department of Equity, Ethics and Policy McGill University School of Population and Global Health  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1614-6779","authenticated-orcid":false,"given":"Jonathan","family":"Kimmelman","sequence":"additional","affiliation":[{"name":"Department of Equity, Ethics and Policy McGill University School of Population and Global Health  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,12]]},"reference":[{"key":"e_1_2_11_2_1","volume-title":"Results for Cancer Clinical Trials","author":"ClinicalTrials.gov","year":"2024"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cct.2011.04.015"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm0604-570"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.4324\/9781315198231-25"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.MR000024.pub3"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.168.6.632"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.38628.561123.7C"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1467-8519.2012.01979.x"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.2307\/3527646"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2016.67.9902"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.21.02125"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-019-0264-7"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2006.04.046"},{"key":"e_1_2_11_15_1","first-page":"vi476","volume-title":"Risks and Benefits of Phase 1 Oncology Trials in the Era of Personalized Medicine","author":"Chakiba C.","year":"2016"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.26258"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0234911"},{"key":"e_1_2_11_18_1","first-page":"2552","volume-title":"Risks and Benefits of Phase 1 Oncology Trials, 2001 Through 2012","author":"Fukuda Y. K.","year":"2014"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1200\/PO.20.00214"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.292.17.2130"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)01390-3"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11523-021-00822-5"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2015.61.5997"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2023.05.015"},{"key":"e_1_2_11_25_1","first-page":"40","article-title":"Risks and Benefits of Anticancer Drugs in Advanced Cancer Patients: A Systematic Review and Meta\u2010Analysis","volume":"40","author":"Bachelard C. M.","year":"2021","journal-title":"EClinicalMedicine"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mds590"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-023-00667-z"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-21-0212"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.11.009"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1136\/esmoopen-2020-000871"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1956"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2023.113503"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2020.11809"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.d5928"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2015.6315"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamainternmed.2019.0583"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/95.1.19"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.critrevonc.2015.10.018"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2022.101753"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.7326\/M23-2515"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2026.112149"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2023.03.028"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2023.04.001"},{"key":"e_1_2_11_44_1","unstructured":"U.S. Department of Health Human Services \u201cDelays in Confirmatory Trials for Drug Applications Granted FDA's Accelerated Approval Raise Concerns \u201d OEI\u201001\u201321\u201000401 09\u201029\u20102022 2022."},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.j4530"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djv253"},{"key":"e_1_2_11_47_1","first-page":"25","article-title":"Clinical Development Success Rates 2006\u20132015","volume":"1","author":"Thomas D. W.","year":"2016","journal-title":"BIO Industry Analysis"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1093\/biostatistics\/kxx069"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(24)00040-8"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-020-01050-w"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2023.102156"},{"key":"e_1_2_11_52_1","unstructured":"Administration USFD \u201cExpansion Cohorts: Use in First\u2010In\u2010Human Clinical Trials to Expedite Development of Oncology Drugs and Biologics \u201d Food and Drug Administration Guidance Document 2018."},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacbts.2019.02.005"},{"key":"e_1_2_11_54_1","unstructured":"U.S. Food Drug Administration \u201cMaster Protocols for Drug and Biological Product Development: Draft Guidance for Industry \u201d 2023."}],"container-title":["International Journal of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ijc.70538","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ijc.70538","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ijc.70538","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T13:08:49Z","timestamp":1787317729000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ijc.70538"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,12]]},"references-count":53,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,10,15]]}},"alternative-id":["10.1002\/ijc.70538"],"URL":"https:\/\/doi.org\/10.1002\/ijc.70538","archive":["Portico"],"relation":{},"ISSN":["0020-7136","1097-0215"],"issn-type":[{"value":"0020-7136","type":"print"},{"value":"1097-0215","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,12]]},"assertion":[{"value":"2025-09-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-12","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}