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However, due to high costs, many remain unavailable to patients in low\u2010 and middle\u2010income countries. Next to exorbitant drug pricing, uncertainty of the magnitude of benefit of new treatments can contribute to differences in global access to cancer treatments, even in high\u2010income countries. Health technology assessment (HTA) organizations employ predetermined criteria to assess whether a drug's efficacy suffices for local approval, ideally informed by randomized controlled trials (RCTs) that provide data on the clinically relevant endpoints overall survival (OS) and quality of life (QoL). Contemporary oncology RCTs increasingly suffer from design and interpretation issues that lead to inadequate data for HTA assessments. The Keynote\u2010177 RCT was the landmark study demonstrating the superiority of pembrolizumab over chemotherapy in terms of progression free survival and subsequently OS, as a first\u2010line treatment for patients with metastatic microsatellite instable high (MSI) colorectal cancer (CRC). However, in a trial testing the initial efficacy of immunotherapy in advanced MSI CRC, the allowance of crossover delayed the OS signal. Along with other design\u2010related limitations, this complicates the precise determination of the absolute benefit of first\u2010line immunotherapy on OS or quality of life in advanced MSI CRC.<\/jats:p>","DOI":"10.1002\/cam4.71817","type":"journal-article","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T02:54:41Z","timestamp":1776221681000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Keynote\u2010177 Randomized Controlled Trial of First\u2010line\n                    <scp>PD<\/scp>\n                    \u20101 Blockade for Microsatellite\u2010High or Mismatch Repair\u2010Deficient Advanced Colorectal Cancer: Potential Consequences of the Cross\u2010Over Trial Design and Related Issues"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6287-4016","authenticated-orcid":false,"given":"S. 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Hamelbergweg  Willemstad Cura\u00e7ao"},{"name":"Institute for Medical Education University Medical Center Groningen  Hanzeplein 1 the Netherlands"},{"name":"Red Cross Blood Bank Foundation Pater Eeuwensweg 36  Willemstad Cura\u00e7ao"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9105-8248","authenticated-orcid":false,"given":"J. 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