{"entity":{"id":"paper-drug-dosing-conundrum-nejm-2021","kind":"paper","name":"FDA's Project Optimus manifesto: cancer drugs are approved at doses that are too high","aka":[],"tldr":"FDA oncology leaders argued that the maximum tolerated dose paradigm inherited from chemotherapy produces targeted drugs and immunotherapies dosed far above what is needed, using sotorasib (960 mg vs 240 mg) as the case study, and launched Project Optimus to require dose optimisation before approval.","summary":"This NEJM perspective from the FDA Oncology Center of Excellence set out why oncology dose selection had to change. Phase 1 trials find the maximum tolerated dose over one cycle, a rational approach for cytotoxics but not for targeted agents and immunotherapies whose effects plateau at lower exposures and whose chronic, low-grade toxicity drives discontinuation.\n\nThe authors cited sotorasib, approved at 960 mg daily although early data showed similar exposure and activity at 240 mg; the FDA required a randomised post-marketing comparison of the two doses, which did not establish the lower dose as equivalent and left the label at 960 mg. Other examples included post-approval dose reductions of cabozantinib, niraparib, ceritinib and dasatinib.\n\nProject Optimus, launched the same year, now expects sponsors to compare more than one dose before pivotal trials; FDA's 2024 guidance on dose optimisation formalised this.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1056/NEJMp2109826"},{"label":"FDA Project Optimus","url":"https://www.fda.gov/about-fda/oncology-center-excellence/project-optimus"}],"tags":[],"related":["idea-tr1-randomised-dose-comparison-before-pivotal","idea-tr1-exposure-response-before-dose-selection","idea-moon-post-approval-dose-deescalation","idea-reg-global-dose-optimisation-guideline"],"cancers":[],"sections":["targeted-therapy"],"technologies":["kinase-inhibitors"],"targets":["kras"],"drugs":["sotorasib","niraparib"],"companies":[],"institutions":[],"pathways":[],"terms":["project-optimus","accelerated-approval"],"trials":[],"people":[],"bottlenecks":["b-dose-optimisation","b-toxicity-qol","b-regulatory-fragmentation"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2021,"doi":"10.1056/NEJMp2109826","pmid":"34623788","authors":"Shah M, Rahman A, Theoret MR, Pazdur R","paperType":"review","findings":["Most targeted agents and immunotherapies have flat exposure-response relationships above a threshold, so the MTD is rarely the optimal dose","Sotorasib: 960 mg chosen despite comparable early activity at 240 mg; a randomised dose comparison was required as a post-marketing commitment","Multiple approved drugs (for example niraparib, cabozantinib, ceritinib, dasatinib) had labelled doses lowered after approval because of toxicity","Proposal: randomised comparison of at least two doses, with patient-reported tolerability, before registrational trials"],"whatItMeans":"The dose on the label is often not the best dose for patients; it is the highest one that was tolerable for a few weeks. Project Optimus means new cancer drugs should arrive with evidence on dose, and it gives clinicians licence to consider dose reduction for toxicity. For older drugs, the evidence gap persists.","caveats":["A perspective rather than a trial; the regulatory shift adds cost and time to development that smaller sponsors resist","Lower doses could under-treat if exposure-response is misjudged; dose comparisons need adequate power","Post-marketing dose studies are slow and often inconclusive, as sotorasib showed","Global regulators have not fully harmonised on dose-optimisation expectations"],"changedPractice":true},"route":"/key-papers/paper-drug-dosing-conundrum-nejm-2021/","neighbours":{"idea":[{"id":"idea-cost-optimus-legacy-drugs","kind":"idea","name":"Apply Project Optimus to drugs already on the market","route":"/ideas/idea-cost-optimus-legacy-drugs/"},{"id":"idea-tr1-exposure-response-before-dose-selection","kind":"idea","name":"Exposure-response modelling with a pre-set target exposure before any dose is chosen","route":"/ideas/idea-tr1-exposure-response-before-dose-selection/"},{"id":"idea-reg-global-dose-optimisation-guideline","kind":"idea","name":"Make pre-approval dose optimisation an ICH standard so it is done once worldwide","route":"/ideas/idea-reg-global-dose-optimisation-guideline/"},{"id":"idea-tr1-randomised-dose-comparison-before-pivotal","kind":"idea","name":"Randomise at least two doses in phase 2 before any pivotal trial","route":"/ideas/idea-tr1-randomised-dose-comparison-before-pivotal/"},{"id":"idea-moon-post-approval-dose-deescalation","kind":"idea","name":"Randomised lower-dose trials for approved drugs with quality of life as the primary endpoint","route":"/ideas/idea-moon-post-approval-dose-deescalation/"}],"section":[{"id":"targeted-therapy","kind":"section","name":"Targeted Therapy","route":"/fronts/targeted-therapy/"}],"technology":[{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}],"target":[{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"}],"drug":[{"id":"niraparib","kind":"drug","name":"Niraparib","route":"/drugs/niraparib/"},{"id":"sotorasib","kind":"drug","name":"Sotorasib","route":"/drugs/sotorasib/"}],"term":[{"id":"accelerated-approval","kind":"term","name":"Accelerated approval","route":"/terms/accelerated-approval/"},{"id":"project-optimus","kind":"term","name":"Project Optimus","route":"/terms/project-optimus/"}],"bottleneck":[{"id":"b-regulatory-fragmentation","kind":"bottleneck","name":"Regulatory divergence between regions","route":"/bottlenecks/b-regulatory-fragmentation/"},{"id":"b-toxicity-qol","kind":"bottleneck","name":"Toxicity and quality of life are undervalued","route":"/bottlenecks/b-toxicity-qol/"},{"id":"b-dose-optimisation","kind":"bottleneck","name":"Wrong doses","route":"/bottlenecks/b-dose-optimisation/"}],"journal":[{"id":"nejm","kind":"journal","name":"New England Journal of Medicine","route":"/journals/nejm/"}],"person":[{"id":"ian-tannock","kind":"person","name":"Ian F. Tannock","route":"/people/ian-tannock/"}],"paper":[{"id":"paper-ostrem-kras-g12c-nature-2013","kind":"paper","name":"Ostrem and Shokat: the hidden pocket that made KRAS G12C druggable","route":"/key-papers/paper-ostrem-kras-g12c-nature-2013/"}]}}