{"entity":{"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","aka":[],"tldr":"Many cancer drugs are approved at the highest dose patients could stand, not the best dose. Run trials that test lower doses on approved drugs and measure how patients feel.","summary":"Maximum tolerated dose remains the default for oral targeted agents and many antibody-drug conjugates; discontinuation for toxicity is common (abemaciclib, lenvatinib, cabozantinib, sotorasib). FDA Project Optimus addresses new drugs, not the existing catalogue. The proposal is a funded programme of post-marketing randomised non-inferiority trials of reduced or adaptive doses with patient-reported tolerability as primary and progression-free survival as a non-inferiority secondary, with regulators committed to label updates.","asOf":"2026-09-08","links":[{"label":"FDA Project Optimus","url":"https://www.fda.gov/about-fda/oncology-center-excellence/project-optimus"}],"tags":[],"related":[],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["abemaciclib","sotorasib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":["b-toxicity-qol","b-dose-optimisation"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"For a majority of tested drugs, a lower or adaptive dose is non-inferior for progression-free survival and clearly superior for tolerability and adherence.","rationale":"Dose-response for many targeted drugs plateaus below the approved dose; sotorasib 240 mg versus 960 mg and several endocrine and kinase inhibitor examples support the pattern. Payers benefit directly.","test":"Payer-academic consortium funds five non-inferiority dose trials in the highest-spend drugs with known toxicity problems; readouts within four years.","maturity":"early-clinical","actor":"research","cost":"medium","horizonYears":4},"route":"/ideas/idea-moon-post-approval-dose-deescalation/","neighbours":{"drug":[{"id":"abemaciclib","kind":"drug","name":"Abemaciclib","route":"/drugs/abemaciclib/"},{"id":"sotorasib","kind":"drug","name":"Sotorasib","route":"/drugs/sotorasib/"}],"bottleneck":[{"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/"}],"paper":[{"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","route":"/key-papers/paper-drug-dosing-conundrum-nejm-2021/"}]}}