# Randomised lower-dose trials for approved drugs with quality of life as the primary endpoint

Source: https://onco.cc/ideas/idea-moon-post-approval-dose-deescalation/  
OnCo record `idea-moon-post-approval-dose-deescalation` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- 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.
- Proposed 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

## Sources

- FDA Project Optimus: https://www.fda.gov/about-fda/oncology-center-excellence/project-optimus

## Connected records

- drugs: [Abemaciclib](https://onco.cc/drugs/abemaciclib/), [Sotorasib](https://onco.cc/drugs/sotorasib/)
- bottlenecks: [Toxicity and quality of life are undervalued](https://onco.cc/bottlenecks/b-toxicity-qol/), [Wrong doses](https://onco.cc/bottlenecks/b-dose-optimisation/)
- key papers: [FDA's Project Optimus manifesto: cancer drugs are approved at doses that are too high](https://onco.cc/key-papers/paper-drug-dosing-conundrum-nejm-2021/)

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