SOCRA 2024 Annual Conference Program Book - Flipbook - Page 54
Lack of activity most common reason for failure at late
stages of development
Contributors to high attrition rate
Suboptimal
preclinical models
(not predictive)
Lack of validated
assays to measure
on‐target activity
Adaptive resistance
Suboptimal
understanding of
target or
population
Toxicities: Right
dose/schedule?
Harrison et al. Nat Rev Drug Discovery 2016
2012‐15
2020‐22
Pre‐Optimus:
dose per label
too high…
INCREASED
POSTMARKET
REQUIREMENT TO
EVALUATE LOWER
DOSES IN THE LAST
DECADE
Novel anticancer agents FDA approved 2012‐2022
From Drugs@FDA selected PMR intended to inform
dosing
71% of PMR to evaluate safety/efficacy of lower doses
TOXICITY!!
Collins et al. Clin Can Res 2024
The cytotoxic era paradigms
Shah et al. NEJM 2021
HIGHER doses and BETTER outcomes…
Dose response relationship for
efficacy (higher dose better)
Small therapeutic window
RP2D is close to MTD
Toxicity is dose related and occurs
early (DLT windows 28 days)
Studies designed to identify MTD not
the optimal biological dose
RP2D recommended phase 2 dose
MTD Maximum tolerated dose
Budman et al. JNCI 1998
Le Torneau et al. Clin Can Res 2009
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