"Are Doses and Schedules of Small Molecule Targeted Anticancer Drugs Recommended by Phase I Studies Realistic?"
A partir de données portant sur des essais de phase I et III de thérapies ciblées ayant fait l'objet d'une autorisation de mise sur le marché par la "Food and Drug Administration" au cours des 12 dernières années, cette étude suggère que les essais de phase I sous-estiment les toxicités d'un traitement dans leurs recommandations de doses pour les essais ultérieurs
Tolerability of molecularly targeted agents (MTA) used in cancer therapeutics are determined in phase I trials. We reviewed the reported incidence of toxicity in phase III trials at doses and schedules recommended by phase I trials to evaluate if these recommendations are realistic when drugs are used in larger populations of patients. We systematically reviewed a safety profile of small molecule (SM-MTA) and monoclonal antibody MTA (MA-MTA) approved by the FDA in the last twelve years. There was a significantly increased percentage of grade 3 or 4 adverse events reported with SM-MTA compared to MA-MTA (40% v 27%, RR 1.5, 95% CI 1.10-2.25 p=0.038) in phase III studies. Importantly, a substantial proportion of patients (45%) treated with SM-MTA required dose modifications due to drug related toxicity in phase III trials. However this toxicity was associated to a definitive study drug discontinuation in only 9%. Overall 25% of SM-MTA declared recommended phase 2 doses below MTD based on pharmacokinetic-pharmacodynamic data and these trials were associated with a significantly reduced number of dose modifications in registration trials (32% vs 50%, RR: 0.64 95% CI 0.43-0.88, p=0.01). Tolerability is going to come into further focus due to the need for combinations of SM-MTA and other anticancer agents. There was a higher incidence of grade 3-4 toxicity in phase III trials in combinations vs single agent SM-MTAs. (64% vs 37%, RR 1.73, 95% CI 1.3-2.3, p=0.001). These results indicate that phase I studies underestimate toxicity while recommending doses of SM-MTA.
Clinical Cancer Research , article en libre accès, 2015