title: Are Doses and Schedules of Small-Molecule Targeted Anticancer Drugs Recommended by Phase I Studies Realistic?
abstract: Tolerability of molecularly targeted agents (MTA) used in cancer therapeutics is 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 whether 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 mAb MTA (MA-MTA) approved by the FDA in the last 12 years. There was a significantly increased percentage of grade 3 or 4 adverse events reported with SM-MTA compared with MA-MTA [40% vs. 27%; RR 1.5; 95% confidence interval (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 II 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 versus 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. Clin Cancer Res; 22(9); 2127-32. ©2015 AACR.
authors.affiliation: The Institute of Cancer Research, London, United Kingdom. The Royal Marsden NHS Foundation Trust, London, United Kingdom.
authors.forename: Desamparados
authors.initials: D
authors.lastname: Roda
authors.affiliation: The Institute of Cancer Research, London, United Kingdom. The Royal Marsden NHS Foundation Trust, London, United Kingdom.
authors.forename: Begoña
authors.initials: B
authors.lastname: Jimenez
authors.affiliation: The Institute of Cancer Research, London, United Kingdom. The Royal Marsden NHS Foundation Trust, London, United Kingdom. udai.banerji@icr.ac.uk.
authors.forename: Udai
authors.initials: U
authors.lastname: Banerji
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods; D009369:Neoplasms / Q000188:drug therapy*; D054852:Small Molecule Libraries / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D054852:Small Molecule Libraries