A comparison of safety and efficacy of cytotoxic versus molecularly targeted drugs in pediatric phase I solid tumor oncology trials

Background Prior reviews of phase I pediatric oncology trials involving primarily cytotoxic agents have reported objective response rates (ORRs) and toxic death rates of 7.9–9.6% and 0.5%, respectively. These data may not reflect safety and efficacy in phase I trials of molecularly targeted (targeted) drugs. Methods A systematic review of pediatric phase I solid tumor trials published in 1990–2013 was performed. The published reports were evaluated for patient characteristics, toxicity information, and response numbers. Results A total of 143 phase I pediatric clinical trials enrolling 3,896 children involving 53 targeted and 48 cytotoxic drugs were identified. A meta‐analysis demonstrated that the ORR is 2.1‐fold higher with cytotoxic drugs (0.066 vs. 0.031 per subject; P = 0.007). By contrast, the pooled estimate of the stable disease rate (SDR) is similar for cytotoxic and targeted drugs (0.2 vs. 0.23 per subject; P = 0.27). The pooled estimate of the dose‐limiting toxicity rate is 1.8‐fold larger with cytotoxic drugs (0.24 vs. 0.13 per subject; P = 0.0003). The hematologic grade 3–4 (G3/4) toxicity rate is 3.6‐fold larger with cytotoxic drugs (0.43 vs. 0.12 per treatment course; P = 0.0001); however, the nonhematologic G3/4 toxicities and toxic deaths occur at similar rates for cytotoxic and targeted drugs. Conclusions In phase I pediatric solid tumor trials, ORRs were significantly higher for cytotoxic versus targeted agents. SDRs were similar in targeted and cytotoxic drug trials. Patients treated with cytotoxic agents were more likely to experience hematologic G3/4 toxicities than those patients receiving targeted drugs.