Analyses of selected safety endpoints in phase 1 and late-phase clinical trials of anti-PD-1 and PD-L1 inhibitors: prediction of immune-related toxicities

PURPOSE Anti-PD1 and PD-L1 antibodies are associated with immune-related adverse effects (irAEs). This analysis aims to assess the discrepancies between frequencies of irAEs observed in phase 1 trials with those seen in late-phase trials and to evolve the field of drug development. METHODS PubMed search was conducted for articles published until December of 2016. Trials needed to have at least one of the study arms consisting of nivolumab, pembrolizumab or atezolizumab monotherapy. Trials were matched based on compound used and similarity of populations. All toxicities were reported as frequencies and percentages. P-values to assess differences between matches and non-matches of phase 1 and late-phase trials and between early and late-phase trials themselves were obtained via Fisher's exact test. Odds ratios were obtained via logistic regression. RESULTS Our search yielded 15 late-phase and 10 matching phase 1 trials; n = 4823 and n = 1650, respectively. The most common AEs seen in phase 1 trials were also observed in late-phase trials except for phase 1 trials (median n = 118) with < 118 patients (P = 0.048). Rash, pruritus, and diarrhea were the most frequently irAEs reported. Only colitis was more frequent in late-phase studies (P = 0.045). CONCLUSION Toxicities of anti-PD-1 and PD-L1 observed in phase 1 trials and late-phase trials are similar. There is positive correlation between phase 1 trial sample size and concordance of toxicity frequencies seen in late-phase studies. In conclusion, current immunotherapy phase 1 trials are appropriate in assessing safety profile of anti-PD-1 and PD-L1 antibodies.