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

Abstract

PurposeAnti-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.MethodsPubMed 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.ResultsOur 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).ConclusionToxicities 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.

Phase I trials as valid therapeutic options for patients with cancer

“…With regard to ICI, the authors of a study of 25 trials of antiprogrammed cell death protein 1 (PD-1) or anti-programmed cell death 1 ligand 1 (PD-L1) antibodies, including 6,473 patients, found that, in trials with >118 patients, the incidence of toxicities reported in early phase trials was consistent with that observed for the same agent in later phase trials (P = 0.048) 60 . The only common toxicity that was reported more often in later-phase studies was colitis (P = 0.045) 60 .…”

Immunotherapy “Shock” a case series of PD-L1 100% and pembrolizumab first-line treatment

“…The cases that we currently present are the first where PD-L1 = 100% with DAKO has been observed along with abscess which we attribute to the connection of pembrolizumab and the high expression of PD-L1. The adverse effects of immunotherapy have been previously well described, however; we have still many to observe [17] , [18] , [19] , [20] . We have observed small differences between the Bio Care kit clone CAL10 and the 22C3 pharmDx™ Kit, DAKO expression.…”

Nanoparticle‐based photothermal and photodynamic immunotherapy for tumor treatment

“…Therefore, new effective antitumor treatments should be urgently developed. [9][10][11][12] Therefore, one considerable strategy is to improve the efficacy of immunotherapeutic drugs and reduce their side effects. For example, the success of immune checkpoint inhibitors, such as antiprogrammed death (PD-1)/programmed death-ligand 1 (PD-L1) and anticytotoxic T lymphocyte-associate antigen-4 (anti-CTLA-4) antibodies, have substantially promoted the development of oncology treatments.…”

“…8 Moreover, immune side effects, including the cascade effect of inflammatory mediators, hematopoietic system dysfunction, organ toxicity and rapid emergence of drug resistance, have limited the clinical optimization of these methods. [9][10][11][12] Therefore, one considerable strategy is to improve the efficacy of immunotherapeutic drugs and reduce their side effects.…”