Research Papers:

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

Ricardo Costa _, Rubens B. Costa, Sarah M. Talamantes, Irene Helenoswki, Benedito A. Carneiro, Young Kwang Chae, William J. Gradishar, Razelle Kurzrock and Francis J. Giles

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Oncotarget. 2017; 8:67782-67789. https://doi.org/10.18632/oncotarget.18847

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Ricardo Costa1, Rubens B. Costa1, Sarah M. Talamantes2, Irene Helenoswki3, Benedito A. Carneiro1, Young Kwang Chae1, William J. Gradishar1, Razelle Kurzrock4 and Francis J. Giles1

1Division of Hematology Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

2Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

3Northwestern University Department of Preventive Medicine, Chicago, Illinois, USA

4Center for Personalized Cancer Therapy, Moores Cancer Center, University of California at San Diego, La Jolla, California, USA

Correspondence to:

Ricardo Costa, email: [email protected]

Keywords: anti-PD-1 antibodies, toxicity, clinical trial, solid tumors

Received: March 29, 2017     Accepted: May 31, 2017     Published: June 29, 2017


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.

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