Secondary Logo

Journal Logo

Institutional members access full text with Ovid®

Association Between Pembrolizumab-related Adverse Events and Treatment Outcome in Advanced Melanoma

Results From the Dutch Expanded Access Program

Bisschop, Cornelis*; Wind, Thijs T.*; Blank, Christian U.; Koornstra, Rutger H.T.; Kapiteijn, Ellen§; Van den Eertwegh, Alfonsus J.M.; De Groot, Jan Willem B.; Jalving, Mathilde*; Hospers, Geke A.P.*

doi: 10.1097/CJI.0000000000000271
Clinical Studies

Toxicity of immune checkpoint inhibitors such as ipilimumab and nivolumab is likely associated with clinical efficacy. In this study, we aim to evaluate this association for pembrolizumab. To this end, data of 147 patients included in the Dutch cohort of the Pembrolizumab Expanded Access Program were collected. All data were collected prospectively. Patients with adverse events (AEs) at any time during therapy showed a higher chance of achieving disease control compared with patients without AEs (low-grade AEs vs. no AEs: odds ratio=12.8, P=0.0002, high-grade AEs vs. no AEs: odds ratio=38.5, P=0.0001) according to a multivariate logistic regression analysis. In addition, Cox regression analysis showed a lower risk of death (hazard ratio: 0.51, 95% confidence interval: 0.28–0.97) and disease progression (hazard ratio: 0.54, 95% confidence interval: 0.30–0.98) over time for patients with high-grade AEs at any time during therapy compared with patients without AEs during therapy. To correct for time dependency of occurrence of AEs, a pseudolandmark analysis at 6 months of therapy was performed. Although significance was lost (Wald test P>0.05), prolonged survival in 3 patients who stopped therapy within 6 months due to the occurrence of AEs was observed, suggesting the potential treatment benefit despite the premature ending of therapy. The occurrence of high-grade toxicity at any time during treatment was associated with higher objective response rates, progression-free survival, and overall survival. There remains a need to assess the predictive value of early occurring AEs on patient survival.

*Department of Medical Oncology, University Medical Center Groningen, Groningen

Department of Medical Oncology, Netherlands Cancer Institute NKI-AVL

Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam

Department of Medical Oncology, Radboud University Medical Center, Nijmegen

§Department of Medical Oncology, Leiden University Medical Center, Leiden

Oncology Center Isala, Zwolle, The Netherlands

Reprints: Geke A.P. Hospers, Department of Medical Oncology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands (e-mail:

Received January 30, 2019

Accepted April 8, 2019

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.