Background Immune checkpoint inhibitor (ICI) can cause severe and sometimes fatal immune-related adverse events (irAEs). Since these irAEs mimick immunological disease, a female predominance has... Show moreBackground Immune checkpoint inhibitor (ICI) can cause severe and sometimes fatal immune-related adverse events (irAEs). Since these irAEs mimick immunological disease, a female predominance has been speculated on. Nevertheless, no demographic or tumour-related factors associated with an increased risk of irAEs have been identified until now. Methods Risk ratios of severe (grade >= 3) irAEs for age, sex, WHO performance status, number of comorbidities, stage of disease, number of metastases and serum lactate dehydrogenases (LDH) were estimated using data from anti-PD1-treated patients with advanced melanoma in the prospective nationwide Dutch Melanoma Treatment Registry. Results 111 (11%) out of 819 anti-programmed cell death 1 treated patients experienced severe irAEs. Patients with non-lung visceral metastases (stage IV M1c or higher) less often experienced severe irAEs (11%) compared with patients with only lung and/or lymph node/soft tissue involvement (stage IV M1b or lower; 19%; adjusted risk ratio (RRadj) 0.63; 95% CI 0.41 to 0.94). Patients with LDH of more than two times upper limit of normal had a non-significantly lower risk of developing severe irAEs than those with normal LDH (RRadj 0.65; 95% CI 0.20 to 2.13). None of the other variables were associated with severe irAEs. Conclusion In patients with melanoma, more advanced disease is associated with a lower rate of severe irAEs. No association with sex was found. Show less
Background The profound disparity in response to immune checkpoint blockade (ICB) by cutaneous melanoma (CM) and uveal melanoma (UM) patients is not well understood. Therefore, we characterized... Show moreBackground The profound disparity in response to immune checkpoint blockade (ICB) by cutaneous melanoma (CM) and uveal melanoma (UM) patients is not well understood. Therefore, we characterized metastases of CM and UM from the same metastatic site (liver), in order to dissect the potential underlying mechanism in differential response on ICB. Methods Tumor liver samples from CM (n=38) and UM (n=28) patients were analyzed at the genomic (whole exome sequencing), transcriptional (RNA sequencing) and protein (immunohistochemistry and GeoMx Digital Spatial Profiling) level. Results Comparison of CM and UM metastases from the same metastatic site revealed that, although originating from the same melanocyte lineage, CM and UM differed in somatic mutation profile, copy number profile, tumor mutational burden (TMB) and consequently predicted neoantigens. A higher melanin content and higher expression of the melanoma differentiation antigen MelanA was observed in liver metastases of UM patients. No difference in B2M and human leukocyte antigen-DR (HLA-DR) expression was observed. A higher expression of programmed cell death ligand 1 (PD-L1) was found in CM compared with UM liver metastases, although the majority of CM and UM liver metastases lacked PD-L1 expression. There was no difference in the extent of immune infiltration observed between CM and UM metastases, with the exception of a higher expression of CD163 (p<0.0001) in CM liver samples. While the extent of immune infiltration was similar for CM and UM metastases, the ratio of exhausted CD8 T cells to cytotoxic T cells, to total CD8 T cells and to Th1 cells, was significantly higher in UM metastases. Conclusions While TMB was different between CM and UM metastases, tumor immune infiltration was similar. The greater dependency on PD-L1 as an immune checkpoint in CM and the identification of higher exhaustion ratios in UM may both serve as explanations for the difference in response to ICB. Consequently, in order to improve current treatment for metastatic UM, reversal of T cell exhaustion beyond programmed cell death 1 blockade should be considered. Show less
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... Show moreToxicity 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. Show less
Jochems, A.; Kooij, M.K. van der; Fiocco, M.; Schouwenburg, M.G.; Aarts, M.J.; Akkooi, A.C. van; ... ; Kapiteijn, E. 2019