ASCO Abstract Link
1. Dept. of Medical Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands 2. Dept. of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands 3. Dept. of Dermatology, University Hospital Zurich, Zurich, Switzerland 4. PamGene International B.V., ‘s-Hertogenbosch, The Netherlands 5. Dept. of Pulmonology, Erasmus University Medical Center, Rotterdam, The Netherlands
Background: Prediction of clinical responses to checkpoint inhibitor therapies is urgently needed. Notably, a significant proportion of patients does not benefit from the treatment, agents are costly and may cause serious toxicity. The kinase activity of peripheral blood cells (PBMCs) may reflect biological mechanisms underlying response to immunotherapy. We hypothesized that kinase activity profiles from PBMCs may constitute a predictive marker for clinical response to CTLA4 and/or PD1 blockade immunotherapy in patients with advanced melanoma. Methods: In a multi-center effort, data were prospectively collected from 6 cohorts of anti-CTLA4- or anti-PD1-treated advanced melanoma patients (n = 138). Kinase activity profiles were generated by analyzing phosphorylation signatures of PBMC lysates on a peptide micro-array. The PamChip (PamGene, Netherlands) microarray comprises 144 different peptides derived from protein phosphorylation sites that are substrates for protein tyrosine kinases. Performance of the predictive model (PLS-DA) was estimated using cross-validation and described by correct classification rate (CCR). Analyses were based on binary grouping of best overall response (RECIST v1.1; CR/PR/SD vs PD) and early/late progression using PFS data (cut-off 140 days). Results: Predictive signatures were discovered for anti-CTLA4 in cohort 1 (anti-CTLA4; n = 10; CCR = 100%; 95%CI 69-100%) and confirmed in cohort 2 (anti-CTLA4; n = 28; CCR = 82%; 95%CI 63-94%), as well as for anti-PD1 in cohort 3 (anti-PD1; n = 17; CCR = 76%; 95%CI 50-93%), which was confirmed in cohort 4 (anti-PD1; n = 29; CCR = 72%; 95%CI 53-87%), cohort 5 (anti-PD1; n = 38; CCR = 75%; 95%CI 57-87%), and cohort 6 (anti-PD1; n = 16; non-evaluable due to the low number of responders). Conclusions: In advanced melanoma patients, kinase activity profiles of baseline PBMCs samples can predict the likelihood of response to anti-PD1 or anti-CTLA4 therapy. This assay may serve as a rapid and fast predictive liquid biomarker to stratify patients prior to treatment. Involvement of receptor tyrosine kinases underlying the mechanism are being further elucidated and a larger validation study is underway.
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