Treatment with immune checkpoint inhibitors (ICIs) is successful, but only in a subset of patients with advanced stage non-small cell lung cancer (NSCLC). Blood-based kinase profiling of peripheral blood mononuclear cells (PBMCs) has previously shown its predictive value for response to ICI treatment in a discovery cohort (Hurkmans et al., JITC 2020). The aim of the current prospective study was to perform a blind validation of the predictive value of kinase activity profiles in PBMCs for ICI response in patients with NSCLC in a standardized setting.
PBMCs from patients with advanced stage NSCLC included in this multicenter study were collected prior to ICI treatment. Tyrosine kinase activity of PBMCs were profiled using a micro-array with 144 different peptide-substrates (Pamchip). Classification analysis was based on grouping of patients with no progression vs. progression (RECIST v1.1) ≤24 weeks after start of treatment. Only patients treated with first-line pembrolizumab (+/- chemotherapy) and ≥24 weeks follow-up were included.
The model was first established based on tyrosine kinase activity profiles, determined in a calibration cohort (N = 61) and then applied to an independent validation cohort (N = 63). The model had a predictive accuracy of 60% (CI95 = 47-72%), which was improved when the model was combined with PD-L1 expression: for patients with a PD-L1 score <50%, the accuracy was 72% (CI95 = 55-86%). For this subgroup of patients, the kinome analysis showed a significant lower progression-free survival for patients for whom progression was predicted vs. those for whom no progression was predicted (p <0.01, hazard ratio= 3.6, CI95 = 1.6-8.1).
The tyrosine kinome of PBMCs before ICI treatment can be applied to predict progressive disease in patients with advanced stage NSCLC, in particular when combined with low PD-L1 expression. This may imply enhanced predictive value of kinome profiling for tumors with low presence of CD8 T cells. The latter needs confirmation, for which data from an ongoing extension study will be used. The final aim is to implement the kinome analysis for clinical use.
The authors.
Pamgene International B.V.
K.D. Joode: Financial Interests, Personal, Other, Travel expenses congress: Ipsen. C.H. Van Der Leest: Financial Interests, Personal, Advisory Board: MSD, Janssens, BMS. B. Pinedo: Financial Interests, Personal, Advisory Board, 2017-2021: Pamgene International B.V., Vitromics; Financial Interests, Personal, Advisory Board: Glycostem B.V., Dulisco U.A., Biox Biosciences B.V., ORCA Therapeutic B.V., Qurin Diagnostics; Financial Interests, Personal, Stocks/Shares: Qurin Diagnostics. E. Kapiteijn: Financial Interests, Personal and Institutional, Advisory Role: Bristol Myers Squibb, Novartis, Merck; Financial Interests, Personal, Advisory Role: Pierre Fabre; Financial Interests, Personal, Research Grant, not related to this paper: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant, not related to this paper: Pierre Fabre. R. Debets: Financial Interests, Institutional, Research Grant, paid to institution: MSD, Bayer; Financial Interests, Personal and Institutional, Advisory Role, paid to institution: Bluebird Gio; Financial Interests, Personal and Institutional, Advisory Board, paid to institution: Genticel; Other, Institutional, Other, Paid to institution: Pan Cancer T; Other, Institutional, Other, no's 21152822.9 and 21184727.2 (pending to Erasmus MC): European patent application. J.P. Groten: Financial Interests, Personal, Advisory Board: Single Cell Discoveries bv; Financial Interests, Personal, Advisory Role: Vitromics Health Care bv; Financial Interests, Personal, Other, employee: Pamgene International B.V.; Non-Financial Interests, Personal, Advisory Role: AstraZeneca Corporation, MSD Europe, Charles River Corporation, Vitromics Healthcare; Non-Financial Interests, Personal, Invited Speaker: European Society of Toxicology; Non-Financial Interests, Personal, Invited Speaker, Visiting professor: Wageningen University research. J.G. Aerts: Financial Interests, Personal, Advisory Board, Speakers fee: Eli Lilly, MSD, Takeda; Financial Interests, Personal, Advisory Board: Amphera, Pfizer, BMS; Financial Interests, Personal, Advisory Role, DMC member, speakers fee: BIOCAD; Financial Interests, Personal, Stocks/Shares: Amphera; Financial Interests, Personal, Stocks/Shares, Patent pending: Pamgene, Amphera; Financial Interests, Institutional, Principal Investigator, present participation in >60 clinical trials related to oncology (all compensation paid to intitution): Multiple; Non-Financial Interests, Personal, Member, Board member IASCL: IASLC. R.H. Mathijssen: Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Role: Servier; Financial Interests, Personal, Stocks/Shares, patent pending: Pamgene International B.V.; Financial Interests, Institutional, Research Grant, Investigator-initiated research: Astellas, Bayer, Boehringer Ingelheim, Cristal Therapeutics, Pamgene, Pfizer, Novartis, Roche, Servier. All other authors have declared no conflicts of interest.