6MO Pan-cancer characterization of receptor tyrosine kinases alterations to sort targetable drivers from passengers

Receptor tyrosine kinases (RTK) or ligands have frequent genetic alterations in cancers. Either amplifications, missense mutations fusions of RTK are biomarkers for some targeted therapies a fraction cancers, with heterogeneous responses to kinase inhibitors (TKI), monoclonal antibodies (mabs) andibody-drug conjugates (ADC). An analysis pan-cancer molecular and clinical outcome RTK-altered cancers was conducted 16 selected targetable (EGFR, HER2, KIT, FLT3, TRKA-B-C, ROS1, ALK, RET, MET, FGFR1-2-3-4). The landscape analyzed public databases (MSK-impact / MSK-MET-Tropism) institutional (DNA-targeted sequencing PROFILER, PROFILER-2 (NCT03163732), RNA-seq FFPE database). profile therapeutic activity TKI, mabs, ADC monotherapy genomic-driven trials through systematic review phase I-II-III studies published up January 2022. Clinical efficacy the best quality across cancer types, defined as n>5 patients objective response rate (ORR) 30% and/or median progression free survival (PFS) >6months. RTK-alterations encompass variety situations since only 2% (19/884) "frequent” (prevalence >10%) RTK-alteration. On whole, TKI-targeting strategies is not associated prevalence, but shaped by type (Table) co-alterations. Some main characteristics summarized table. also variable genomic background term tumor mutation count, mutational burden, fusion genome altered. Mutual exclusivity found statistically significant RTK-translocations EGFR KIT FGFR3. Most copy number variations co-occurrent. Despite strong benefit few atypical partners underlying instability challenge notion histology-agnosticism RTK-translocations.Table: 6MOMissense MutationsAmplificationsTranslocationsRemarksPrevalence 18 types (mean min-max)2.9%(0-65%)1%(0-39.2)0.1%(0-16%)Difference (t-test p<10-6)Not targetabilityClinical TKI targeting cancersVariableOnly 64% reached efficacyWeakNone 0% efficacyStrongAll 100% efficacity>1300 screenedSignificant different profileOther characteristicsRole cellular backgroundEfficient involve chemo-therapies ADCsTranslocation partner specificities Open table new tab These analyses reveal wide heterogeneity defining select patient unlabeled rare tumors/alterations. Single agent may be proposed 1) expressed other 2) activating involved normal cell lineage physiology. mab+chemo preferred amplifications.