A multicenter, retrospective study of non-small-cell lung carcinoma (NSCLC) harboring EGFR exon 20 insertions: Distribution, variants, and prevalence of coalterations

Background EGFR exon 20 activating insertions (ex20ins) represent around 4% of EGFR mutations in NSCLC, being more prevalent than other actionable drivers such as ROS1 or NTRK fusions. More than 60 activating EGFR ins20 have been identified to date, which can be classified in three subtypes according to the corresponding position in the protein, namely C-helix, near-loop (near-L) and far-loop (far-L). Most of them confer primary resistance to first, second and third-generation tyrosine kinase inhibitors.MethodsWe conducted a multicenter, retrospective analysis in NSCLC patients genotyped by next-generation sequencing (NGS) and carrying an EGFR ex20ins mutation at the time of diagnosis. Different NGS-based assays were employed in the different institutions participating in the study, using between 6 and 523-gene panels. Demographics (age, sex and smoking history) and coalteration profile data were analyzed.ResultsOverall, 124 patients with NSCLC harboring EGFR ex20ins mutations were included in the study. Of them, 108 had been genotyped using FFPE samples and 16 liquid biopsies. The majority were female (63%), non-smokers (48%) and median age at diagnosis was 63 years (36-88). Seventy-six percent were stage IV at diagnosis. The most frequent location of the ex20ins was the near-L (71%), followed by the far-L (22%) and the C-helix (7%). Regarding the more prevalent specific variants, 24 patients (19%) harbored the near-L p.(Ala767_Val769dup), 20 patients (16%) the near-L p.(Ser768_Asp770dup) and 16 patients (13%) the far-L p.(His773_Val774insX). Co-mutations in TP53 were found in 42/92 (46%) samples analyzed for this gene, followed by PIK3CA mutations in 5/107 (5%). Amplifications in EGFR, CDK4 and MET were present in 11/71 (16%), 2/39 (5%) and 2/72 (3%) samples analyzed for these genes, respectively.ConclusionsThe identification of all EGFR ex20ins variants is important when implementing dedicated targeted therapies. The most frequent location of the ex20ins was the near-loop, followed by the far-loop. Co-mutations in TP53 were found in ∼50% samples. Survival data and its association with coalterations will be presented during the congress.Legal entity responsible for the studyThe authors.FundingHas not received any funding.DisclosureI.G. Sullivan: Financial Interests, Personal, Advisory Board: Roche, Takeda, Sanofi, Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, Takeda. U. Malapelle: Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim, Roche, MSD, Amgen, Thermo Fisher Scientifics, Eli Lilly, GSK, Merck, AstraZeneca; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Roche, MSD, Amgen, Thermo Fisher Scientifics, Eli Lilly, Diaceutics, GSK, Merck, AstraZeneca, Janssen, Diatech, Novartis, Hedera, Diatech; Non-Financial Interests, Leadership Role, Scientific Secretary and Editor in Chief of The Journal of Liquid Biopsy (Official Journal of the Society): ISLB. A. Barba Joaquín: Financial Interests, Personal, Invited Speaker: Pfizer, MSD, Sanofi, BMS, Novartis, Roche, AstraZeneca, Pierre Fabre; Financial Interests, Personal, Advisory Board: BMS, Sanofi, Roche, AstraZeneca; Non-Financial Interests, Principal Investigator, PI - Clinical Trial C4221016: Pfizer; Non-Financial Interests, Principal Investigator, Clinical Trial CA224-1044: BMS. S. Viteri: Financial Interests, Personal, Advisory Board: Merck Healthcar KGAA Germany, Bristol Myers Squibb S.A. U, Ipsen, Affimed; Financial Interests, Personal, Invited Speaker: MSD de España SA; Financial Interests, Institutional, Advisory Board: Roche; Financial Interests, Institutional, Invited Speaker: Canon Medical; Financial Interests, Personal, Officer: Mi Cancer Center SLP; Financial Interests, Personal, Ownership Interest, Private Healthcare Practice: Mi Cancer Center SLP; Financial Interests, Institutional, Steering Committee Member: OSE immunotherapeutics; Financial Interests, Institutional, Local PI: Nuvalent, AbbVie, Genfleet, Dizal, Taiho, GSK, Anheart Therapeutics. All other authors have declared no conflicts of interest.