Epidemiological and genomic features of patients (pts) with advanced/metastatic (a/m) non-small cell lung cancer (NSCLC) with HER2/ERBB2 mutations within and outside the tyrosine kinase domain (TKD)

BackgroundA greater understanding of a/m NSCLC with HER2/ERBB2 (HER2) mutations, particularly within and outside the TKD, is critical for the development of effective therapies. Here, we report results from a real-world evidence (RWE) study investigating the epidemiological and genomic features of pts with HER2-mutation positive (m+) a/m NSCLC.MethodsData were analyzed from the US community practice-based deidentified Flatiron Health-Foundation Medicine NSCLC Clinico-Genomic Database. Genomic results were based on the Foundation Medicine FoundationCore database. OncoKB was used to characterize the oncogenic effects of HER2 mutations. Data were analyzed overall and by HER2 mutation type (TKD [exons 18–21] or non-TKD [mutations outside exons 18–21]). Pts with both HER2 TKD and non-TKD mutations were classed as HER2 TKD.ResultsOf 14,768 adults diagnosed with a/m NSCLC between 2015–2022, 559 pts (3.8%) were HER2m+. In these pts, median age was 69 years (range: 34–85), 298 (53%) were female, 151 (27%) had never smoked, 351 (63%) were white, 40 (7%) were African American, 24 (4%) were Asian, and 94 (17%) had brain metastases at baseline. Among HER2m+ pts, 43% (n=239) had HER2 TKD mutations (76% had exon 20 mutations) and 57% (n=320) had HER2 non-TKD mutations. Compared with pts with non-TKD mutations, pts with TKD mutations were more likely to be female (62% vs 47%), never-smokers (45% vs 13%), had more non-squamous histology (93% vs 71%), with lower tumor mutational burden (26% vs 65% had ≥10 mutations/megabase) but higher co-HER2 amplification (11% vs 5%). Among 589 HER2 variants, of which 341 were unique, the most common were A775_G776 insYVMA (19%, n=109), S310F (4%, n=24), and G776>VC (4%, n=22). More variants in the TKD (n=243) were oncogenic (76%, n=184) or likely oncogenic (6%, n=14) than variants in non-TKD regions (n=346; 13% [n=46] oncogenic, 6% [n=21] likely oncogenic).ConclusionsPts with a/m NSCLC with HER2 TKD mutations were more frequently female, never smokers and had a lower mutational burden than pts with HER2 non-TKD mutations. More variants in the TKD were annotated as oncogenic than those in non-TKD regions.Editorial acknowledgementMedical writing support for the development of this abstract, under the direction of the authors, was provided by Ellie Sherwood of Ashfield MedComms, an Inizio Company, and funded by Boehringer Ingelheim.Legal entity responsible for the studyBoehringer Ingelheim.FundingBoehringer Ingelheim.DisclosureX. Le: Financial Interests, Personal, Advisory Board: Eli Lilly, EMD Serono (Merck KGaA, AstraZeneca, Spectrum Pharmaceutics, Novartis, Regeneron, Boehringer Ingelheim, Hengrui Therapeutics, Bayer, Teligene, Taiho, Daiichi Sankyo, Janssen, Blueprint Medicines, Sensei Biotherapeutics, SystImmune, Blueprint Medicines, ArriVent, Abion, AbbVie; Financial Interests, Personal, Advisory Role: Eli Lilly, EMD Serono (Merck KGaA), AstraZeneca, Spectrum Pharmaceutics, Novartis, Regeneron, Boehringer Ingelheim, Hengrui Therapeutics, Bayer, Teligene, Taiho, Daiichi Sankyo, Janssen, Blueprint Medicines, Sensei Biotherapeutics, SystImmune, ArriVent, Abion; Financial Interests, Personal, Research Grant: Eli Lilly, EMD Serono, ArriVent, Dizal, Teligene, Regeneron, Janssen, Thermo Fisher, Takeda, Boehringer Ingelheim; Financial Interests, Personal, Speaker, Consultant, Advisor: Eli Lilly, EMD Serono (Merck KGaA), AstraZeneca, Spectrum Pharmaceutics, Novartis, Regeneron, Boehringer Ingelheim, Hengrui Therapeutics, Bayer, Teligene, Taiho, Daiichi Sankyo, Janssen, Blueprint Medicines, Sensei Biotherapeutics, SystImmune, ArriVent, Abion, AbbVie; Financial Interests, Personal, Stocks/Shares: BlossomHill. C.S. Baik: Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo, Bristol Myers Squibb, Pfizer, Boehringer, Ingelheim, Genentech, Jansen; Financial Interests, Institutional, Local PI: Blueprint, Daiichi Sankyo, Nuvalent, AbbVie, Bristol Myers Squibb, TurningPoint, AstraZeneca, Lilly, Pfizer, Jansen, Boehringer Ingelheim, Ellipses. M. Nagasaka: Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo, Takeda, Novartis, EMD Serono, Janssen, Pfizer, Eli Lilly, Bayer, Regeneron, Bristol Myers Squibb, Genentech; Financial Interests, Personal, Speaker, Consultant, Advisor: Caris Life Sciences, Blueprint Medicines, Janssen, Mirati, Takeda; Financial Interests, Personal, Other, Travel: AnHeart Therapeutics; Financial Interests, Personal, Stocks/Shares: MBrace Therapeutics. T. Patil: Financial Interests, Personal, Advisory Role: AstraZeneca, Biocept, Boehringer Ingelheim, Bristol Myers Squibb, Bicara, Caris, Daiichi Sankyo, Guardant Health, Guidepoint, MD Soreno, Janssen, AZZ Pharamceuticals, Merus, Mirati Therapeutics, Natera, Pfizer, Sanofi, Regeneron, Roche/Genentech, Takeda; Financial Interests, Personal, Other, Advisory Committees: Elevation Oncology (DSMB); Financial Interests, Personal, Research Funding: EMD Soreno, Janssen, Gilead. S.S. Maruti, S. Stanhope, N.A. Kaya, S. Herbertz: Financial Interests, Personal, Full or part-time Employment: Boehringer Ingelheim. C.M. Lovly: Financial Interests, Personal, Advisory Board: Amgen, AnHeart, Arrivent, AstraZeneca, Blueprints Medicine, Bristol Myers Squibb, Boehringer Ingelheim, Cepheid, D2G, Daiichi Sankyo, EMD Serono, Foundation Medicine, Genentech, Gilead, Guardant, Indupro, Janssen, Medscape, Novartis, Pfizer, Regeneron, Roche, Takeda, Tempus; Non-Financial Interests, Personal, Other, DSMB chair: Janssen.