Pan-cancer landscape of IDH1/2 mutations with a focus on non-small cell lung cancer: Insights from the AACR GENIE Registry

Background: IDH1 and IDH2 mutations are oncogenic drivers across several tumor types. Their prevalence, mutational spectrum, and co-alteration profiles in Non-Small Cell Lung Cancer (NSCLC) remain incompletely defined. Given the availability of approved IDH1 and IDH2 inhibitors, characterizing these mutations has potential therapeutic relevance. Methods: We queried the AACR GENIE v18 database (n=250,018 tumor samples) to assess IDH1/2 mutation frequency, subtype distribution, associated histologies, co-mutations and survival outcomes in NSCLC. Results: IDH1 and IDH2 mutations were identified in 5,380 (2.2%) and 2,761 (1.1%) patients, respectively. IDH1 mutations-primarily R132H (50.4%) and R132C (20.6%)-were enriched in gliomas (42.6%), cholangiocarcinoma (6.0%), lung adenocarcinoma (4.8%), and melanoma (4.4%). IDH2 mutations-mainly R140Q (20%) and R172K (9.8%)-were most frequent in AML (20.3%), colorectal cancer (7.4%), and NSCLC (5.9%). Among 30,454 NSCLC patients, IDH1 and IDH2 mutations occurred in 1.2% and 0.7%, respectively. EGFR co-mutations were found in 83 (21.8%) of IDH1- and 39 (22%) of IDH2-mutant NSCLC. KRAS co-mutations were seen in 170 (44.5%) of IDH1- and 51 (29%) of IDH2-mutant NSCLC (Table). Across major oncogenic subgroups, IDH co-mutations occurred in 1.04% (IDH1) and 0.60% (IDH2) of EGFR L858R, 1.18% and 0.13% of EGFR E746_A750del, and in 2.01% and 0.81% of KRAS G12C, respectively. Among 1,846 patients with available survival data, the median overall survival (OS) was 14.7 months for stage IV KRAS G12C+/IDH1/2- patients compared with 9.7 months for KRAS G12C+/IDH1/2+ (P = 0.02). Conclusions: In stage IV KRAS G12C-mutant NSCLC, IDH1/2 co-mutations were linked to shorter median OS. These findings, along with the frequent co-alterations of IDH1/2 with EGFR and KRAS, warrant further study of targeted and combination strategies. Table: IDH1/2 Co-Alterations in NSCLC Feature IDH1 (n=366) IDH2 (n=199) EGFR co-mutations 83 (21.8%) 39 (22%) L858R / E746_A750del 19 / 18 11 / 2 KRAS co-mutations 170 (44.5%) 51 (29%) G12C / G12V / G12D 62 / 28 / 24 25 / 15 / 4 G12A / G12F / G12S / G12R 10 / 2 / 2 / 1 2 / 2 / 1 / 1 Other KRAS variants 41 6