Bodor, J. Nicholas

Abstract Background: While most EGFR-mutant NSCLC tumors are resistant to checkpoint inhibitors, a small subset has durable responses. Certain molecular subtypes of EGFR may be more responsive. There is a lack of clarity on the genomic and immune profiles of EGFR subtypes, and further elucidation of this may assist in optimally identifying those likely to respond to immune-based therapies. Methods: Profiles of 5,510 lung adenocarcinoma specimens were obtained utilizing next-generation sequencing of 592 genes (Caris Life Sciences) and categorized by EGFR subtype. PD-L1 expression (Ab: 22c3), tumor mutational burden (TMB), immune cell type fractions, and co-mutations in TP53 were assessed by EGFR subtype and compared to wild-type (WT) tumors. Results: Of the total cohort, 791 (14.4%) were EGFR-mutant (Table). Among EGFR-mutant tumors, exon 19 deletions were most common (49.7%), followed by L858R, (32.9%), exon 20 insertions (13.0%), L861Q (2.9%), and G719X (1.5%). PD-L1 positivity of each EGFR subtype as compared to WT did not vary, except for L858R tumors which had a significantly lower percentage of PD-L1 positive cases. Exon 19 deletion, L858R, and exon 20 insertion tumors were significantly less likely to have high PD-L1 or high TMB compared to WT. Among the EGFR subtypes, L861Q and G719X tumors had the greatest percentage with high TMB. TP53 co-mutations were frequent in EGFR tumors, especially among L861Q and G719X tumors. Exon 19 deletion and L858R tumors had significantly less CD8+ and greater CD4+ T cell fractions compared to WT. Neutrophil and M2 macrophage cell fractions were significantly higher in exon 19 deletion, L858R, and exon 20 insertion tumors compared to WT. Conclusions: Most subtypes of EGFR have profiles consistent with decreased immunogenicity; however L861Q and C719X tumors have a greater percentage with high TMB or TP53 co-mutations. Such features in uncommon EGFR subtypes may correlate with responsiveness to immune-based therapies and warrant further study. Tumor Characteristic EGFR WT(n=4719) Exon 19 del(n=393) L858R(n=260) Exon 20 ins(n=103) L861Q(n=23) G719X(n=12) PD-L1 positive (≥1%) 57.7% 51.0% 49.0% a 49.5% 47.8% 50.0% PD-L1 high (≥50%) 30.6% 19.7% a 18.8% a 14.4% a 21.7% 16.7% TMB high (≥10 mut/Mb) 35.3% 1.0% a 3.7% a 1.0% a 9.5% 18.2% TP53 co-mutation 53.9% 61.7% 63.6% a 59.2% a 69.6% a 83.3% a Median % cell fraction CD8+ 0.7 0.3 a 0.4 a 0.3 0.6 0.2 CD4+ 0.0 0.6 a 0.8 a 1.3 a 1.7 1.1 Neutrophils 5.5 8.0 a 7.3 a 7.8 a 7.4 6.4 M2 macrophages 5.5 6.4a 6.9a 6.7a 5.8 4.3 aq-value < 0.05 when compared to EGFR WT (corrected for multiple comparisons) Citation Format: J. Nicholas Bodor, Joanne Xiu, Vinicius Ernani, Supreet Kaur, Hirva Mamdani, Pavel Brodskiy, Sai-Hong I. Ou, Patrick C. Ma, Margie L. Clapper, W. Michael Korn, Joseph Treat. Genomic and immune characteristics of EGFR subtypes in non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4119.

505 Background: MSI is a tumor biomarker for immunotherapy efficacy that is closely associated w/deficient MMR, and is also variably associated w/somatic muts of the MMR genes, loss of MMR protein expression by immunohistochemistry (IHC), and high TMB. Germ-line muts (Lynch syndrome/LS) in the 4 MMR genes are recognized to have distinct cancer spectrums/penetrance in LS, yet across all tumors, gene-specific variability in MMR IHC, MMR muts, and TMB is understudied. Methods: Results of TGPs performed by Caris Lifesciences (2015-17) were analyzed in colorectal (CRC), endometrial (EC) and all other cancers/tumors (OT) as: 1) all MSI-H tumors (n = 1057) and 2) all tumors w/ ≥1 mut in an MMR gene (n = 470). A subset of cases had IHC for MMR protein and PD-L1 expression. MSI and TMB were determined by NGS. Results: Characteristics of MSI-H tumors and tumors w/ ≥1 MMR mut are seen in the Table. A single MSH6 mut [F1088fs] in a coding microsatellite represented 31% of all MMR muts detected. F1088fs was found in 58% tumors w/MLH1/PMS2 loss (IHC) but only 25% w/MSH2/MSH6 loss (p < 0.001), was more commonly seen in EC vs CRC/OT (p < 0.001), and was negatively associated w/somatic POLE mut (p = 0.002). Distinct mut signatures in the MMR genes (e.g. GLUàSTOP) were seen in tumors w/POLE muts and DNA repair genes. Conclusions: MSI-H and MMR mutated tumors demonstrate marked gene-specific heterogeneity in IHC patterns, TMBs, and somatic muts that may be relevant to treatment selection, resistance, and response. [Table: see text]