229P Clinicopathologic and genomic features of patients with mucinous lung adenocarcinoma and response to systemic therapies

Approximately 10% of lung adenocarcinomas (LUAD) have mucinous features (LUADMuc). The efficacy of immune checkpoint inhibitors (ICI) and KRAS inhibitors for these patients is undefined. Clinicopathologic, genomic, and outcomes data were abstracted from patients with LUAD at three academic centers. LUAD with any mucinous component as assessed by a thoracic pathologist was classified as LUADMuc and compared to LUAD without mucinous components (LUADNon-muc). LUADMuc represented 9.9% of LUAD (N=406/4,106). Compared to LUADNon-muc, patients with LUADMuc had lower tobacco use history (median pack-years: 15 vs 20, P=0.002) and PD-L1 tumor proportion score (median: 0% vs 5%, P<0.0001). At stage IV diagnosis, compared to LUADNon-muc, in LUADMuc contralateral lung metastasis were more frequent (50% vs 39%, P=0.02) and brain metastases were less frequent (30% vs 43%, P=0.02). Among 3,577 patients with genomic profiling, compared to LUADNon-muc (N=3,206), LUADMuc (N=371) had a lower tumor mutational burden (TMB) (median: 6.8 vs 8.5 mut/Mb, P<0.001), a higher prevalence of KRAS, STK11, SMARCA4, NKX2-1, and GNAS mutations, and a lower prevalence of TP53, EGFR, and BRAF mutations (q<0.05). Among patients who received ICIs for advanced disease, compared with LUADNon-muc (N=1,359), LUADMuc (N=96) cases had a lower objective response rate (ORR 10% vs 25%, P<0.001), shorter median progression-free survival (mPFS 2.6 vs 4.0 months, P<0.001) and median overall survival (mOS 10.9 vs 18.1 months, P<0.001). Among patients who received chemo-immmunotherapy, compared with LUADNon-muc (N=1,064), LUADMuc (N=122) had lower ORR (24% vs 38%, P=0.002), shorter mPFS (5.1 vs 7.1 months, P<0.001) and mOS (11.9 vs 20.2 months, P<0.001). Among KRAS G12C-mutated patients who received KRAS inhibitors, compared to LUADNon-muc (N=126), LUADMuc (N=12) had similar ORR (17% vs 36%, P=0.17) and mPFS (4.6 vs 5.7 months, P=0.31), but shorter mOS (7.3 vs 13 months, P=0.04). Compared to LUADNon-muc, LUADMuc is associated with distinct mutations, a lighter smoking history, lower PD-L1 and TMB. In addition, advanced LUADMuc commonly has contralateral lung metastasis and worse outcomes to standard treatments than LUADNon-muc.