The impact of specific KRAS mutation on treatment outcomes remain unclear. We compared the association between systemic anti-cancer treatment (SACT) outcomes and specific KRAS mutations [G12C versus non-G12C mutants] in metastatic non-squamous NSCLC patients (mNSCLC). Patients’ data were retrieved from the institutional Glans-Look Lung Cancer Research database. mNSCLC (AJCC TNM 8th edition Stage IV) treated with guideline-recommended first-line SACT (1L) in Southern Alberta, Canada during 2018-2020 periods were included while excluding those with concurrent multiple malignancies. Outcomes including overall response rate (ORR, RECIST v1.1), adverse events (CTCAE criteria v5), progression-free and overall survival were compared using descriptive (Fisher’s Exact test), Kaplan-Meier survival (Log-Rank) and multivariate (Cox Proportional Hazard) statistics. A priori statistical significance was p < 0.05. Analyses were performed using SPSS statistical software (version 25). A total of 86 KRAS mutant mNSCLC were identified with a preponderance of G12C variant (45%) and women (63%). The non-G12C includes 36% G12V, 15% G12A, 13% G12D, 13% Q61H & 23% others. The median age was 67 years, ECOG performance of 0-1 in 52%, ≥2 in 28% and unknown in 20%. 95% were adenocarcinoma and 55% PD-L1 high (>50%). 1L were 51% pembrolizumab, 30% platinum-based chemotherapy and 17% pembrolizumab/chemotherapy. About 70% already discontinued 1L. 2L rate was 23%, immune therapy was the most common (55%). KRAS mutant G12C versus non-G12C differ by gender with more female only in G12C (p=0.02) and ECOG status at presentation with less ECOG 0-1 in G12C (p<0.01). Pembrolizumab was the commonest 1L regimen in both subtypes. Outcomes by SACT are summarized in Table 1. There were similar 1L treatment outcomes in G12C vs. non-G12C: ORR (21 vs. 30%, p=0.37), disease progression rate (67 vs 68%, p>0.05), grade ≥3 adverse event (8 vs. 9%, p=0.42) or immune-related events (18 vs 19%, p>0.05), median progression-free (5 vs. 6 months, p=0.9) and overall survival (15 months vs not yet reached, p=0.6). 31% of G12C received 2L versus 17% in non-G12C. Only pembrolizumab relative to chemotherapy receipt was significantly associated with better PFS [HR (chemotherapy)=2.34 (95 CI: 1.04-5.29)] and OS [HR (chemotherapy)=3.25 (1.17-9.0)] in multivariate analyses.Table 1Comparison of guideline-recommended treatment outcomes between G12C and non-G12C mutant KRAS metastatic non-squamous NSCLCG12C vs. non-G12C mutant KRAS NSCLCPembrolizumab (n= 44)Chemotherapy (n=26)Chemo/pembro (n=16)Uptake rate, %56 vs. 4728 vs. 3215 vs. 21DCR (PR & stable), %59 vs. 5555 vs. 5383 vs. 60PR-partial response, % (n)23 vs. 36 (5 vs 8)0 vs. 20 (0 vs 3)50 vs. 30 (3 vs. 3)Stable disease, % (n)36 vs 18 (8 vs 4)55 vs 33 (6 vs 5)33 vs 30 (2 vs 3)PFS, median, mo15 vs. 196 vs. 710 vs. 8PFS, HR for non-G12C (95% CI)0.97 (0.48-2.00)PFS, HR for Platin doublet (Pembro as reference)2.48 (1.10-5.60)**PFS, HR for Platin/pembro (Pembro as reference)1.52 (0.41-5.67)OS, median, mo18 vs. NR6 vs. 7Both= NROS, HR for non-G12C (95% CI)0.51 (0.22-1.17)OS, HR for Platin doublet (Pembro as reference)3.25 (1.17-9.0)**OS, HR for Platin/pembro (Pembro as reference)1.39 (0.31-6.33)** denotes statistical significance. CI= confidence interval, DCR= disease control rate, HR= hazard ratio, OS= overall survival, PFS= progression-free survival, mo. = month Open table in a new tab ** denotes statistical significance. CI= confidence interval, DCR= disease control rate, HR= hazard ratio, OS= overall survival, PFS= progression-free survival, mo. = month 67 There was no significant difference in response or survival outcomes with 1L in specific mutant KRAS variants (G12C versus non-G12C). 2L receipt in ∼1/3rd of G12C mutant patients suggest there may be greater appetite for further treatment of progressive disease should more tolerable treatment becomes available.