Real-World Outcomes of Non-Small Cell Lung Cancer Patients Harboring KRAS G12D Mutation

Background: KRAS mutations are among the most frequent oncogenic drivers in NSCLC, with codon 12 variants being the most prevalent. KRAS G12D represents a less common (≈15%) but clinically significant subtype. Unlike KRAS G12C, no approved targeted therapies currently exist for G12D. Limited real-world data exist on treatment patterns and outcomes in this population. Methods: We retrospectively analyzed 19 patients with KRAS G12D-mutant lung adenocarcinoma treated at Ludwig Maximilians University Clinic Munich (2015–2024). Demographic, clinical, treatment, and survival data were collected. Descriptive statistics summarized patient characteristics. Kaplan–Meier analysis was used for overall survival (OS). Results: Median age at metastatic diagnosis was 71 years; 63% were female, 84% had ECOG 0–1, and 84% were past or current smokers. PD-L1≥50% was present in 32%, and 53% harbored co-mutations. Metastatic sites included bone (47%), lung (47%), adrenal (32%), CNS (26%), and liver (5%); 42% had≥3 metastatic sites. First-line systemic therapy was administered in 58%, including chemoimmunotherapy (32%), immunotherapy monotherapy (16%), and chemotherapy alone (5%). Definitive local treatment was used in 21%, while 26% received best supportive care only. Among three patients progressing after first-line therapy, only one received second-line chemoimmunotherapy. Preliminary efficacy outcomes suggest limited benefit from standard therapies for most KRAS G12D patients, with a subgroup showing prolonged response to checkpoint inhibition, reflecting the aggressive and heterogeneous clinical course of KRAS G12D NSCLC. Median OS will be calculated for the entire cohort Conclusion: KRAS G12D-mutant NSCLC patients are predominantly elderly, smokers, and frequently present with multi-organ metastases. Standard first-line therapies yield modest outcomes, and second-line options are rarely administered. These findings highlight the urgent need for effective targeted therapies for KRAS G12D NSCLC. Publication History Article published online: 04 March 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany