Molecular and clinical characteristics of patients with non-small-cell lung cancer (NSCLC) harboring KRAS G12V mutations.
Authors: John Felix , Ruge Lea , Scharpenseel Heather , Siemanowski Janna , Fassunke Jana , Riedel Richard , Michels Sebastian Yves Friedrich , Fischer Rieke Nila , Rasokat Anna , Schulte Wolfgang , Franke Karl-Josef , Graeven Ullrich , Kappes Jutta , Kron Anna , Siebolts Udo , Merkelbach-Bruse Sabine , Büttner Reinhard , Wolf Juergen , Scheffler Matthias 
Published: June 2024

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Background: KRAS G12V is one of the most common drivers of non-small cell lung cancer (NSCLC), accounting for around 3 percent of cases. Recently, there have been promising approaches in early clinical research to therapeutically target this mutation. However, this subset of patients is poorly characterized both molecularly and clinically, and data on therapy-dependent outcome are lacking. We performed this real world analysis to gain insight into the genomic and clinical characteristics of a large cohort of NSCLC patients with KRAS G12V mutations. Methods: Molecular data of 662 UICC stage I-IV lung cancer patients diagnosed between 2018 and 2023 and harbouring a KRAS G12V mutation in their tumor tissue were linked to the medical record data in the Network Genomic Medicine (NGM) database. The mutational status was determined by next-generation sequencing (NGS) and further immunohistochemistry (IHC) for PD-L1 status was performed. Results: 662 patients with a KRAS G12V mutation were diagnosed between 01/2018 and 03/2023 (stage I: 33 (6.0%), II: 29 (5.3%), III: 89 (16.3%), IV: 396 (72.4%)), which is a proportion of 15.3% among all registered KRAS-mutated lung cancer patients in this period (n=4332). Among the KRASG12V positive primary lung carcinomas, 605 (94.3%) showed an adenocarcinoma and 17 (2.6%) a squamous cell carcinoma. The median age at diagnosis was 67 years (range: 33-91), of which 338 were men (52.6%) and 304 women (47.4%). The majority of the cohort were active or former smokers (active: 289 (54.9%); former: 208 (39.2%)). In the group of never smokers (n=33, 6.2%), there were 5 men (15.2% of never smokers) and 28 women (84.8% of never smokers). The most common mutation site at initial diagnosis in patients with metastatic disease was brain and bone metastases with 41.5% and 37.4%, respectively. The most common co-mutations with a frequency of ≥ 5% were TP53 (40.2%), STK11 (28.3%), KEAP1 (22.6%) and NTRK1-3 (8.7%). Preliminary median overall survival at UICC stage IV was 525 (95% CI: 427 – 579) days. The first PD-L1-independent analysis showed a response rate of 40.9% (18/44) to initial chemotherapy (CTX)/immune-checkpoint blockade (ICB) combination, 66.7% (8/13) to ICB alone and 18.8% (6/32) to CTX alone. Conclusions: The cohort is characterized by heavy tobacco consumption. Among the never-smokers, the high proportion of women is noteworthy and will be analyzed further. Metastases at first diagnosis and concurrent mutations show clear differences to other KRAS subtypes, which highlights the heterogeneity of KRAS subtypes. We will continue to analyze the overall prognosis as well as the first indications of a PD-L1-independent benefit of immunotherapy compared to chemotherapy alone.