Abstract 12: Characterizing KRAS G12C and other mutations in plasma ctDNA from patients with lung cancer
Authors: Murciano-Goroff Yonina R. , Lebow Emily S. , Tu Hai-Yan , Li Mark , Lim Lee P. , Arbour Kathryn C. , Travis William , Solit David B. , Ladanyi Marc , Jones David R. , Rudin Charles M. , Martinez Andres , Myers Mackenzie L. , Makhnin Alexander , Razavi Pedram , Offin Michael D. , Isbell James W. , Riely Gregory J. , Hyman David M. , Lito Piro , Li Bob T. 
Published: August 2020

Abstract
Background: KRAS is the most common oncogene in lung cancers, but despite decades of intense research, there are no FDA-approved drugs targeting these cancers. Recent recognition that KRAS G12C harbors a binding pocket near the mutant cysteine residue has enabled the development of a new class of allele-specific inhibitors that are currently in early-phase trials. However, the mutational landscape and clinical characteristics of KRAS G12C mutant lung cancers are not well understood. The clinical use of plasma circulating tumor DNA (ctDNA) provides an opportunity to characterize this disease.
Methods: Plasma was collected from 636 patients seen at Memorial Sloan Kettering Cancer Center between 11/2016 and 5/2019. ctDNA was extracted and analyzed using the validated 23-gene ctDx-Lung assay (Resolution Bioscience; Kirkland, WA). Categorical comparisons were carried out using Fisher’s exact test.
Results: 95 NSCLC patients were identified as having alterations in KRAS based on ctDNA analysis, of whom 93.7% were metastatic at the time of plasma testing. 81.8% and 80.6% of G12C and non-G12C patients were systemic treatment naive at the time of testing, respectively. 33 patients had KRAS G12C mutations (34.7%), and 62 had other KRAS mutations (65.3%), including mutations in G12D in 24 patients, G12V in 9 patients, Q61H in 5, G12A in 8, G12S in 7, G13C in 3, G13D in 2, G13V and G12F in one patient each, as well as both Q61L and G13C in 2 patients. 60.6% of KRAS G12C patients and 53.2% of KRAS non-G12C were female. 97% of patients with G12C mutations were former smokers as compared to 77.4% in the non-G12C group (p=0.02). Of patients with stage IV adenocarcinoma with plasma KRAS detection, 9 of 25 patients with G12C were alive at the time of data analysis (36%), while 28 of 53 (52.8%) patients with KRAS non-G12C disease were alive (p =0.23; days from metastatic diagnosis to data analysis: G12C patients: 113-608, median: 396.0; non-G12C patients: 79-2248, median: 427.5). For patients with KRAS G12C mutations, co-alterations were found in TP53 (n=12, 36.4%), as well as SNVs in ROS1 (n=2), and in ALK (n=1). In patients with non-G12C KRAS detected on plasma, co-alterations were found in TP53 (n=26, 41.9%), and PIK3CA (n=3), with additional concurrent alterations in RTKs, including one patient with EGFR K714N, one with EGFR L858R, one patient with an FGFR1 amplification, and one each with an FGFR1 and FGFR3 mutation. Alterations were also detected in MET R988C (n=1) and a MET exon 14 splice variation, with SNVs in RET (n=2), as well as in ALK, ROS1, and AKT1, with a MET as well as a RICTOR amplification in one patient each.
Conclusion: Patients with KRAS G12C mutations detected on plasma analysis were more likely to be smokers. Our data support the need for further analysis of co-alterations both in plasma and on tissue sequencing to aid the development of therapies for patients with KRAS mutations as well as to advance research on combinations of G12C inhibitors with other pathway inhibitors.
Citation Format: Yonina R. Murciano-Goroff, Emily S. Lebow, Hai-Yan Tu, Mark Li, Lee P. Lim, Kathryn C. Arbour, William Travis, David B. Solit, Marc Ladanyi, David R. Jones, Charles M. Rudin, Andres Martinez, Mackenzie L. Myers, Alexander Makhnin, Pedram Razavi, Michael D. Offin, James W. Isbell, Gregory J. Riely, David M. Hyman, Piro Lito, Bob T. Li. Characterizing KRAS G12C and other mutations in plasma ctDNA from patients with lung cancer [abstract]. In: Proceedings of the AACR Special Conference on Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies; Jan 9-12, 2020; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_1):Abstract nr 12.