Abstract 102: Clinicopathological and molecular characteristics, treatment patterns, and outcomes in patients with KRAS p.G12C-mutated metastatic non-small cell lung cancer (NSCLC) in the AACR Project GENIE database
Authors: Ricciuti Biagio , Wang Chenguang , Rizvi Hira , Egger Jacklynn , LeNoue-Newton Michele , Holt Marilyn , Aggarwal Shivani , Tu Huakang , Hsu Hil , Wang Xuena , Ngarmchamnanrith Gataree , Chia Victoria , Lee Jocelyn , Scharpf Robert , Anagnostou Valsamo , Lovly Christine , Riely Greg , Awad Mark 
Published: July 2021

Abstract
Introduction: Mutations in the RAS family of proto-oncogenes are frequently found in NSCLC, with KRAS being the most prevalent mutated isoform. Of KRAS mutations, the most common is KRAS G12C, representing ~40% of KRAS mutations and occurring in ~13% of all lung adenocarcinoma cases. The objective of this study is to describe clinicopathological and molecular characteristics, treatment patterns, and outcomes in patients with KRAS G12C-mutated metastatic NSCLC using the AACR Project GENIE database.
Methods: An observational retrospective study of adult patients (&gt;18 years of age) with KRAS G12C-mutated metastatic NSCLC from three US academic comprehensive cancer centers in the AACR Project GENIE database was undertaken using de-identified data. Patients were eligible if their tumor tested positive for KRAS G12C mutation by next-generation sequencing at the participating institutions. Event-time distributions were estimated using the Kaplan-Meier method, and multivariable models were fitted to estimate adjusted hazard ratios (aHRs) by Cox proportional models. Patients with large panel sequencing performed up to Dec 31, 2018 were included. All available data until Aug 1, 2019 were collected.
Results: Of the 416 eligible patients included in this analysis, 91.6% were white, 64.4% were female, median age at metastatic diagnosis was 68.2 years (range: 37.6-86.2), and 97.1% were former or current smokers. 65.1% of patients had stage 4 NSCLC at diagnosis, and most tumors were adenocarcinomas (85.8%). The KRAS G12C mutation was nearly mutually exclusive (≤ 1.0%) with other actionable driver mutations in EGFR, ALK, ROS1, and BRAF but was co-occurred with STK11 (23.6%) and KEAP1 (9.9%) mutations. Among patients who received PD-(L)1 monotherapy (n=110), median progression-free (mPFS) and overall survival (mOS) were 4.6 and 11.9 months, respectively, while among those who received chemotherapy only (n=133) mPFS and mOS were 4.1 and 12.1 months, respectively. When clinical outcomes were analyzed according to co-occurring genomic alterations, we found that KRAS/STK11 co-mutations were associated with significantly worse outcomes with immunotherapy (PFS: aHR 0.44, P=0.002; OS: aHR 0.42, P=0.003) but not with chemotherapy (PFS: aHR 0.82, P=0.44; OS: aHR 0.81, P=0.43). There was no significant impact of co-occurring KRAS mutations with KEAP1, SMARCA4, ATM, RBM10 and TP53 on clinical outcomes to either PD-(L)1 inhibition or chemotherapy.
Conclusions: KRAS G12C mutant NSCLC represents a heterogeneous group of lung cancers and its genomic diversity is reflected in differential responses to therapy. These findings highlight the urgent clinical need for molecular biomarker-driven therapies in this subset of patients.
Citation Format: Biagio Ricciuti, Chenguang Wang, Hira Rizvi, Jacklynn Egger, Michele LeNoue-Newton, Marilyn Holt, Shivani Aggarwal, Huakang Tu, Hil Hsu, Xuena Wang, Gataree Ngarmchamnanrith, Victoria Chia, Jocelyn Lee, Robert Scharpf, Valsamo Anagnostou, Christine Lovly, Greg Riely, Mark Awad. Clinicopathological and molecular characteristics, treatment patterns, and outcomes in patients with KRAS p.G12C-mutated metastatic non-small cell lung cancer (NSCLC) in the AACR Project GENIE database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 102.