Real-world clinicopathological and molecular characteristics, treatment patterns, and outcomes in patients with KRAS G12C–mutated metastatic colorectal cancer in AACR Project GENIE.
Authors: Hsu Hil , Aggarwal Shivani , Balan Archana , Ricciuti Biagio , Egger Jacklynn V. , LeNoue-Newton Michele , Holt Marilyn Elaine , Lee Jocelyn , Chia Victoria M. , Chan Emily , Rehn Marko , Wang Xuena , Lovly Christine M. , Riely Gregory J. , Awad Mark M. , Anagnostou Valsamo 
Published: January 2023

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Background: KRAS mutation accounts for ~37% of colorectal cancer (CRC), with KRAS G12C occurring in ~3% of CRC tumors. KRAS G12C mutation is associated with poorer prognosis in terms of real-world progression-free survival (rwPFS) and overall survival (OS) compared to other KRAS mutations and KRAS wild-type. As KRAS G12C mutated metastatic CRC (mCRC) is recognized as a discrete potentially druggable target, there is a need to further describe this patient population. This retrospective cohort study provides real-world clinicopathological and molecular characteristics, treatment patterns, and outcomes (OS, rwPFS) in patients with KRAS G12C mutated mCRC. Methods: Adult (≥18 years old) patients diagnosed between 01 January 2009 and 01 February 2019 with KRAS G12C mutated mCRC were assessed from three US academic centers in AACR Project GENIE: Dana-Farber Cancer Institute, Memorial Sloan Kettering Cancer Center, and Vanderbilt-Ingram Cancer Center. Patient characteristics and treatment patterns were reported, and median OS and rwPFS by line of therapy (LOT) were estimated with the Kaplan-Meier method, including exploratory analyses by co-mutation profile. Results: Among 71 mCRC patients, median age at initial diagnosis was 52.1 years, 59% were women, 83% were White, and 68% had initial stage 4 disease. Co-mutations with an oncogenic, likely oncogenic, or predicted oncogenic OncoKB annotation were assessed, and the most commonly observed were APC in 79% of patients, TP53 in 63%, and PIK3CA in 20%. Only 8% of patients had high tumor mutational burden (>10 mut/Mb), and no patients had microsatellite instability-high among those measured (n=48). Most patients (71%) had evidence of surgical resection in the metastatic setting. Nearly all (93%) patients had received systemic therapy: 15 (23%) had only one LOT, 20 (30%) had only two LOTs, and 31 (47%) had three or more. Most patients received oxaliplatin- or irinotecan-based regimens in the first two LOTs. Median OS from the start of first LOT was 33.5 months (95% CI: 26.9, 37.1), 20.7 months (95% CI: 6.4, 23.2) from start of second LOT, and 15.8 months (95% CI: 3.1, 23.4) from start of third LOT. Median rwPFS from start of first LOT was 20.9 months (95% CI: 8.4, 32.0), 4.0 months (95% CI: 2.2, 9.7) from start of second LOT, and 3.1 months (95% CI: 1.1, 7.2) from start of third LOT. Patients with FBXW7 co-mutation had shorter OS and patients with PIK3CA co-mutation had longer rwPFS, compared to those with KRAS G12C alone. Conclusions: In this select patient cohort with KRAS G12C mutated mCRC from US academic centers, outcomes, particularly rwPFS, were poor in later lines of therapy. Frontline OS and rwPFS were longer than in other similar studies, which may be attributable to the young median age and high proportion of surgical resection in the metastatic setting observed in this cohort.