Real-World Study of Characteristics and Treatment Outcomes Among Patients with KRAS p.G12C-Mutated or Other KRAS Mutated Metastatic Colorectal Cancer

Abstract

Background The KRAS p.G12C mutation has recently become an actionable drug target. To further understand KRAS p.G12C disease, we describe clinicopathologic characteristics, treatment patterns, overall survival (OS), and real-world progression-free survival (rwPFS) in patients with metastatic colorectal cancer (mCRC), KRAS p.G12C mutations (KRAS G12C), and other KRAS mutations (KRAS non-G12C) using a de-identified database. Patients and Methods Clinical and tumor characteristics, including treatments received, genomic profile, and clinical outcomes were assessed for patients from a US clinical genomic database with mCRC diagnosed between January 1, 2011, and March 31, 2020, with genomic sequencing data available. Results Of 6477 patients with mCRC (mCRC cohort), 238 (3.7%) had KRAS G12C and 2947 (45.5%) had KRAS non-G12C mutations. Treatment patterns were generally comparable across lines of therapy (LOT) in KRAS G12C versus KRAS non-G12C cohorts. Median (95% CI) OS after the first LOT was 16.1 (13.0-19.0) months for the KRAS G12C cohort versus 18.3 (17.2-19.3) months for the KRAS non-G12C cohort, and 19.2 (18.5-19.8) months for the mCRC overall cohort; median (95% CI) rwPFS was 7.4 (6.3-9.5), 9.0 (8.2-9.7), and 9.2 (8.6-9.7) months, respectively. The different KRAS non-G12C mutations examined did not affect clinical outcomes. Median OS and rwPFS for all cohorts declined with each subsequent LOT. Conclusions Patients with KRAS p.G12C-mutant mCRC have poor treatment outcomes, and outcomes appear numerically worse than for those without this mutation, indicating potential prognostic implications for KRAS p.G12C mutations and an unmet medical need in this population.

Clinical efficacy of sequential treatments in KRASG12C-mutant metastatic colorectal cancer: findings from a real-life multicenter Italian study (CRC-KR GOIM)

“… 19 , 20 , 21 , 22 The percentage of KRASG12C -mutant mCRC is low, however, and the prognostic and predictive role of this mutation is still debated and poorly understood. 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 …”

“…In this respect, in other similar studies, results with FOLFOXIRI-based regimens have not been described. 9 , 12 , 13 , 14 , 15 In the subgroup of patients receiving FOLFOXIRI-based therapies, a numerical increase in objective responses was observed (ORR, 56.25%) compared with irinotecan-based (34.5%) or oxaliplatin-based (36.4%) doublets. This finding was accompanied by a numerically better PFS in patients who were treated with chemotherapy triplets.…”

“… 7 , 8 The presence of KRASG12C is rare (2%-4%), however, and so far, merely few and heterogenous retrospective series have evaluated the impact of KRASG12C on the response to chemotherapy and as a prognostic biomarker, with discordant results. 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 KRASG12C tumors were associated with a shorter OS compared with non- KRASG12C tumors. 9 , 10 , 11 , 12 , 13 Other studies reported that KRASG12C mutation conferred resistance with reduced overall response rate (ORR) to first-line chemotherapy doublets plus bevacizumab compared with different KRAS mutations, but did not affect progression-free survival (PFS) or OS.…”

“… 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 KRASG12C tumors were associated with a shorter OS compared with non- KRASG12C tumors. 9 , 10 , 11 , 12 , 13 Other studies reported that KRASG12C mutation conferred resistance with reduced overall response rate (ORR) to first-line chemotherapy doublets plus bevacizumab compared with different KRAS mutations, but did not affect progression-free survival (PFS) or OS. 14 Finally, another study reported no difference in terms of response and OS across KRASG12C and other KRAS -mutant mCRC.…”

The Impact of KRAS Mutational Status on Long-Term Survival following Liver Resection for Hilar Cholangiocarcinoma

“…KRAS mutation is reportedly associated with poor prognosis in patients with different cancer types [ 21 , 22 , 23 , 24 , 25 , 26 ]. However, mutational data on PHC are few and controversial.…”