Retrospective Comparative Analysis of KRAS G12C vs. Other KRAS Mutations in mCRC Patients Treated With First-Line Chemotherapy Doublet + Bevacizumab

Abstract

BackgroundKRAS mutations in metastatic colorectal cancer (mCRC) define a subset of tumors that have primary resistance to anti-EGFR-based therapy. Data concerning whether different KRAS mutations may also have a prognostic value are lacking. Furthermore, novel KRAS G12C inhibitors are currently in development. The aim of our analysis was to compare response rates in patients treated with first-line chemotherapy doublet + Bevacizumab among different KRAS variants. Secondary end-points were progression free survival (PFS) and overall survival (OS).MethodsPatients with KRAS mutated mCRC treated with either FOLFIRI/FOLFOX/XELOX + Bevacizumab were eligible for enrollment. Patients whose tumor harbored NRAS mutations or that coexpressed also BRAF mutations were excluded from this retrospective analysis. Patients’ individual data were collected from patients’ records. Propensity score matching (nearest method, 1:2 ratio) was used to define the two different groups of patients for comparison (KRAS G12C mutated vs other KRAS variants). Eastern Cooperative Oncology Group Performance Status (ECOG PS), sex, metastatic site of involvement, synchronous vs metachronous metastatic disease, tumor sidedness, mucinous histology, primary tumor surgery, more than two lines of treatment for metastatic disease, and radical surgery of metastases were used as matching factors. Response rate (RR) was calculated by RECIST 1.1 criteria. Both progression free-survival and overall survival were calculated by Kaplan–Meier method. Categorical variables were compared by Fisher exact test for binomial variables and by chi-square test for all other instances. The level of statistical significance p was set at 0.05 for all tests.ResultsA total of 120 patients were assessed in the final analysis. Out of the 120 patients, 15 (12%) were KRAS G12C mutated. In the whole cohort of patients, 59/120 (49%) had partial response (PR), 42/120 (35%) had stable disease (SD), and 19/120 (16%) had progressive disease (PD) as the best response. In KRAS G12C patients, 4/15 (27%) had PR, 6/15 (40%) had SD, and the remaining 5/15 (33%) had PD as the best response. In patients with other KRAS mutations, 55/105 (52%) had PR, 37/105 (35%) had SD, and the remaining 13/105 (12%) had PD as the best response. The difference in RR between the two groups of patients was statistically significant (p=0.017). On the other hand, no difference in PFS (p=0.76) and OS (p=0.56) was observed. After matching procedures, the difference in response rates between KRAS G12C mutated patients vs the matched cohort of patients with other KRAS mutations remained statistically significant (p=0.016). KRAS G12C mutations were not associated with differences in sites of metastatic involvement, sex, and ECOG PS. On the other hand, synchronous vs metachronous metastatic disease (p=0.039), age > 75 years (p=0.043), and mucinous histology (p=0.008) were more frequent in G12C mutated tumors.ConclusionsIn our cohort of patients, it was observed that KRAS G12C mutations are associated with worse response rates compared to other KRAS variants when treated with standard chemotherapy doublet + Bevacizumab. On the other hand, both PFS and OS were not significantly different. Based on these findings, we believe that new treatment options focused on KRAS G12C inhibition should be tested mainly in first-line setting and in addition to standard chemotherapy doublet + Bevacizumab for mCRC patients, as they might “fill the gap” in response rates that was seen in our study.

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

“… 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 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. 15 Furthermore, due to the retrospective nature of those studies, the small number of patients included in the studies and the setting and/or the type of chemotherapy regimens (mono-chemotherapy versus chemotherapy doublets, post-operative chemotherapy versus palliative treatment), the best treatment strategy is still unknown.…”

KRAS-G12C Mutation in One Real-Life and Three Population-Based Nordic Cohorts of Metastatic Colorectal Cancer

“…The importance of different KRAS mutations on the clinical behavior of metastatic CRC (mCRC) has been explored, and differences have been reported (9). The clinical relevance of KRAS-G12C is unclear (10)(11)(12)(13)(14)(15)(16)(17). The frequency of KRAS-G12C has been reported to be 2%-8% in large databases of molecularly analyzed CRCs (12,14,18,19).…”

“…The frequency of KRAS-G12C has been reported to be 2%-8% in large databases of molecularly analyzed CRCs (12,14,18,19). In hospital-based series, the proportion of KRAS-G12C tumors was 2%-4% of all mCRC tumors (11,15,16,20), whereas greater variability was seen in the proportion of the KRAS-mutated population (6%-17%) (11,13,16,17,(20)(21)(22). Sex-and age-related differences and differences in the metastatic pattern have been reported between different KRAS mutations, with no consistent results (12,13,22).…”

“…A Japanese study including 1632 patients treated with chemotherapy at 4 hospitals found 45 (6%) KRAS- G12C tumors among 696 KRAS mutated tumors and similarly found that both PFS and OS were worse for the KRAS- G12C cases compared to those having other KRAS mutations ( 16 ). Finally, in yet another Italian hospital-based study, 120 patients with KRAS mutated tumors were treated with a doublet chemotherapy regimen and bevacizumab; 15 (12%) patients with a KRAS- G12C had a lower response rate than those with another mutation (27% vs. 52%, p = 0.017); however, no differences in PFS or OS were seen ( 17 ).…”