Background: Clinical benefit and survival data utilizing later lines of therapy with TAS in metastatic CRC is limited, highlighting the need for better patient selection (Mayer, NEJM 2015). Recently, codon-specific KRAS mutations have been implicated as biomarkers for TAS treatment. KRAS G12 was associated with a lack of benefit and G13 displayed improved benefit (Van de Haar, Nat Med 2023) However, it is unknown whether this differential prognostic impact occurs on TAS + Bev which has now supplanted TAS as the standard of care (Prager, NEJM 2023).

Methods: We retrospectively investigated outcomes in a cohort of 100 mCRC patients treated with TAS + Bev for ≥1 month between September 2019 and April 2023 at MD Anderson (cohort A) using institutional databases. For validation, a cohort of 205 mCRC patients from the Tempus database was used (cohort B). Mutation status was determined from tissue biopsy using clinical NGS (Beaubier, Nat Biotechnol 2019). The primary endpoint was overall survival (OS), determined by Kaplan Meier estimators and risk set adjustment methods and compared using the log-rank test.

Results: Baseline characteristics were similar in the two cohorts; in cohort A, 52% (N = 52) patients were male and median age at diagnosis was 56 years (IQR:47-61y). Correspondingly, 56% (N = 93) of cohort B were male and the median age at diagnosis was 56 (IQR: 47-66y). Table 1 shows the distribution of codon-specific RAS mutations and their OS across the two cohorts. Comparative analysis of median OS (mOS) between KRAS G12, KRAS G13 and RAS/RAF-WT subgroups showed no significant differences (p = 0.06 and 0.94 for cohort A and B, respectively).

Conclusions: In this cohort of mCRC treated with TAS-Bev, codon-specific KRAS mutations did not appear to predict survival benefit, unlike previously reported for TAS treated patients. Overall, KRAS G13 mutated patients appeared to have a worse outcome. Further investigations into codon-specific impact are required prior to incorporating this for patient selection for treatment.

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