Comparison of <i>MET</i> genomic alterations (GA) identified in colorectal cancer (CRC) vs gastric cancer (GCA).

3570 Background: MET signaling promotes tumor progression and therapeutic resistance across many solid tumors through diverse oncogenic signaling pathways. While MET-targeted therapies are approved in non-small cell lung cancer with novel agents in clinical trials for tumors with MET exon 14 splice site mutations, MET amplifications, and MET expression, their role in CRC and GCA is still emerging. We aim to understand the co-mutation landscape and genomic context of MET alterations across a large cohort of CRC and GCA cases to identify potential therapeutic targets. Methods: FFPE blocks of clinically advanced CRC (50,500 cases) and GCA (9,566 cases) were analyzed by hybrid capture-based comprehensive genomic profiling (CGP) that evaluated all classes of genomic alterations (GA). MSI-high status, tumor mutational burden (TMB), genomic ancestry, mutational signature, and homologous recombination deficiency signature (HRDsig) were assessed for patients with activating MET GA. PD-L1 expression was determined by IHC (Dako 22C3 with TPS scoring system). Results were compared using the Fisher exact test with the Benjamini-Hochberg adjustment. Results: MET GA (METmut) were more frequently identified in GCA than CRC (4.4% vs 1.0%; p &lt; .0001). Median ages were similar in all groups with MET altered CRC and GCA. Median GA per tumor was higher in the METmut cases in both tumor types (p &gt; .0001 for both). MSI-high status was less frequent in METmut GCA (1.7% vs 5.5%; p = .001) compared with METwt tumors. CRC cases featured higher frequencies of TMB &gt; 10 mutations/Mb in both METmut and METwt groups (p &lt; .0001 for all comparisons). Low level PD-L1 expression (1-49% TPS) was higher in CRC than GCA, but similar within tumor type across METmut and METwt tumors. METmut CRC had lower frequencies of GA in KRAS (34.7% vs 48.8%; p &lt; 0.0001) which was also found in GCA (6.6% vs 16.9%; p &lt; .0001). CDK6 GA were more frequent in GCA than CRC and also were more frequent in METmut cases in both tumor types (19.6% vs 5.2% in GCA and 10.2% vs 0.6%; p &lt; 0.0001). ERBB2 GA were more frequent in both METmut and METwt GCA (13.5% vs 13.8%; NS) than CRC (9.6% vs 5.2%; p = 0.0004). TP53 GA were more frequent in METmut vs METwt CRC (84.1% vs 75.9%; p &lt; 0.0001) and GCA (81.8% vs 60.8%; p &lt; .0001). BRAF V600E GA were identified in 5.9% METmut CRC and 8.4% METwt CRC (p = .051). BRAF V600E GA were uncommon in both METmut and METwt GCA (0.2% vs 0.4%; p = 1.0). Conclusions: This large-scale analysis reveals distinct genomic profiles of MET-altered tumors in CRC and GCA, characterized by lower prevalence of KRAS and MSI-high status, with enrichment for CDK6 . These molecular differences suggest distinct biologic subsets that could inform patient selection and rational drug combination strategies for novel MET-targeted therapies.