600 Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is associated with a high mortality burden. Lenvatinib is an effective frontline tyrosine kinase inhibitor for HCC but is associated with primary and acquired resistance in most patients. Molecular mechanisms of resistance to lenvatinib remain unclear. Methods: We retrospectively analyzed 227 patients with HCC who underwent baseline ctDNA profiling as a component of routine clinical care, including 46 patients who had serial ctDNA analysis done at baseline and after progression to lenvatinib or ICI. Clinical data including demographics, treatment history, tumor responses, and survival outcomes were abstracted from the electronic medical record. Tumor response was categorized according to RECIST 1.1. A national registry of HCC that underwent ctDNA testing using Guardant360 was analyzed to determine the prevalence of EGFR/ERBB2 alterations in HCC. Results: Nearly a third of patients who progressed on lenvatinib demonstrated a gain in EGFR/ ERBB2 amplifications or activating mutations. No consistent trend in EGFR/ ERBB2 amplifications and alterations was found among ICI refractory HCC. Disease control rates (including complete response, partial response, and stable disease) were 20% in EGFR/ERBB2 altered HCC treated with lenvatinib, 62.5% in EGFR/ERBB2 wildtype HCC treated with lenvatinib (p = 0.05), and 58% in EGFR/ERBB2 altered HCC treated with ICIs (p = 0.09). PFS was also longer in EGFR/ERBB2 wildtype HCC treated with lenvatinib (5.9 months) and EGFR/ERBB2 altered HCC treated with ICIs (7.1 months) compared to EGFR/ERBB2 altered HCC treated with lenvatinib (2.2 months, p = 0.002). In a national cohort of 1739 patients with HCC, EGFR amplifications and activating mutations occurred in 6.5% and 1.5% of cases, respectively, and ERBB2 amplifications and activating mutations occurred in 1.9% and 0.7% of cases, respectively. Among EGFR/ERBB2 mutations, we identified recurrent gatekeeper mutations, including multiple A547T and T790M mutations, in 31% of patients. Conclusions: Our study substantiates EGFR/ERBB2 amplifications and mutations as putative drivers of lenvatinib resistance in patients with HCC and identifies the genetic mechanisms for EGFR pathway activation in refractory cancers. EGFR/ERBB2 alterations may thus represent predictive and pharmacodynamic markers of lenvatinib resistance. These findings lend support to the use of EGFR inhibitors combined with lenvatinib in previously untreated or lenvatinib refractory cancers.

3549 Background: The incidence of early-onset colorectal, stomach, esophageal, and pancreatic cancer, which occur in individuals <50 years of age, is rising worldwide. However, little is known about why rates have been up trending. Previous studies have linked poor diet and nutrition to an increased risk of typical-onset gastrointestinal (GI) malignancies. In this study, we aimed to describe dietary quality in individuals with early-onset GI malignancies and compare it to typical-onset GI malignancies. Methods: We queried the 2005-2018 National Health and Nutrition Examination Survey (NHANES) database for all survey participants diagnosed with GI malignancies, including colorectal, esophageal, gallbladder, liver, pancreas, rectal, and stomach cancer. We classified early and typical-onset GI cancer based on age of diagnosis of <50 and ≥50 years, respectively. Participants <50 without a history of cancer were classified as controls. We assessed the dietary quality by calculating the healthy eating index score (HEI-2015) from NHANES database for all participants. The primary outcome was mean HEI-2015 score for early onset GI malignancies. We performed propensity score weighted analysis to balance gender, race, income, education level, and BMI between the groups. We used logistic regression analysis to assess the relationship between early-onset GI malignancies and HEI-2015 quintiles. Results: Out of 32,235 participants in NHANES database, 330 individuals (1%) reported a diagnosis of GI malignancy. Sixty-eight (20.5%) individuals had early-onset GI malignancies. We identified 17,420 controls who were <50 years old with no reported history of malignancy. Fifty-three percent of early-onset GI cancers were female vs 47% of typical-onset GI cancers; 59% vs 59% were non-Hispanic White; 66% vs 40% had a college degree; 13% vs 7% had high income and 40% vs 36% were obese. The mean HEI-2015 score in early-onset GI cancer was 52.9 (SD 14.7) compared to 53.6 (SD 13.0) in typical-onset GI cancers, which was not significantly different (p=0.72). There was no significant association between poor HEI-2015 scores in individuals with early-onset vs typical-onset GI malignancies on logistic regression analysis (OR 0.84 [0.35-2.03]). In addition, HEI-2015 quintiles were not significantly associated with those with early-onset GI malignancies compared to controls <50 years old (OR 2.06 [0.72-5.9]). Conclusions: The diet quality of early-onset GI malignancies does not align with the national Dietary Guidelines. However, in this analysis of the NHANES database, we did not find a significant difference in HEI-2015 scores between early-onset versus typical-onset GI malignancies.