Molecular profile of hepatocellular carcinoma (HCC) in older (OA) versus younger adults (YA) receiving tyrosine kinase inhibitors: Does age matter?

4124 Background: While age is not an independent risk factor for poor outcomes it can have significant influence on outcomes in HCC. The median age of diagnosis is 65 years, and HCC is associated with significant geriatric comorbidities. Further, multi-kinase inhibitors (MKIs) are associated with up to 60% of grade 3-4 toxicities. We aim to analyze survival association with age in HCC and identify molecular markers, associated with survival in older patients with HCC receiving tyrosine kinase inhibitors (TKIs). Methods: 1473 HCC specimens with DNA/RNA sequencing were profiled at Caris Life Sciences. The study cohort was stratified based on median age into two groups: OA: age > 65 and YA: age < = 65. Real-world overall survival (OS) information was obtained from insurance claims data, and Kaplan–Meier estimates of OS were calculated from specimen collection to last clinical contact; and MKI time on treatment (TOT) from the initiation to termination of treatment. Hazard ratios (HR) and p-values were calculated using the Cox proportional hazards model and the log-rank test, respectively. Results: Median OS (mOS) among patients with OA was 14.8 months(m) vs 17.1m among YA (HR: 1.18, p < 0.01). The difference in mOS was even more pronounced among White OA (HR:1.43, p < 0.0001) and Asian/Pacific Islanders (HR:1.62, p = 0.084). Interestingly, although not statistically significant, OA was associated with longer mOS in Black/African Americans (HR:0.73, p = 0.082). OA was not associated with MKI-TOT such as sorafenib or cabozantinib. However, OA was associated with a shorter TOT (HR 1.6, p < 0.01) on lenvatinib (len). No molecular alterations were statistically significantly different between the two age groups on len. CTNNB1, TP53, CDKN2A mutations and PDL1+ were among the most differentially altered and were more common in OA. DNAJB1-PRKACA fusions were prevalent only in YA (13%, potentially representative of Fibrolamellar HCC), while SLC45A2-AMACR fusions were more prevalent among OA (6.6 vs 1.1%). Multivariate analysis revealed that OA was independently associated with shorter len-TOT (HR 1.6, p 0.01), while CTNNB1 mutations and DNAJB1-PRKACA fusions were independently associated with longer len-TOT (HR 0.4-0.5, both p < 0.05). Conclusions: OA was associated with differing survival trends between whites and Asian/PI compared to Black/AA. Further, OA was associated with shorter len-TOT, potentially due to anti-angiogenic toxicity. Our limitations include an inability to investigate race-based differences on len-TOT due to small sample sizes (Black/AA: n = 18, Asian/PI: n = 15) and the lack of toxicity and geriatric assessment data. Future studies including race, geriatric assessments and toxicity profiles should be considered to understand survival and tolerability differences.