(P 102) ANALYSIS OF BLOOD-BASED BIOMARKERS AS PROGNOSTIC FACTORS IN PATIENTS WITH EHE TREATED WITH TRAMETINIB IN SARC033

Objective: Patients with epithelioid hemangioendothelioma (EHE) have widely variable disease behavior and outcomes, from very indolent disease with survival duration of more than 10 years to rapidly progressing disease resulting in death in less than 1 year from diagnosis. Biomarkers of prognosis may be useful to determine patients who are most likely to benefit from early intervention with drug therapy. Retrospective studies have suggested that sex, site of disease, presence of symptoms related to EHE and anemia may associate with prognosis but have not been consistent across studies. Blood-based prognostic biomarkers may provide an easy objective measure to select patients for treatment.

Methods: SARC033 prospectively evaluated clinical outcomes of patients with locally advanced or metastatic EHE, that was progressing per RECIST1.1 or causing pain requiring treatment with opiates, treated with trametinib. Exploratory analyses of hemoglobin (HGB), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and connective tissue growth factor (CTGF) levels in blood prior to and after 4 weeks of trametinib, and patient sex as prognostic biomarkers for disease progression-free survival (PFS) and patient overall survival (OS) were performed. HGB, CRP and ESR values were obtained from clinical laboratories at participating sites. CTGF levels were obtained from patient plasma using a commercial ELISA in a research laboratory at Cleveland Clinic. Cox Proportional Hazards model was performed using R version 4.3.0 on blood-based biomarker data from 41 patients with diagnosis of EHE confirmed by central pathology review who enrolled and were treated with trametinib. Hazard ratios for continuous variables represent the hazard of a one unit increase of that variable. A log-rank test was used to analyze impact of sex on outcomes. The median follow-up time was 540 days.

Results: Baseline HGB (n=41), CRP (n=32) and ESR (n=36) but not CTGF (n=27) levels prior to starting treatment with trametinib associated with PFS and OS. Patients with HGB >12 gm/dL (n=23) had improved PFS (HR 0.34; 95% CI 0.16, 0.73; p=0.005) and OS (HR 0.33; 95% CI 0.14, 0.76; p=0.009) compared to patients with HGB < 12 gm/dL (n=18). Higher CRP was associated with worse PFS (HR 1.23; 95% CI 1.11, 1.38; p< 0.001) and OS (1.21; 95% CI 1.07, 1.37; p=0.003). Additionally, an increase in CRP after 4 weeks on therapy was associated with worse PFS (HR 1.18; 95% CI 1.08, 1.29, p< 0.001) and OS (HR 1.20; 95% CI 1.09, 1.32, p< 0.001). Higher ESR was associated with worse OS (HR 1.03; 95% CI 1.00, 1.05; p=0.019) but not PFS. Change in ESR or CTGF on therapy was not associated with PFS or OS. There was no difference in PFS between males (n=15) and females (n=26); whereas, there was a trend towards worse OS for males but this did not reach significance (p=0.15).

Conclusion: In our prospective trial, patients with locally advanced or metastatic EHE who had lower HGB or higher CRP values prior to treatment had increased risk of more rapid disease progression and shorter survival duration. Additionally, patients with an increase in CRP on treatment had worse outcomes. Hemoglobin and CRP values may be useful prognostic biomarkers to identify patients with EHE who may benefit from early systemic therapy.