A Phase II Study of Temsirolimus in Previously Treated Advanced Hepatocellular Carcinoma (HCC).

4098 Background: After Sorafenib failure,there is no effective systemic therapy for advanced HCC. Preclinical data show upregulated mTOR signaling in HCC. We tested the IV mTOR inhibitor (i), Temsirolimus (T), as salvage therapy for HCC. Methods: Patients (Pts) had locally advanced or metastatic HCC, progressed on or intolerant of sorafenib, Child Pugh A/B liver cirrhosis, ECOG 0-2. Primary end point of this Simon 2-stage, single-arm phase II study was 3 month PFS. ≥ 1/15 Pts in stage 1 and ≥ 4/25 Pts overall had to achieve this endpoint to reject the H0 (Type I and II errors 0.05 and 0.1). We gave 25 mg T weekly until progression or intolerance, with CT/MRI scans Q 6 wks. Modified (m) RECIST for HCC was used. Results: See the Table for Pt characteristics. 17 Pts progressed or died (4 still on study, 4 off study without progression). 13/23 (57%; 95% CI: 34-77%) evaluable Pts were alive without progression at 3 months. Median PFS, 17 wks (95% CI 12-35 wks); PFS at 24 wks, 37%; median OS, 30 wks (95% CI: 27-44 wks). Of 21 Pts evaluable by mRECIST, best responses were 8 PR (38%), 10 SD (48%) and 3 PD (14%) for a disease control rate at ≥ 12 weeks of 43% (9/21). Mean and median decreases in target lesions from baseline were 33% and 23% respectively. Exploratory textural analysis of baseline scans correlated with response (p = 0.008) suggesting a predictive CT marker for anti-tumor activity. Grade 3/4 treatment related AE in ≥10% Pts: thrombocytopenia, neutropenia, AST elevation and hyperglycemia. 2 on-treatment deaths occurred, both unrelated to drug. Conclusions: T showed higher responses than previously reported with systemic Rx for HCC. The primary end point was met with >1/2 of the Pts progression free at 3 months, and >1/3 at 6 months. We speculate that IV administration may have overcome compliance issues in drug administration, favorably impacting efficacy, as reflected by the response rates in this study, in contrast with those reported with the oral mTORi. Confirmatory studies with novel correlative biomarkers should clarify the role of this mTORi in HCC. Clinical trial information: NCT01567930. Enrolled 26 Evaluable 25 Median age (range) 62 (52-89) Male 23 Female 2 AA 13 Caucasian 12 Child Pugh A B 17 8 BCLC stage A B C D 1 2 22 0 Hepatitis B Y N 1 24 Hepatitis C Y N 16 9 Prior Rx Resection RFA TACE Sorafenib Chemotherapy 4 4 16 25 2