Assessment of safety and drug-induced tumor necrosis with sunitinib in patients (pts) with unresectable hepatocellular carcinoma (HCC)

Abstract

3546 Background: VEGFRs and PDGFRs play key roles in the proliferation of HCC and tumor angiogenesis. Sunitinib malate (SU) is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET and FLT3. This study reports the results of the first European/Asian, open-label, single-agent SU phase II study in pts with unresectable HCC. Methods: Key eligibility criteria include histologically confirmed measurable HCC; ECOG PS =1; Child-Pugh (CP)-A/-B; adequate organ function; and no brain metastases, ascites, or prior liver transplant. Pts receive SU at 50 mg/d for 4 wks every 6 wks (4/2 schedule). The primary endpoint is ORR by RECIST. Other assessments include safety (NCI CTCAE v3.0), PK and antitumor activity (tumor density, volumetric measurement of percent tumor necrosis [VMTN] and intratumor blood perfusion on monthly CT scan). Results: 37 pts (median 61 yrs [range 34–82]; male 92%; PS 0:1, 50%:44%; CP-A/-B, 84%/14%; 40.5% with prior local treatments) received a median of 2 cycles (range 1–7+) of SU. Grade 3–4 toxicities included thrombocytopenia (43%), neutropenia (24%), CNS symptoms (24%), asthenia (22%) and hemorrhage (14%). Grade 1–2 skin toxicity was frequently reported. Dose reductions were required in 27% of pts. Four pts developed grade 5 events including ascites, edema, bleeding, drowsiness and hepatic encephalopathy. Decreased tumor density was observed in 68% of pts and activity assessed by VMTN showed minor (<50%) and major (=50%) post-treatment tumor necrosis in 25% and 46% of pts, respectively. One confirmed PR and 39% SD (best confirmed response) have been achieved. Post-treatment tumor blood perfusion parameters (blood volume and blood flow), decreased by an average of 39% (range: 13–72%). Preliminary PK data do not suggest any differences in drug exposure between risk groups (CP-A or CP-B). Conclusions: Evidence of =50% tumor necrosis in 46% of pts receiving SU suggests outstanding antitumor activity. However, change in tumor size (RECIST) may be inappropriate as a primary endpoint to evaluate SU in patients with HCC. Initial safety findings indicate that further evaluation of SU in this pt population with improved pt selection and dose schedule modification is warranted. [Table: see text]