A phase II open-label study of cetuximab in unresectable hepatocellular carcinoma: Final results

Abstract

4598 Background: Hepatocellular carcinoma (HCC) express the epidermal growth factor receptor (EGFR), and EGFR-targeting therapies are known to block tumor growth. We tested the activity of cetuximab (CET) in HCC and evaluated serial tumor biopsies for biomarker analyses. Methods: Patients (pts) with advanced or metastatic HCC with ECOG = 2 and adequate organ function were eligible. Prior therapy was permitted. CET was given iv weekly (400 mg/m2 loading dose, 250 mg/m2 thereafter). The primary endpoint was the rate of progression-free survival (PFS) at 24 wks. Serial tumor biopsies were performed prior to treatment, after 4 wks and at time of progression. 32 pts were enrolled. 27 pts are evaluable for tumor response. Results: Stable disease (SD) was achieved in 44.4% (12 pts) for at least 8 weeks of treatment. 55.6% failed to respond to CET (15 pts). The median time to progression (TTP) for all pts was 8.0 wks. Pts, which were stable for more than 8 wks achieved a median TTP of 22.5 wks (11–48 wks) compared to a median TTP of 6.0 wks (3–8 wks) in progressive pts. No treatment-related severe adverse events were noted throughout the study. Preliminary evaluation of surrogate markers showed no correlation with cytogenetic abnormalities based on FISH analyses for chromosome 1 and 8. Furthermore, only 5 of 21 tumor specimens were positive for EGFR expression without gene amplification, evaluated by FISH analyses. Serial tumor specimens are available in 5 responding and in 7 non-responding pts for changes of p27 and p21 expression. p27 and p21 were upregulated simultaneously in 60% (3/5 pts) of responding pts, whereas in pts with treatment failure p27 and p21 expression was detectable in 14% (1/7 pts) only. Conclusions: Cytogenetic aberrations of chromosome 1 and 8 failed to predict response to CET. In a subgroup of pts with SD >8 weeks, induction of p21 and p27 were associated with prolonged TTP >20 wks. Further evaluation of p21 and p27 as early molecular tumor response is warranted to identify pts, which benefit from anti-EGFR therapies. [Table: see text] No significant financial relationships to disclose.