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Efficacy of cetuximab in metastatic castration-resistant prostate cancer might depend on EGFR and PTEN expression: results from a phase II trial (SAKK 08/07)

Richard Cathomas, Christian Rothermundt, Dirk Klingbiel, Lukas Bubendorf, Rolf Jaggi, Daniel C Betticher, Peter Brauchli, Denise Cotting, Cornelia Droege, Ralph Winterhalder, Daniele Siciliano, Dominik R Berthold, Miklos Pless, Ralph Schiess, Roger Von Moos, Silke Gillessen Sommer & Swiss Group For Clinical Cancer Research SAKK

abstract

PURPOSE
The EGF receptor (EGFR) is overexpressed in the majority of metastatic castration-resistant prostate cancers (mCRPC) and might represent a valid therapeutic target. The combination of docetaxel and cetuximab, the monoclonal antibody against EGFR, has not been tested in patients with prostate cancer.

EXPERIMENTAL DESIGN
Patients with mCRPC progressing during or within 90 days after at least 12 weeks of docetaxel were included in this phase II trial. Treatment consisted of docetaxel (75 mg/m(2) every 3 weeks or 35 mg/m(2) on days 1, 8, 15 every 4 weeks) in combination with cetuximab (400 mg/m(2) on day 1 and then 250 mg/m(2) weekly). The primary endpoint was progression-free survival (PFS) at 12 weeks defined as the absence of prostate-specific antigen (PSA), radiographic, or clinical progression. Evaluation of known biomarkers of response and resistance to cetuximab (EGFR, PTEN, amphiregulin, epiregulin) was conducted.

RESULTS
Thirty-eight patients were enrolled at 15 Swiss centers. Median age was 68 years and median PSA was 212 ng/mL. PFS at 12 weeks was 34% [95% confidence interval (CI), 19%-52%], PFS at 24 weeks was 20%, and median overall survival (OS) was 13.3 months (95% CI, 7.3-15.4). Seven patients (20%) had a confirmed ≥ 50% and 11 patients (31%) a confirmed ≥ 30% PSA decline. About 47% of enrolled patients experienced grade 3 and 8% grade 4 toxicities. A significantly improved PFS was found in patients with overexpression of EGFR and persistent activity of PTEN.

CONCLUSIONS
EGFR inhibition with cetuximab might improve the outcome of patients with mCRPC. A potential correlation between EGFR overexpression, persistent expression of PTEN, and EGFR inhibition should be investigated further.
   
citation Cathomas R, Rothermundt C, Klingbiel D, Bubendorf L, Jaggi R, Betticher D C, Brauchli P, Cotting D, Droege C, Winterhalder R, Siciliano D, Berthold D R, Pless M, Schiess R, von Moos R, Gillessen Sommer S, Swiss Group for Clinical Cancer Research SAKK . Efficacy of cetuximab in metastatic castration-resistant prostate cancer might depend on EGFR and PTEN expression: results from a phase II trial (SAKK 08/07). Clin Cancer Res 2012; 18:6049-57.
   
type journal paper/review (English)
date of publishing 12-09-2012
journal title Clin Cancer Res (18/21)
ISSN print 1078-0432
pages 6049-57
PubMed 22977195
DOI 10.1158/1078-0432.CCR-12-2219