Phase II trial of cetuximab in patients (pts) with metastatic and/or locally advanced soft tissue and bone sarcomas

Abstract

10537 Background: Cytotoxic therapy has resulted in limited improvement in outcomes of pts with advanced sarcoma. The epidermal growth factor receptor (EGFR) pathway plays a role in tumorigenicity and is expressed in many sarcoma subtypes. Blockade of EGFR in certain sarcoma cell lines has decreased cell growth and increased tumor apoptosis. Therefore, we conducted a phase II trial of the anti-EGFR monoclonal antibody cetuximab in EGFR positive(+) and negative sarcoma and report here results of the EGFR+ group. Methods: Pts ≥ 16 years old with advanced sarcoma who progressed on ≥ 1 prior therapy were eligible. Cetuximab was administered at 400mg/m2 on day 1 and 250mg/m2 during subsequent weekly infusions. A cycle was defined as 4 weeks of therapy with radiographic assessment every 2 cycles. The primary objective was 4-month progression-free survival (PFS) rate in EGFR+ pts. Using a Simon two-stage design and a 10 and 30% rate as the null and alternative hypothesis, 22 pts were to be accrued in the first stage, with an additional 11 pts if ≥ 3 pts met primary endpoint. EGFR+ was defined by immunohistochemistry (IHC) as 1+, 2+, or 3+. Secondary objectives included assessment of response rate and evaluation of molecular alterations in EGFR pathway by IHC and mutational analysis using PCR/direct sequencing. Results: 22 evaluable pts with EGFR+ sarcoma were enrolled. Subtypes included synovial (32%), liposarcoma (27%), malignant fibrous histiocytoma (18%), leiomyosarcoma (14%), myxofibrosarcoma (4%), and malignant peripheral nerve sheath (4%). The median number of prior therapies was 2; the median number of cycles was 2; the median PFS was 52 days (95% CI: 48 - 54). One patient was free of progression for over 4 months. No objective responses were seen. Two patients withdrew from study due to ileus and acute renal failure. MAP-K, PTEN, and phospho-EGFR staining revealed variable expression without discernible pattern. No EGFR mutations were detected in exons tested in available specimens. Conclusions: Cetuximab has minimal activity in advanced EGFR+ sarcoma, and further investigation as a single agent is not indicated. Cetuximab in combination with cytotoxic therapy or following definition of specific molecular abnormalities in sarcoma requires further study. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb