Abstract 3718: A Phase II Study of Sorafenib plus Cetuximab in colorectal cancer (CRC) expressing epidermal growth factor receptor (EGFR) and mutated K-ras
Authors: Kummar Shivaani , Chen Alice , Duffy Austin , Turkbey Ismail B. , Steinberg Seth , Cao Liang , Gutierrez Martin E. , Larkins Erin , Holkova Beata , Crandon Sonja , Juwara Lamin , Horneffer Yvonne , Choyke Peter , Melillo Giovanni , Murgo Anthony J. , Wright John , Doroshow James H. 
Published: February 2011

Abstract
Background: The presence of K-ras mutation predicts for a lack of response to EGFR-directed therapies in CRC. We hypothesized that a drug capable of inhibiting Raf kinase, which is downstream of Ras, could restore tumor sensitivity to cetuximab. We conducted a Phase II single-arm optimal two-stage design trial of cetuximab, a monoclonal antibody directed against EGFR, in combination with sorafenib, a small molecule inhibitor of VEGFR2 and Raf kinase, in patients with EGFR-positive (+) CRC bearing K-ras mutations.
Trial Design: Objectives were to determine clinical benefit rate (CBR) (CR+PR+SD for 4 months) and PFS. Eligible patients were ≥ 18 years old and had histologically documented EGFR+ metastatic CRC bearing K-ras mutations which had recurred or progressed following at least one prior chemotherapy regimen; measurable disease; ECOG PS 0-1; adequate bone marrow, hepatic and renal function. Patients previously treated with an EGFR inhibitor were excluded. Cetuximab was given IV at 400 mg/m2 initially as a loading dose on week 1, followed by 250 mg/m2 weekly, in 28-day cycles. Sorafenib was self-administered orally at 400 mg BID. Radiologic assessment was performed at baseline and every 2 cycles; response was determined based on RECIST criteria. Changes in tumor vascularity were evaluated by dynamic contrast-enhanced MRI (DCE-MRI) at baseline and after 2 cycles.
Results: A total of 9 patients received at least 2 cycles of therapy and were evaluable for response. The median age was 51 years (range 21-81 years), and all patients had an ECOG PS of 1 and had received prior FU, oxaliplatin, irinotecan, and bevacizumab. Rash, electrolyte abnormalities, hypertension, and diarrhea were the most common toxicities. Grade 2 and 3 toxicities (number of patients in parentheses) were hypophosphatemia (5), hypokalemia (1), hypomagnesemia (1), acneiform rash (2), hand-foot syndrome (1), diarrhea (3), transaminitis (2), hyperbilirubinemia (1), lymphopenia (6), hypertension (1), anemia (1), and hypoalbuminemia (4). The only grade 4 events were lymphopenia (1) and hypokalemia (1). Although no patients had objective responses, 3 patients had stable disease for 6, 6 and 4 months respectively. DCE-MRI results showed reduction in the parameters of permeability, with decrease in ktrans and kep values. Quantitative biomarker analysis with determination of plasma angiogenic factors is ongoing.
Conclusions: Sorafenib in combination with cetuximab is well tolerated in CRC patients and was associated with disease stabilization in 3 of 9 patients with EGFR+ CRC bearing K-ras mutations. Sorafenib plus cetuximab may have a role in the treatment of patients with CRC bearing Kras mutations. We have met the response goals for the first stage of the trial, and accrual continues for the second stage.
Funded by NCI Contract No. HHSN261200800001E.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3718.