A phase I study of selumetinib (AZD6244/ARRY-142866), a MEK1/2 inhibitor, in combination with cetuximab in refractory solid tumors and KRAS mutant colorectal cancer

作者：Deming Dustin A^*; Cavalcante Ludmila L; Lubner Sam J; Mulkerin Daniel L; LoConte Noelle K; Eickhoff Jens C; Kolesar Jill M; Fioravanti Suzanne; Greten Tim F; Compton Kathryn; Doyle Austin G; Wilding George; Duffy Austin; Liu Glenn

来源：Investigational New Drugs, 2016, 34(2): 168-175.

DOI：10.1007/s10637-015-0314-7

• Selumetinib
• AZD6244
• Cetuximab
• Phase I
• KRAS
• Colon cancer

Background KRAS mutations are clinically important predictors of resistance to EGFR-directed therapies in colorectal cancer (CRC). Oncogenic activation of the RAS/RAF/MEK/ERK signaling cascade mediates proliferation independent of growth factor signaling. We hypothesized that targeting MEK with selumetinib could overcome resistance to cetuximab in KRAS mutant CRC. Methods A phase I study (NCT01287130) was undertaken to determine the tolerability, and pharmacokinetic profiles of the combination of selumetinib and cetuximab, with an expanded cohort in KRAS-mutant CRC. Results 15 patients were treated in the dose escalation cohort and 18 patients were treated in the expansion cohort. Two dose-limiting toxicities were observed. One grade 3 acneiform rash and one grade 4 hypomagnesemia occurred. The most common grade 1 and 2 adverse events included rash, nausea/vomiting, diarrhea, and fatigue. The maximum tolerated dose was established at selumetinib 75 mg PO BID and cetuximab 250 mg/m(2) weekly following a 400 mg/m(2) load. Best clinical response in the dose escalation group included 1 unconfirmed partial response in a patient with CRC and stable disease (SD) in 5 patients (1 squamous cell carcinoma of the tonsil, 1 non-small cell lung cancer, and 3 CRC), and in the KRAS-mutant CRC dose expansion cohort, of the 14 patients who were evaluable for response, 5 patients had SD and 9 patients had progressive disease. Conclusions The combination of selumetinib and cetuximab is safe and well tolerated. Minimal anti-tumor activity was observed in KRAS-mutant refractory metastatic CRC. Further investigations might be warranted in other cancer subtypes.

• 出版日期2016-4