BACKGROUND: More than half of colorectal tumors harbor activating mutations in RAS/RAF proteins. Selumetinib (AZD6244, ARRY-142886) is a small molecule kinase inhibitor targeting MEK kinase, downstream of RAS. We examined the efficacy and safety of selumetinib with irinotecan in second-line therapy. METHODS: Patients with K-RAS mutated colorectal cancer, progressing on first-line oxaliplatin-based chemotherapy with bevacizumab, were eligible for this multicenter open-label phase I/II trial. In part A, a dose was determined using a standard "3 + 3" design; in part B, efficacy was determined. The primary endpoint was RECIST response rate. Historical data for irinotecan were used as reference. Secondary endpoints included progression-free survival and overall survival. RESULTS: Thirty-two patients entered the study, and 31 were treated. All had K-RAS exon 2 mutated tumors. In phase I, the recommended oral dose of selumetinib was 75 mg twice per day with intravenous (IV) irinotecan, 180 mg/m² every 2 weeks. Three patients (9.7 %) had partial response . Sixteen patients (51.6 %) had stable disease for ≥4 weeks, including three >1 year. The most common grade 3 adverse events included diarrhea, neutropenia, fatigue, anemia, nausea, and dehydration. The study was terminated before a pre-planned accrual of 45 subjects. CONCLUSIONS: Despite termination before full accrual, the point estimates of RR and median PFS show promising results, suggesting that further investigations of MEK inhibition in the treatment of metastatic colorectal cancer are warranted. Studies combining MEK inhibitors with cytotoxics or other targeted agents may lead to improved clinical activity based on the emerging preclinical data.
BACKGROUND: More than half of colorectal tumors harbor activating mutations in RAS/RAF proteins. Selumetinib (AZD6244, ARRY-142886) is a small molecule kinase inhibitor targeting MEK kinase, downstream of RAS. We examined the efficacy and safety of selumetinib with irinotecan in second-line therapy. METHODS:Patients with K-RAS mutated colorectal cancer, progressing on first-line oxaliplatin-based chemotherapy with bevacizumab, were eligible for this multicenter open-label phase I/II trial. In part A, a dose was determined using a standard "3 + 3" design; in part B, efficacy was determined. The primary endpoint was RECIST response rate. Historical data for irinotecan were used as reference. Secondary endpoints included progression-free survival and overall survival. RESULTS: Thirty-two patients entered the study, and 31 were treated. All had K-RAS exon 2 mutated tumors. In phase I, the recommended oral dose of selumetinib was 75 mg twice per day with intravenous (IV) irinotecan, 180 mg/m² every 2 weeks. Three patients (9.7 %) had partial response . Sixteen patients (51.6 %) had stable disease for ≥4 weeks, including three >1 year. The most common grade 3 adverse events included diarrhea, neutropenia, fatigue, anemia, nausea, and dehydration. The study was terminated before a pre-planned accrual of 45 subjects. CONCLUSIONS: Despite termination before full accrual, the point estimates of RR and median PFS show promising results, suggesting that further investigations of MEK inhibition in the treatment of metastatic colorectal cancer are warranted. Studies combining MEK inhibitors with cytotoxics or other targeted agents may lead to improved clinical activity based on the emerging preclinical data.
Authors: Emilie M J van Brummelen; Sanne Huijberts; Carla van Herpen; Ingrid Desar; Frans Opdam; Robin van Geel; Serena Marchetti; Neeltje Steeghs; Kim Monkhorst; Bas Thijssen; Hilde Rosing; Alwin Huitema; Jos Beijnen; Rene Bernards; Jan Schellens Journal: Oncologist Date: 2020-12-29
Authors: Anuradha Krishnamurthy; Arvind Dasari; Anne M Noonan; Janice M Mehnert; Albert C Lockhart; Stephen Leong; Anna Capasso; Mark N Stein; Hanna K Sanoff; James J Lee; Aaron Hansen; Usha Malhotra; Sarah Rippke; Daniel L Gustafson; Todd M Pitts; Kim Ellison; S Lindsey Davis; Wells A Messersmith; S Gail Eckhardt; Christopher H Lieu Journal: Cancer Res Date: 2018-07-24 Impact factor: 12.701
Authors: Anuradha Banerjee; Regina I Jakacki; Arzu Onar-Thomas; Shengjie Wu; Theodore Nicolaides; Tina Young Poussaint; Jason Fangusaro; Joanna Phillips; Arie Perry; David Turner; Michael Prados; Roger J Packer; Ibrahim Qaddoumi; Sridharan Gururangan; Ian F Pollack; Stewart Goldman; Lawrence A Doyle; Clinton F Stewart; James M Boyett; Larry E Kun; Maryam Fouladi Journal: Neuro Oncol Date: 2017-08-01 Impact factor: 12.300
Authors: S Lindsey Davis; Kelli M Robertson; Todd M Pitts; John J Tentler; Erica L Bradshaw-Pierce; Peter J Klauck; Stacey M Bagby; Stephanie L Hyatt; Heather M Selby; Anna Spreafico; Jeffrey A Ecsedy; John J Arcaroli; Wells A Messersmith; Aik Choon Tan; S Gail Eckhardt Journal: Front Pharmacol Date: 2015-06-16 Impact factor: 5.810