title: Phase II study of the Multikinase inhibitor of angiogenesis, Linifanib, in patients with metastatic and refractory colorectal cancer expressing mutated KRAS.
abstract: Background Targeting angiogenesis in advanced colorectal cancer (CRC) has been one of the many factors prolonging survival. Bevacizumab was the first agent to demonstrate this, but even after progression on bevacizumab, continued VEGF-inhibition continues to improve survival. Combining epidermal growth factor receptor monoclonal antibodies with standard frontline therapies have also improved clinical outcomes, yet the improved benefit is not observed in patients with mutant KRAS. Thus, an unmet medical need exists to develop additional therapeutic options for patients with KRAS mutant CRC. Methods Patients received the anti-angiogenic agent linifanib at the recommended phase II dose of 17.5 mg. Primary endpoint was objective response rate (ORR), with a goal of 10%. Secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. Simon's optimal two-stage design was used to assess futility. Linifanib was considered inactive if two or fewer patients among the first 30 achieved an objective response. Results Thirty patients were enrolled on study. Grade 3 treatment-related toxicities occurring in at least two patients were fatigue, hypertension, proteinuria, diarrhea, nausea, oral pain, vomiting, thrombocytopenia, and arthralgia. Although no responses were observed, 63.5% of patients achieved stable disease. The median PFS and OS were 4.7 months and 9.5 months, respectively. Stopping rules for lack of clinical efficacy led to study closure. Conclusion Despite observing zero responses, a majority of patients had stable disease and eight patients had stable disease lasting longer than 5 months. These results suggest that linifanib has some anti-tumor activity in KRAS mutant metastatic and refractory CRC.
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. emily.chan@vanderbilt.edu.|Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, 777 PRB, Nashville, TN, 37232, USA. emily.chan@vanderbilt.edu.
authors.forename: Emily
authors.initials: E
authors.lastname: Chan
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.|Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, 777 PRB, Nashville, TN, 37232, USA.
authors.forename: Laura W
authors.initials: LW
authors.lastname: Goff
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.|Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, 777 PRB, Nashville, TN, 37232, USA.
authors.forename: Dana B
authors.initials: DB
authors.lastname: Cardin
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.|Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, 777 PRB, Nashville, TN, 37232, USA.
authors.forename: Kristin
authors.initials: K
authors.lastname: Ancell
authors.affiliation: Vanderbilt-Ingram Cancer Center at Cool Springs, Franklin, TN, USA.
authors.forename: Stephen James
authors.initials: SJ
authors.lastname: Smith
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.|Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, 777 PRB, Nashville, TN, 37232, USA.
authors.forename: Jennifer G
authors.initials: JG
authors.lastname: Whisenant
authors.affiliation: Department of Cancer Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.|Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, 777 PRB, Nashville, TN, 37232, USA.
authors.forename: Jordan D
authors.initials: JD
authors.lastname: Berlin
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007191:Indazoles / Q000009:adverse effects / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000556:secondary; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D007191:Indazoles; C117307:KRAS protein, human; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; C513486:linifanib; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Advanced and refractory colorectal cancer; Antiangiogenic therapy; Linifanib; Mutated KRAS