Phase II study of the Multikinase inhibitor of angiogenesis, Linifanib, in patients with metastatic and refractory colorectal cancer expressing mutated KRAS.
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.
['Chan|Emily|E|', 'Goff|Laura W|LW|', 'Cardin|Dana B|DB|', 'Ancell|Kristin|K|', 'Smith|Stephen James|SJ|', 'Whisenant|Jennifer G|JG|', 'Ye|Fei|F|', 'Berlin|Jordan D|JD|']
D000328:Adult D000368:Aged D020533:Angiogenesis Inhibitors D015179:Colorectal Neoplasms D018572:Disease-Free Survival D019008:Drug Resistance, Neoplasm D005260:Female D006801:Humans D007191:Indazoles D053208:Kaplan-Meier Estimate D008175:Lung Neoplasms D008297:Male D008875:Middle Aged D009154:Mutation D010671:Phenylurea Compounds D047428:Protein Kinase Inhibitors D016283:Proto-Oncogene Proteins p21(ras) D014057:Tomography, X-Ray Computed D016896:Treatment Outcome
Linifanib Mutated KRAS Advanced and refractory colorectal cancer Antiangiogenic therapy