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Phase II study of the Multikinase inhibitor of angiogenesis, Linifanib, in patients with metastatic and refractory colorectal cancer expressing mutated KRAS

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Summary

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.

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Acknowledgements

This study was supported in part by Abbvie and the Vanderbilt-Ingram Cancer Center (2P30 CA068485-14).

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Authors and Affiliations

  1. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Emily Chan, Laura W. Goff, Dana B. Cardin, Kristin Ancell, Jennifer G. Whisenant & Jordan D. Berlin

  2. Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, 777 PRB, Nashville, TN, 37232, USA

    Emily Chan, Laura W. Goff, Dana B. Cardin, Kristin Ancell, Jennifer G. Whisenant & Jordan D. Berlin

  3. Vanderbilt-Ingram Cancer Center at Cool Springs, Franklin, TN, USA

    Stephen James Smith

  4. Department of Cancer Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA

    Fei Ye

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Correspondence to Emily Chan.

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Conflicts of interest

EC has served on advisory boards for Castle Biosciences, Taiho, EMD-Serono, Amgen, Lilly, Advaxis, Bayer and Merrimack and has institutional research funding from Merrimack, Advaxis, Bristol Myers Squibb, Genentech, Array BioPharma, Leap Therapeutics, Aduro Biotech, and Karyopharm Therapeutics. LWG has served as a consultant for Celgene and has institutional research funding from Astellas Pharma, Pfizer, Onyx, SunPharma, Lilly, and Bristol-Myers Squibb. DBC has served as a consultant for Merrimack and has institutional research funding from Synta, Incyte, Celgene, Hoffman-LaRoxhe, EMD-Serono, and Oncolytics Biotech. JB has served as a consultant for Celgene, Genentech, Aduro, Boston Biomedical, Janssen, Cornerstone, Symphogen, and Bayer and has institutional research funding from Genentech, Abbvie, Taiho, Bayer, FivePrime, Phoenix, Incyte, and Vertex. All other authors have no conflicts to disclose.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained for all individual participants included in the study.

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Chan, E., Goff, L.W., Cardin, D.B. et al. Phase II study of the Multikinase inhibitor of angiogenesis, Linifanib, in patients with metastatic and refractory colorectal cancer expressing mutated KRAS . Invest New Drugs 35, 491–498 (2017). https://doi.org/10.1007/s10637-017-0458-8

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