Abstract
Background
Sunitinib treatment results in a compensatory increase in plasma VEGF levels. Acute withdrawal of sunitinib results in a proliferative withdrawal flare, primarily due to elevated VEGF levels. Concurrent sunitinib plus bevacizumab is poorly tolerated with high (37 %) incidence of microangiopathic hemolytic anemia (MAHA). We evaluated a sequential design administering bevacizumab during the sunitinib treatment break to suppress the sunitinib withdrawal flare.
Methods
Patients with no prior VEGF treatment were enrolled in this study. All patients had target lesions amenable to serial FLT PET/CT imaging. Sunitinib 37.5 mg was given on days 1–28 every 6 weeks with bevacizumab 5 mg/kg on day 29. If safe and tolerable, sunitinib increased to 50 mg. FLT PET/CT scans would be obtained at baseline (D1), week 4, and week 6 to evaluate pharmacodynamics of the sequential combination. Sunitinib pharmacokinetics and total, free, and bound VEGF levels were obtained on each cycle at D1, pre-bevacizumab (D29), 4 h post-bevacizumab (D29H4), and day 42 (D42).
Results
Six patients enrolled in the safety cohort of sunitinib 37.5 mg plus bevacizumab (see Table). One patient experienced grade 1 MAHA, and after discussion with the Cancer Therapy Evaluation Program (CTEP), the trial was closed to further accrual. No imaging scans were obtained due to early closure.
Total and free VEGF levels during cycle 1
Cycle 1 | Total VEGF (pg/mL) Mean ± SD | Free VEGF (pg/mL) Mean ± SD |
---|---|---|
D1 | 80 ± 70 | 51 ± 47 |
D29 | 150 ± 62 | 103 ± 35 |
D29H4 | 10 ± 12 | 2 ± 5 |
D42 | 177 ± 34 | 97 ± 18 |
Conclusions
Subclinical MAHA was seen despite using sequential sunitinib with low-dose bevacizumab, and this combination was not feasible for further development. As predicted, VEGF levels increased during sunitinib exposure followed by a rapid decline after bevacizumab. Due to the long half-life of bevacizumab, we expected VEGF ligand suppression through D42, but instead observed a complete rebound in total/free VEGF levels by D42. The increase in VEGF at D42 was unexpected based on sunitinib alone and contrary to the hypothesis that we would block VEGF flare with low-dose bevacizumab. VEGF ligand production may increase as a result of bevacizumab, implying a robust host compensatory mechanism to VEGF signaling pathway inhibition. A greater understanding of the compensatory mechanism would aid future sequencing strategies of new agents.
Similar content being viewed by others
References
Rini BI, Garcia JA, Cooney MM et al (2010) Toxicity of sunitinib plus bevacizumab in renal cell carcinoma. J Clin Oncol 28:e284–e285 author reply e6–e7
Thompson Coon JS, Liu Z, Hoyle M et al (2009) Sunitinib and bevacizumab for first-line treatment of metastatic renal cell carcinoma: a systematic review and indirect comparison of clinical effectiveness. Br J Cancer 101:238–243
Liu G, Jeraj R, Perlman S et al (2008) Pharmacodynamic study of FLT-PET imaging in patients treated with sunitinib. J Clin Oncol 26 Suppl:abstr 3515
American Cancer Society (2012) Cancer facts and figures 2012. American Cancer Society, Atlanta, p 2012
Motzer RJ, Hutson TE, Tomczak P et al (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356:115–124
Sternberg CN, Davis ID, Mardiak J et al (2010) Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 28:1061–1068
Rini BI, Escudier B, Tomczak P et al (2011) Axitinib versus sorafenib as second-line therapy for metastatic renal cell carcinoma (mRCC): results of phase III AXIS trial. J Clin Oncol 29 Suppl:Abstr 4503
Willett CG, Boucher Y, di Tomaso E et al (2004) Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 10:145–147
Liu G, Jeraj R, Vanderhoek M et al (2011) Pharmacodynamic study using FLT PET/CT in patients with renal cell cancer and other solid malignancies treated with sunitinib malate. Clin Cancer Res 17:7634–7644
Feldman DR, Baum MS, Ginsberg MS et al (2009) Phase I trial of bevacizumab plus escalated doses of sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol 27:1432–1439
Rini BI, Garcia JA, Cooney MM et al (2009) A phase I study of sunitinib plus bevacizumab in advanced solid tumors. Clin Cancer Res 15:6277–6283
Deprimo SE, Bello CL, Smeraglia J et al (2007) Circulating protein biomarkers of pharmacodynamic activity of sunitinib in patients with metastatic renal cell carcinoma: modulation of VEGF and VEGF-related proteins. J Transl Med 5:32
Motzer RJ, Escudier B, Tomczak P et al (2013) Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol 14:552–562
Rini BI, Escudier B, Tomczak P et al (2011) Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 378:1931–1939
Eisenhauer EA, Therasse P, Bogaerts J et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247
Loupakis F, Falcone A, Masi G et al (2007) Vascular endothelial growth factor levels in immunodepleted plasma of cancer patients as a possible pharmacodynamic marker for bevacizumab activity. J Clin Oncol 25:1816–1818
Ternant D, Ceze N, Lecomte T et al (2010) An enzyme-linked immunosorbent assay to study bevacizumab pharmacokinetics. Ther Drug Monit 32:647–652
Gordon MS, Margolin K, Talpaz M et al (2001) Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol 19:843–850
Ebos JM, Lee CR, Christensen JG, Mutsaers AJ, Kerbel RS (2007) Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy. Proc Natl Acad Sci USA 104:17069–17074
Acknowledgments
The authors would like to thank the University of Wisconsin Carbone Cancer Center (UWCCC) for use of its Shared Services to complete this research. This work was supported in part by NIH/NCI P30 CA014520—UW Comprehensive Cancer Center Support, NIH/NCI U01 CA062491, Early Clinical Trials of New Anti-Cancer Agents with Phase I Emphasis [PI: Glenn Liu], and the Pfizer Investigator-Initiated Research Award GA4061YX. The UWCCC is a center of research and hope inspired by our patients and their families whose time and effort made this research possible. The authors would also like to thank the nurses and research specialists of the UWCCC Cancer Therapy Discovery and Development program for their efforts in conducting and managing this trial.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Bruce, J.Y., Kolesar, J.M., Hammers, H. et al. A phase I pharmacodynamic trial of sequential sunitinib with bevacizumab in patients with renal cell carcinoma and other advanced solid malignancies. Cancer Chemother Pharmacol 73, 485–493 (2014). https://doi.org/10.1007/s00280-013-2373-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00280-013-2373-9