Effects of pazopanib therapy on mean corpuscular volume in patients enrolled in MC1112: Analysis of correlation with time to disease progression in solid tumors.

Abstract

e13596 Background: Pazopanib is a multi-targeted kinase inhibitor approved for use in renal cell carcinoma and soft tissue sarcoma and has also shown benefit in other cancers. Macrocytosis has been reported consequent to therapy with some kinase inhibitors (e.g. sunitinib, imatinib) but not previously with pazopanib. Interestingly, macrocytosis has been correlated with tumor response in some reports. We assessed both changes in Mean Corpuscular Volume (MCV) and its potential association with time to disease progression (TTP) observed in conjunction with a phase I pharmacokinetic (PK)-guided dose-individualized pazopanib clinical trial in solid tumors (MC1112, clinicaltrials.gov identifier: NCT01552356). Methods: We collected and analyzed MCV data on patients who received pazopanib as part of MC1112 from April 2012 to December 2014 (N = 35). Patients who discontinued therapy (N = 4) due to toxicity were censored for analysis of TTP. Logrank test was used to assess whether TTP differed with respect to MCV changes. Results: Changes in MCV associated with pazopanib therapy varied temporally: an initial drop in MCV was observed in 27/35 (77%) patients after 4 weeks of therapy [median: -1.41% (range: -4.77 to +4.83%)]; MCV increased progressively thereafter, and subsequently plateaued around cycle 6. Median change in MCV after 2, 3, 6 and 12 cycles were +1.8% (N = 32), +5.9% (N = 18), +13.3% (N = 12) and +11 % (N = 6) respectively. There was a trend towards increased TTP in patients with > 2% increase in MCV from baseline after 8 weeks of pazopanib therapy (p = 0.021). Conclusions: Pazopanib therapy is associated with initial drop in MCV after 4 weeks of therapy, followed by a progressive rise in MCV, reaching a plateau around cycle 6. MCV changes may be a biomarker of pazopanib antitumor effects; however, these findings need further validation in larger studies and across distinct tumor types. Supported by: UL1 TR000135 and CA186686 (NIH/NCI). Clinical trial information: NCT01552356.