Abstract CT334: Pazopanib as third-line therapy for metastatic renal cell carcinoma: Clinical efficacy and temporal analysis of cytokine profile

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: Pazopanib was assessed in a phase III study conducted in patients (pts) with mRCC who were either cytokine-refractory or treatment-naive, and clinical outcomes with pazopanib have been associated with a specific immunologic profile (IP). The activity of pazopanib in the third-line setting and temporal changes in molecular profile during therapy are poorly understood, however. Methods: Eligibility was limited to pts with 2 prior lines of therapy (including at least 1 VEGF-directed therapy), ECOG PS 0-2, and clear cell histology. Pts received pazopanib 800 mg/daily on a 28d cycle. A Simon MinMax 2-stage design was employed, with 80% power of declaring an encouraging overall response rate (ORR) of 23% (type I error=10%). IPs were assessed monthly on a Luminex platform using the Human Cytokine 30-plex Cytokine Immunoassay (Invitrogen). Results: 28 pts were enrolled with a median age of 63 (range, 45-86). In the pre-specified intent-to-treat analysis, 12/28 pts (43%) had a confirmed response (1 CR, 11 PR), with 1 additional unconfirmed PR. Median progression-free survival for the cohort was 17.4 mos (95% CI 14.7-NR). No grade 4 treatment-related toxicities were observed. The most common grade 3 toxicities included hypertension (46%) and proteinuria (14%). Amongst patients still on therapy at 6 months and 12 months, responders had lower levels of HGF, VEGF, IL-6, IL-8 and soluble IL-2R (P<0.05 for each). Non-responders also showed increased numbers of myeloid-derived suppressor cells (MDSCs) at both time intervals. Phenotypic and functional studies confirmed that MDSCs from these mRCC patients were granulocytic. Conclusions: The ORR observed with pazopanib in the current study is the highest to date in a third-line trial in mRCC. Differences in cytokine profile and granulocytic MDSC quantity between responders and non-responders suggest that the mechanism of pazopanib resistance is at least partly related to generation of systemic tumor immune tolerance. Citation Format: Sumanta K. Pal, Dewan Md Sakib Hossain, Qifang Zhang, Chan Gao, Jeremy O. Jones, Paul H. Frankel, Robert A. Figlin, Marcin Kortylewski. Pazopanib as third-line therapy for metastatic renal cell carcinoma: Clinical efficacy and temporal analysis of cytokine profile. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT334. doi:10.1158/1538-7445.AM2014-CT334