Abstract CT093: Axitinib in combination with pembrolizumab (AXI+PEMBRO) in patients (pts) with advanced renal cell carcinoma (aRCC): Analysis of immune-related biomarkers
Authors: Atkins Michael , Martini Jean-Francois , Plimack Elizabeth , McDermott David , Puzanov Igor , Fishman Mayer , Cho Daniel , Vaishampayan Ulka , Rosbrook Brad , Fernandez Kathrine , Tarazi Jamal , George Saby , Choueiri Toni 
Published: August 2019

Abstract
Background: In an open-label, phase Ib dose-finding and dose-expansion study in pts with aRCC, AXI+PEMBRO was tolerable; objective response rate (ORR) was 73.1%, and median progression free survival (mPFS) was 20.9 months (Lancet Oncol. 2018;19:405-15). These planned exploratory analyses evaluated candidate biomarkers that may confer sensitivity/resistance to AXI+PEMBRO.
Materials & Methods: Tumor tissue (de novo biopsy or archival), serum and whole blood samples were collected at baseline (BL). Biomarkers were chosen based on known angiogenesis/immunomodulation roles. Clinical outcomes included ORR and PFS. Comparisons for responders vs non-responders were made using Wilcoxon rank sum test. Comparisons of PFS for &lt;median vs ≥median analyte values were made using Kaplan-Meier analysis. All statistical analyses were univariate. For T-cell receptor (TCR) repertoire sequencing analysis, richness, a measure of the number of different species in a repertoire, was assessed using the Daley-Smith estimate (Nat Methods. 2013;10:325-7). Dose-finding and dose-expansion cohorts were analysed together.
Results: 52 pts were treated. Tumor tissue, serum and whole blood samples were analyzed from 39 (75.0%), 51 (98.1%) and 52 (100%) pts, respectively. Immunohistochemical analysis of tumor tissue biomarkers revealed no significant associations between CD68, CD8 or PD-L1 levels at BL and ORR or PFS. However, pts whose tumor CD8 % positive cells was ≥median had a numerically longer PFS than pts whose CD8 % positive cells was &lt;median (median PFS 26.2 vs 15.4 months, respectively; hazard ratio (HR): 0.4; 95% CI: 0.2, 1.2; unadjusted 2-sided p=0.091). For serum biomarkers, higher CXCL10 levels at BL were associated with better ORR (2-sided p=0.0197; false discovery rate-adjusted p=0.2235). In addition, pts with BL CEACAM1 levels ≥median (26.0ng/mL) had a numerically longer PFS (HR: 0.5; 95% CI: 0.2, 1.1; unadjusted 2-sided p=0.085). There was no association between BL levels of other serum biomarkers and ORR or PFS. Whole blood sample assessment of TCR repertoire dynamics showed no association with clinical outcomes. While the Daley-Smith richness estimate at BL was not associated with ORR, the Daley-Smith estimates at cycle 2, day 1 and end of treatment showed a trend toward greater richness estimate being associated with better response (unadjusted p-values = 0.0866 and 0.0324, respectively).
Conclusions: In pts with aRCC, higher tumor levels of CD8 and serum levels of CXCL10 and CEACAM1 at BL may indicate potential sensitivity to AXI+PEMBRO treatment. Further validation of the value of these biomarkers in an independent cohort with a large sample size is warranted.
Citation Format: Michael Atkins, Jean-Francois Martini, Elizabeth Plimack, David McDermott, Igor Puzanov, Mayer Fishman, Daniel Cho, Ulka Vaishampayan, Brad Rosbrook, Kathrine Fernandez, Jamal Tarazi, Saby George, Toni Choueiri. Axitinib in combination with pembrolizumab (AXI+PEMBRO) in patients (pts) with advanced renal cell carcinoma (aRCC): Analysis of immune-related biomarkers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT093.