PD59-02: Prostate Specific Membrane Antigen Expression is Associated with Angiogenesis and Tyrosine Kinase Inhibitor Response in Clear cell Renal Cell Carcinoma

Sari Khaleel*, Marlon Perera, Fengshen Kuo, Philip Rappold, Robert Motzer, Paul Russo, Jonathan Coleman, Martin Voss, Eduard Reznik, Ari Hakimi, New York, NY

Introduction: Combination systemic therapies (ST) including immunotherapy (IO) and Tyrosine Kinase Inhibitors (TKI) have become the standard of care for management of metastatic clear cell renal cell carcinoma (m-ccRCC). However, treatment outcomes vary between patients, and no biomarkers currently exist to identify the optimal treatment regimen (IO/IO or IO/TKI) per patient. Prostate Specific Membrane Antigen (PSMA), encoded by the FOLH1 gene, has been shown to be a marker of tumor neovasculature in ccRCC. We evaluated the relation between FOLH1 expression and angiogenesis, as well as clinical outcomes, in two prior large trials of IO and/or TKI in m-ccRCC.

Methods: We assessed the correlation between FOLH1 expression with published gene expression signatures (GES’s) corresponding to angiogenesis- and immune-related features of the tumor microenvironment in ccRCC using patient samples from COMPARZ (Pazopanib vs Sunitinib; Motzer et al, 2012), and IMmotion 150 (Atezolizumab ± Bevacizumab vs Sunitinib; McDermott et al, 2018) trials. Correlation between FOLH1 expression and each GES was assessed using Spearman’s rank correlation (SPRC) test. Kaplan-Meier method and Wilcoxon rank sum test were used to compare overall survival (OS) and progression-free survival (PFS) in COMPARZ, and objective response rate (ORR) in IMmotion 150, respectively, in relation to FOLH1 expression.

Results: In both studies, increased FOLH1 expression was positively associated with higher GES scores for angiogenesis (SPRC coefficient +0.5, p < 0.001), but did not consistently correlate with immune feature GES’s, such as overall immune and T-cell infiltration. In COMPARZ, patients with high FOLH1 expression (> median expression value) had improved OS and PFS compared to those with low FOLH1 expression in the sunitinib, but not pazopanib, arm (Log-rank p = 0.014 and 0.024 vs 0.44 and 0.29, respectively). In IMmotion 150, patients with complete/partial response to sunitinib had significantly higher expression of FOLH1 than non-responders (mean score 30 vs 24, Wilcoxon p = 0.049), while FOLH1 expression did not differ significantly by ORR class in the atezolizumab and atezolizumab/bevacizumab arms.

Conclusions: PSMA expression correlates with neoangiogenesis, therapeutic response, and survival in m-ccRCC patients treated with sunitinib TKI, potentially providing as a theranostic biomarker for tumors that may respond best to anti-angiogenic agent monotherapy or combination therapy.

Source of Funding: None