ASCO GU 2020: Emerging Therapies in Renal Cell Carcinoma: From PARP Inhibition to Novel Immunotherapeutics
The rationale for targeting HIF stems from an understanding of the pathogenesis of clear cell RCC (ccRCC). Inactivation of the Von Hippel-Lindau (VHL) tumor suppressor gene results in the stabilization of the alpha subunit of the HIF family, leading to uncontrollable activation of HIF target genes. HIF-2a regulates the expression of hundreds of hypoxia associated genes. Dr. Rose highlighted two HIF-2a inhibitors that have shown efficacy in the management of mRCC. PT2385 has been associated with an overall response rate (ORR) of 14% and stable disease (SD) rate of 52%. PT2977 has been associated with an ORR of 24% and 80% of patients taking this medication demonstrated a clinical benefit. Currently, a phase III trial is underway comparing the efficacy of PT2977 versus everolimus.
Inhibition of PARP leads to the accumulation of single-strand deoxyribonucleic acid (DNA) breaks and eventually catastrophic double-strand DNA breaks, which results in cell death. Although renal cell carcinoma (RCC) classically does not respond to DNA damaging strategies such as platinum-based chemotherapy or radiation, preclinical studies have suggested that PARP inhibition may have utility in the management of RCC. Studies have shown that loss of BAP1 leads to tumors with homologous recombination repair deficiency and sensitivity to PARP inhibition. Also, PARP inhibition has been shown to have utility in patient-derived xenografts of fumarate hydratase and succinate dehydrogenase deficient tumors. Lastly, ARID1A deficiency may confer sensitivity to PARP inhibition. Dr. Rose highlighted seven clinical trials currently in-progress that are hoping to evaluate the efficacy of PARP inhibitors in the management of RCC.
Glutaminase converts glutamine to glutamate, which is used to drive the tricarboxylic acid cycle, make amino acids and nucleotides, and fuel cancer growth. Telaglenastat (CB-839), an oral glutaminase inhibitor, has shown promise in the management of mRCC. Investigators have suggested that CB-839 may potentially be synergistic with current management strategies. For example, CB-839 may be synergistic with PARP inhibitors due to a decrease in nucleotide pools and synergy in preclinical models. Also, phase I data have demonstrated tolerability and promising response rates for CB-839 in combination with cabozantinib.
Immunomodulation therapies refers to those that improve the immune system’s ability to attack and eliminate cancer. Dr. Rose highlighted two immunomodulators that have demonstrated potential in the management of mRCC. Sitravatinib is a tyrosine kinase inhibitor that targets several receptors, including TAM, VEGFR, and c-MET. When combined with nivolumab, it has been shown to have an ORR of 39%. NKTR-214 is an oral, PEGylated prodrug of IL-2 that specifically binds to IL2RBy (CD122). It causes expansion of CD4+ and CD8+ T cells in peripheral blood and tumor. When combined with nivolumab, it has shown significant promise in treatment naïve RCC. A phase III study evaluating NKTR-214 with nivolumab versus sunitinib or cabozantinib is currently ongoing.
Presented by: Tracy L. Rose, MD, MPH, The University of North Carolina Chapel Hill School of Medicine and UNC Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina
Written By: Ziho Lee, MD, Fellow in Advanced Robotic Oncology and Reconstruction, Temple University, Philadelphia, PA, Twitter: @ZLeeGU at the 2020 Genitourinary Cancers Symposium, ASCO GU #GU20, February 13-15, 2020, San Francisco, California