The Association Between PD-L1 Expression and the Clinical Outcomes to Vascular Endothelial Growth Factor-Targeted Therapy in Patients With Metastatic Clear Cell Renal Cell Carcinoma

Abstract

Purpose. To evaluate the maximum tolerated regimen (MTR), dose‐limiting toxicities, and pharmacokinetics of pazopanib, an oral small‐molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptor, platelet‐derived growth factor receptor, and c‐Kit, in combination with paclitaxel. Patients and Methods. Pazopanib was given daily with weekly paclitaxel on days 1, 8, and 15 every 28 days. Dose levels of pazopanib (mg/day)/paclitaxel (mg/m2) were 400/15, 800/15, 800/50, and 800/80. An expanded cohort was enrolled at the MTR. Plasma samples were collected to evaluate the effect of pazopanib, an inhibitor of cytochrome P450 (CYP)3A4, on the pharmacokinetics of paclitaxel, a CYP3A4 and CYP2C8 substrate. Results. Of 26 enrolled patients, 17 were treated at the MTR of 800 mg pazopanib and 80 mg/m2 paclitaxel. Dose‐limiting toxicities included a grade 3 abscess and grade 2 hyperbilirubinemia. Other toxicities included elevated liver transaminases and diarrhea. Six patients (23%) had partial responses and 15 patients (58%) had stable disease. Administration of 800 mg pazopanib resulted in a 14% lower paclitaxel clearance and a 31% higher paclitaxel maximal concentration than with administration of paclitaxel alone at 15, 50, and 80 mg/m2. At the MTR, coadministration of 800 mg pazopanib and 80 mg/m2 paclitaxel resulted in a 26% higher geometric mean paclitaxel area under the curve. Conclusion. Pazopanib, at a dose of 800 mg daily, can be safely combined with a therapeutic dose of paclitaxel at 80 mg/m2 when administered on days 1, 8, and 15, every 28 days. The observed greater plasma concentrations of paclitaxel given concurrently with pazopanib suggest that pazopanib is a weak inhibitor of CYP3A4 and CYP2C8.

Association between PD-L1 Expression and the Prognosis and Clinicopathologic Features of Renal Cell Carcinoma: A Systematic Review and Meta-Analysis

“…Table 1. A total of 1,644 patients were included in the 8 studies [19][20][21][22][23][24][25][26] for the metaanalysis. The 8 included studies were published between 2006 and 2016.…”

The role of vascular endothelial growth factor in the hypoxic and immunosuppressive tumor microenvironment: perspectives for therapeutic implications

“…Tregs in the peripheral blood are increased in patients with recurrent GBs after development of resistance to VEGFR inhibitors [89]. An increased level of PD-1 expression on CD4 and CD8 T cells was reported in patients with GBs or metastatic renal cell carcinoma that is refractory to VEGFR-targeted therapy [89,109]. Previous studies have demonstrated changes in the TME using tumor specimens resected under and after Bev therapy.…”

Significance of tumor microenvironment in acquiring resistance to vascular endothelial growth factor‐tyrosine kinase inhibitor and recent advance of systemic treatment of clear cell renal cell carcinoma

“…Furthermore, a relationship was not observed between PD-L2 expression and any clinicopathological parameter or patient prognosis. 54 A previous study reported that the PD-L2 expression status did not affect the outcomes of RCC patients treated with VEGF-TKI. 55 Collectively, these findings demonstrate that the expression of PD-1 and PD-L1 by infiltrating immune cells, but not tumor cells, may be involved in the development of resistance to VEGF-TKI, and suggest that sequential or combination therapy with ICI and VEGF-TKI has potential for VEGF-TKI-resistant patients.…”

“…An immunohistochemical analysis of the localization of PD-1 and PD-L1 in cancer cells and immune cells in the tumor microenvironment of ccRCC tissues revealed that the number of PD-1 and PD-L1-positive tumor-infiltrating immune cells positively correlated with the World Health Organization/International Society of Urological Pathology grade and a poor prognosis in ccRCC patients. 53,54 In addition, ccRCC patients with a high number of PD-1-and PD-L1-positive tumorinfiltrating cells were more likely to exhibit resistance to VEGF-TKI. Moreover, the number of PD-1-and PD-L1-positive tumorinfiltrating immune cells was significantly higher in VEGF-TKItreated ccRCC tissue than in untreated tumors (Fig.…”