The VEGF-targeted antiangiogenic agents induce tumor hypoxia, leading to an upregulation of programmed
death-ligand 1 (PD-L1) in different cancer entities including hepatocellular carcinoma [
14], lung cancer [
15] and RCC [
16]. Generally, hypoxic zones in the tumor can attract different immunosuppressive
myeloid cells, such as myeloid-derived suppressor cells (MDSC). Under hypoxic conditions, HIF-1alpha leads to an
upregulation of PD-L1 expression on MDSCs in the tumor microenvironment, thereby increasing interleukin (IL)-6 and IL-10 secretion from MDSCs, causing a MDSC-induced immunosuppression, T cell inactivation, and promoting tumor progression [
17,
18]. In RCC, hypoxia, and in addition, a loss of the VHL protein (pVHL) results in the constitutive stabilization of HIF1alpha and HIF2alpha, inducing various HIF-transcriptional targets [
19]. The PD-L1 as a HIF2alpha target was upregulated in VHL protein deficient ccRCC in vitro [
20]. In RCC patients, PD-L1 expression positively correlated with VHL mutation, HIF-2alpha expression, adverse pathological features such as higher nuclear grade, necrosis and sarcomatoid transformation, c‑MET and VEGF expression [
16,
21], thus resulting in a shorter progression-free and cancer-specific survival [
21]. Based on these data, simultaneous blockade of PD-L1 with the inhibition of the VHL/HIF/VEGF pathway may represent a novel and innovative treatment concept [
17]. Thus, various randomized phase III trials in the first-line setting of mRCC are currently ongoing, testing this combined therapeutic approach consisting of checkpoint inhibitors (avelumab, pembrolizumab, atezolizumab, nivolumab, ipilimumab) combined with VEGF-targeted antiangiogenic agents (axitinib, lenvatinib, bevacizumab) in comparison to standard first-line drugs alone (sunitinib) (Table
1). Results of these trials are expected soon.
Table 1
Ongoing phase III trials in the first-line setting of mRCC, focusing on the combination of VEGF-targeted antiangiogenic drugs and checkpoint inhibitors
Avelumab + Axitinib | PD-L1 VEGFR-1/2/3 | Sunitinib | JAVELIN RENAL 101 | III | Recruiting | 583 | NCT02684006 | PFS | OS OR DCR DOR TTR EQ-5D/FKSI-19 |
Lenvatinib + Everolimus or | VEGFR-1/2/3 FGFR-1/2/3/4 | Sunitinib | E7080-G000-307 | III | Recruiting | 735 | NCT02811861 | PFS | ORR OS HRQoL PFS2 |
Lenvatinib + Pembrolizumab | PDGFR-alpha RET c-KIT mTOR PD-1 |
Pembrolizumab + Axitinib | PD-1 VEGFR-1/2/3 | Sunitinib | KEYNOTE-426 | III | Recruiting | 840 | NCT02853331 | PFS OS | ORR DCR AEs |
Atezolizumab + Bevacizumab | PD-L1 VEGF | Sunitinib | ImMotion151 | III | Ongoing, but not recruiting | 915 | NCT02420821 | PFS OS | OS (PD-L1) CR/PR (%) DOR |
Nivolumab + Ipilimumab | PD-1 CTLA-4 | Sunitinib | CheckMate-214 | III | Ongoing, not recruiting | 1070 | NCT02231749 | PFS OS ORR | AE rate |