[Article image reference (added by editor): Leppanen, V.,et al (2009), 'Structural determinants of growth factor binding and specificity by VEGF receptor 2', PNAS, vol. 107 no.6]
1Eli Lilly and Company, Bridgewater, NJ, USA
Hallmarks of cancer include angiogenesis and immunosuppression. Preclinical evidence suggests targeting both processes simultaneously may have synergistic effects, with no additive toxicities. Anti-angiogenic therapies have several noted immunostimulatory effects including increased trafficking of T cells into tumors, and reduction of immunosuppressive cytokines and T regulatory cells, suggesting anti-angiogenic therapies may complement subsequent or concurrent immunostimulatory therapies.
Vascular endothelial growth factor receptors (VEGFR) -1 and -2 and their ligands (including VEGF A-D) are important mediators of tumor angiogenesis. Targeting the VEGF/VEGFR pathway with tyrosine-kinase inhibitors and/or antibodies to VEGF or VEGFR-2 disrupts tumor microvessels interfering with tumor growth and metastasis. Programmed cell death-ligand 1 (PD-L1) and the receptor programmed death 1 (PD-1) are frequently overexpressed in many types of cancer. The PD-1/PD-L1 pathway functions as a negative regulator of T-cell activation, limiting T-cell function in tumor progression. Promising antitumor activity has been observed in multiple tumor types with anti-PD-1/PD-L1 immune checkpoint inhibitors.
Ramucirumab (marketed under the brand name CYRAMZA®) is an immunoglobulin G1 VEGFR-2 monoclonal antibody that binds to the extracellular domain of VEGFR-2 with high specificity and affinity, competing with VEGF-A, -C, and –D. CYRAMZA (ramucirumab) is approved for use in certain patients with previously treated advanced or metastatic gastric or gastroesophageal junction adenocarcinoma, non-small-cell lung cancer (NSCLC), and colorectal cancer. Three ongoing phase 1 trials combining ramucirumab with either pembrolizumab (anti-PD-1; NCT02443324), durvalumab (anti-PD-L1; NCT02572687), or LY3300054 (anti-PD-L1; NCT02791334) will evaluate the safety and preliminary efficacy of these combinations in multiple tumor types. The combination with pembrolizumab is the furthest in development and interim safety and efficacy data were recently presented at ESMO 2016 (Herbst et al, Abstract #LBA38). The combination of ramucirumab and pembrolizumab did not generate any new safety signals and showed promising clinical activity, including durable responses, in patients with advanced NSCLC. Interim safety data for the combination of ramucirumab and durvalumab were recently presented at the ESMO Symposium on Immuno-Oncology 2016 (Lin et al, Abstract #93) and further validated the safety of combining ramucirumab with an immune checkpoint inhibitor. The emerging clinical data from these trials support continued development of anti-angiogenic agents in combination with anti-PD-1/PD-L1 antibodies in patients with advanced cancer.