Other Targets of Angiogenesis
Efforts are underway to exploit additional angiogenic factors to produce more significant responses than what has been seen with VEGFR inhibitors. The angiopoietin (ANGPT)-TIE system is such a potential target. It consists of two tyrosine kinase receptors (TIE1 and TIE2) and two major secreted ligands (angiopoietin1 [ANGPT1], angiopoietin2 [ANGPT2]. TIE1 has no known ligand and serves to regulate TIE2. TIE2 is expressed on endothelial cells and binds to ANGPT ligands. PF-04856884 (previously known as CVX-060) is a molecule described as a CovX-body, a covalent fusion between a biologically active peptide and a monoclonal antibody, which in this case, sequesters ANGPT2.27 In a Phase 1 trial, the primary AEs were fatigue, decreased appetite, back pain, and dyspnea. Grade 3 AEs included cholecystitis, colitis, and diarrhea.28 A Phase 2 trial is underway in RCC patients who have experienced tumor progression after one system therapy comparing PF-04856884 alone to PF-04856884 plus axitinib.29 The data collection period for PFS is planned to end in the latter part of 2013.
mTOR and PI3K/Akt Pathways
mTOR is an intracellular signal transduction regulator critical for cellular growth and metabolism, especially in a condition of nutrient and hypoxic stress.30 Activation of the pathway is commonly detected in RCC.31 As shown in Table 1, both temsirolimus and everolimus have produced positive results in Phase 3 trials. Experimental evidence suggests that inhibition of the mTOR pathway activates PI3K/Akt signaling pathways, promoting survival and proliferation and thus allowing development of resistance to this class of agent.32 Two agents are in early phase RCC trials to test this concept.
BEZ235 is a dual inhibitor of PI3K and mTOR cell signaling pathways. In vitro experiments with RCC cell lines indicate synergism with sorafenib.32 A Phase 1b/2 clinical trial has recently been initiated with planned completion in 2013.33
MK2206 is an inhibitor of Akt signaling pathways that shows broad preclinical activity and results of a phase 1 trial demonstrated a long half-life that may allow every other day or once weekly scheduling.34 A phase 2 trial in patients with advanced RCC who have received 1 or 2 prior treatments, including an anti-VEGF approach is comparing MK2206 with everolimus. Planned enrollment is 114 and data collection for the primary end point (PFS) is projected to conclude at the end of 2012.35
Novel Cell Signal Targets
BMS-936558 (MDX-1106) is a fully human monoclonal antibody developed to block the programmed death-1 (PD-1, CD279) inhibitory co-receptor expressed on antigen-activated and exhausted T and B cells. One ligand for the receptor, B7-H1, is upregulated in many tumors and expression is associated with poor outcomes.36 A Phase 2 trial in patients with RCC that has been treated with one to three prior systemic treatments (at least one being anti-angiogenic) began enrollment in 2011. Patients (N=150) will be randomized to one of three intravenous doses given every three weeks, and data collection for PFS is due to be completed in late 2012.37 In addition, a Phase 1 study of BMS-936558 in combination with sunitinib or pazopanib is slated to begin in early 2012.38
The Notch signaling pathway, which influences interactions between neighboring cells, is gaining increasing recognition for its role in carcinogenesis. Aberrant activity has been associated with several solid tumors, including RCC.39 RO4929097 is an inhibitor of gamma secretase, a key enzyme in Notch activation. In a Phase 1 trial, common AEs included fatigue, nausea, emesis, diarrhea, hypophosphatemia, pruritus, and rash. Only 8% overall were grade 3, and there were no grade 4 toxicities.40 A Phase 2 trial to evaluate overall response rate is underway in 39 patients with RCC that have failed a VEGF-targeted therapy.41