For the elements related to caboxantinib use in renal cell cancer for this review, we undertook a systematic assessment of literature and peer-reviewed presentations by searching PubMed, MEDLINE, and major oncology meeting (ASCO.org, ESMO.org, and ECCO.org) abstracts. The following keywords were used in the database searches: (cabozantinib or cabozantinib-s-malate or RTK inhibitor or XL 184 or tyrosine kinase inhibitor or TKI or multi-TKI) and (c-MET or MET or VEGFR or VEGFR2 or AXL or RET) and (renal cell carcinoma or kidney cancer or clear cell renal carcinoma or renal cancer) and (tumor growth or angiogenesis). Hits were confirmed as having full text or full presentation content that was accessible and vetted by the authors for relevance to the review. Content was then tabulated and summarized for use in the review. Study design, sample size, treatment effect, and adverse effects were reviewed by the three authors. The search included preclinical studies and human studies. Publications not primarily published in English were excluded.
CURRENT THERAPIES IN ADVANCED RCC
Prior to 2005, high-dose interleukin-2 and interferon alpha (IFNα) were the only approved treatments for advanced or metastatic RCC disease with ~5% of patients achieving a complete response.7 However, the use of high-dose interleukin-2 is limited to relatively young, healthy patients and restricted to administration in centers with experience in managing the considerable toxicities of the regimen. With the recognition of the biologic basis of RCC due to loss of the von Hippel Lindau (VHL) tumor suppression of angiogenic pathways, therapeutic development focused on targeting vascular endothelial growth factor (VEGF) and mTOR pathways. The first agents to be approved were multitargeted receptor tyrosine kinase inhibitors (TKIs). Currently, the US Food and Drug Administration (FDA) approved the following five VEGF pathway inhibitors in metastatic RCC: bevacizumab, sunitinib, sorafenib, pazopanib, and axitinib. The inhibition of the VEGF/VEGFR pathway by these drugs has moved the overall survival in metastatic RCC to a median of 2 years in the first-line setting.8 In addition to targeting the VEGF receptor, these agents inhibit a variety of receptors including PDGF and c-kit.
While these TKIs significantly prolonged progression-free survival (PFS) compared to IFNα in previously untreated patients with advanced or metastatic RCC, issues including toxicity led to further development of additional agents such as axitinib and pazopanib.9–12 Axitinib is highly selective for the inhibition of VEGFR-1, VEGFR-2, and VEGFR-3 and was approved by the FDA for progressive disease after one “first-line” therapy based largely on the AXIS trial.12 A Phase III randomized trial, the AXIS trial, randomized 723 patients with metastatic RCC to axitinib or sorafenib after failure of first-line therapy and demonstrated that axitinib had significantly longer PFS than sorafenib (6.7 vs 4.7 months; hazard ratio [HR] 0.665; 95% CI 0.544–0.812; P<0.0001). However, no overall survival benefit was observed. In a Phase III trial with 435 patients, pazopanib, another VEGF, PDGF, and Kit inhibitor, doubled the PFS but had no improvement in OS in locally advanced or metastatic disease when compared with placebo.13 When compared with sunitinib head-to-head in the COMPARZ trial, there was no difference in PFS or OS.14 An alternative approach to suppressing VEGF signaling was to target the ligand with bevacizumab, a monoclonal antibody that binds to circulating VEGF and prevents it from activating the VEGF receptor. This strategy was also successful with prolonged PFS in combination with interferon compared to IFNα alone in the AVOREN and CALGB trials, leading to FDA approval for its use in RCC.15,16 The mTOR pathway plays a central role in the regulation of cell growth, influencing many critical molecular functions, including angiogenesis, cell proliferation, and glucose homeostasis. mTOR signaling is upregulated in RCC, making it an attractive therapeutic target.17 The following two agents were developed based on their ability to inhibit mTOR signaling: temsirolimus, an intravenous preparation administered weekly, and everolimus, an oral analog of rapamycin. A Phase III trial led to the approval of temsirolimus for previously untreated, poor-risk RCC. Six hundred twenty-six previously untreated patients were randomly assigned to temsirolimus, temsirolimus + IFNα, or IFNα monotherapy. Temsirolimus significantly prolonged the median overall survival compared to IFNα as a single agent (10.9 vs 7.3 months, HR 0.73, 95% CI 0.58–0.92).18 However, in VEGF-pretreated patients, temsirolimus demonstrated a shorter overall survival than sorafenib in 512 patients who had progressed on sunitinib.19 On the other hand, everolimus initially was approved based on its efficacy in VEGF-pretreated patients. In the RECORD-1 trial, a double blind, randomized, placebo-controlled Phase III trial, everolimus demonstrated PFS superiority over placebo in patients with metastatic RCC progressing on VEGF TKIs. A total of 416 patients were randomized to either everolimus or placebo, resulting in a median PFS of 4.9 months in the everolimus group vs 1.9 months in the placebo group.20
VEGF AND MET IN RCC
Angiogenesis involves the formation of new blood vessels from the preexisting blood vessels and is one of the hallmarks of cancer. Neoangiogenesis supplies the tumor with nutrients for progression and invasion into surrounding tissue and contributes to lymphatic invasion and distant metastasis.21 The process is controlled by growth factors such as vascular endothelial growth factor, fibroblast growth factor, hepatocyte growth factor, insulin-like growth factor, and transcription factors such as hypoxia inducible factor to increase endothelial cell proliferation, migration, and survival (Figure 1).22 In the majority of renal cell cancer, the VHL is inactivated causing upregulation of VEGF and also other factors. VEGF stimulates the endothelial cells, which form the walls of the vessels and help in maintaining the transport of oxygen and nutrients to the tissues, hence promoting growth. The upregulation of VEGF leads to an increased angiogenesis, endothelial permability, and tumor cell viability and a more invasive tumor phenotype.23 Therapy with agents directed against the VEGF protein or the VEGF receptor is a central basis of current treatments with today’s antiangiogenic drugs.
Within the VEGF family of glycoproteins, there are VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placental growth factors, each involved in angiogenesis and formation of other vessels.24 Each glycoprotein is activated by binding to an extracellular tyrosine kinase receptor on the cell surface called VEGFR-1, VEGFR-2, and VEGFR-3. These receptors dimerize and phosphorylate, activating the cellular responses exhibited by VEGF glycoproteins.25 VEGFR-2 is hypothesized to mediate all the cellular functions of VEGF, and VEGFR-1 seems to modulate the function of VEGFR-2, although its exact function is not defined. The most important glycoprotein in the VEGF family is VEGF-A. This ligand is particularly important because it has a dramatic upregulation of its expression levels under hypoxic conditions. During hypoxic conditions, hypoxia inducible factor is stabilized, binding to specific promoter elements, which are present in the promoter region of VEGF-A.26 This activated VEGF-A gets bound to the VEGFR, mostly with VEGFR-2, inducing angiogenesis. In preclinical models, targeting the VEGF signaling pathway has proven to be efficacious, inhibiting neovascularization and yielding tumor regression in animal models.27
Targeting the VEGF has been a very successful strategy for treating metastatic RCC. However, suppression of VEGF signaling is not universally effective; there are patients with primary refractory disease as well as nearly universal acquired resistance. Redundancy in mechanisms for angiogenesis likely account for some resistance, including induction of the protooncogene called mesenchymal–epithelial transition (MET) factor.28,29 VEGF and MET are overexpressed in hypoxic environments to promote survival by stimulating angiogenesis or facilitating migration away from the hypoxic zone (Figure 2).30–32 Inhibition of the VEGF pathway alone can induce hypoxemia and also trigger a compensatory upregulation of MET expression, which helps drive tumor invasion.25 Targeting the MET is the rational strategy to overcome VEGF-targeted therapy resistance.