The MET signaling pathway is important in tumor growth, survival, and metastasis and acts synergistically with VEGF to promote angiogenesis.33–35 In mouse models, the hepatocyte growth factor–MET pathway plays a key role in bone metastasis development.36 In renal cancer cells, MET protects cells from apoptosis, increases invasion and motility, and fosters epithelial–mesenchymal transition.37 As demonstrated in animal models and preclinical studies, inhibition of VEGF alone without MET produces rapid progression of tumors.27 Preclinical studies have shown that by blocking the VEGF pathway, hypoxia is induced, but the stress on the tumor cells results in a compensatory upregulation of MET expression, which further stimulates angiogenesis and migration away from the hypoxic zone.38 After inhibition of cellular receptors of VEGF that promote angiogenesis, tumor cells attempt to escape the hypoxic environment by metastasizing and seeking a more hospitable location. This rapid revascularization and subsequent metastasis is presaged by MET overexpression, leads to resistance of the VEGF pathway, and is a fundamental mechanism that tumor cells use to survive. In in vivo studies of sunitinib, the MET pathway was identified as important in the development of resistance to VEGF signaling inhibition. In the experimental model, flow cytometry showed that MET expression was higher in resistant tumor cells. Combining sunitinib with a selective MET inhibitor significantly enhanced tumor suppression when compared with sunitinib or MET inhibitor alone in resistant tumors.39
The discovery that VEGFR and MET pathways work synergistically in tumor cells underlies the development of cabozantinib.40–42 Similar to other VEGF TKIs, cabozantinib inhibits vascular endothelial cell tubule formation in vitro, cellular migration, invasion, and tumor cell proliferation in a variety of tumor types. Uniquely, cabozantinib inhibits MET and VEGFR2 phosphorylation in vivo, preventing compensatory metastasis following intravenous tumor cell inoculation. By targeting both pathways simultaneously, cabozantinib blocks metastatic escape pathways and inhibits the expression of other potential resistance factors such as phosphatidylinositol-3-kinase, phospholipase C, pp60src, and Grb2/Sos1.43 Preclinical studies found that cabozantinib inhibited the appearance of liver metastasis in a transgenic mouse xenograft model.44 Treatment with cabozantinib resulted in a more extensive tumor shrinkage and a decreased tumor invasiveness and metastasis than treatment with vehicle or anti-VEGF antibody alone. The median survival was 14.7 weeks for vehicle-treated animals and 16.4 weeks for anti-VEGF antibody-treated animals, while animals treated with MET inhibitors demonstrated an improved survival of >20 weeks (P<0.05). Of significance in the study, all of the mice treated with cabozantinib survived until the experiment ended at 20 weeks, whereas none of the vehicle- or anti-VEGF antibody-treated mice survived to that endpoint.45 This study suggests that dual inhibition of MET and VEGFR2 with cabozantinib is more effective and results in a more sustained response than inhibition of VEGF pathway alone.
ROLE OF CABOZANTINIB
In 2011, cabozantinib emerged as a new, orally bioavailable, small-molecule receptor TKI with dual VEGF and MET inhibition properties. Preclinical experiments found that inhibition of MET and VEGFR2 phosphorylation in vitro and in tumor models in vivo led to significant reductions in cell invasion. In vivo, the effect of disruption of tumor vasculature by cabozantinib was studied on antiangiogenic-sensitive tumor cells expressing MET and VEGF in animal models.44,46–49 The animals were divided into two groups in which one group was administered the drug with vehicle and the second group was administered only the drug. Both the groups were administered the same dose orally, and after first 4 and 8 hours intervals, tumors were collected. Consecutive tumor collection was done after 4 hours interval following second, third, and fourth administrations of the drug. Cabozantinib-treated tumor cells exhibited ~13 times greater levels of tumor hypoxia and 2.5 times greater levels of apoptosis, measured by cell death marker TUNEL, after the first and second doses as compared to the vehicle-treated tumors.25 In mouse models, cabozantinib dramatically altered tumor pathology, resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in various tumors. Cabozantinib was also found to bind to and inhibit other tyrosine kinases implicated in tumor pathobiology involved in angiogenesis including RET, KIT, AXL, and FLT3 (Figure 3).50,51
A Phase I study was undertaken using cabozantinib in a dose de-escalation design beginning at 140 mg orally daily in 25 heavily pretreated patients with metastatic renal cell cancer.52 The most common clinical side effects were fatigue (80%), diarrhea (64%), anorexia (36%), and vomiting (36%). Common grade ≥3 adverse events included fatigue (20%), diarrhea (12%), pulmonary embolism (12%), hypophosphatemia (40%), proteinuria (8%), appetite decreased (4%), palmar-plantar erythrodysesthesia (4%), and vomiting (4%). Dose reductions occurred in 20 of the 25 patients: the final daily dose was 100 mg for 6 patients, 60 mg for 11 patients, 40 mg for 2 patients, and 20 mg for 1 patient. The median average daily dose was 75.5 mg. Of the 21 subjects assessable for radiological response by RECIST, partial response was reported in 7 patients (28%) while 13 patients (52%) had stable disease and only 1 patient had progressive disease as the best response. The median PFS was 12.9 months, and the median overall survival was 15.0 months. At the conclusion of this trial, it was clear that cabozantinib promised significant efficacy compared to historical controls for cancer control and PFS and overall survival. Questions remained regarding toxicity; therefore, the optimal dose in renal cell cancer was decided based on experiences in other solid tumor studies.53–57
With robust Phase I evidence of cabozantinib activity in RCC, researchers embarked on a phase III trial, known as the METEOR trial, without conducting intercurrrent Phase II trials.58 The METEOR trial compared cabozantinib with everolimus in 658 patients with RCC who had experienced disease progression following treatment with a VEGF receptor TKI. Patient selection required histological or cytological diagnosis of renal cell cancer with a clear-cell component, measurable disease, recovery from prior toxicities related to any prior treatments. 658 patients were randomized in a 1:1 ratio to receive cabozantinib at a starting dose of 60 mg daily (330 patients) or everolimus (328 patients). The median age of patients was ~62 years (range, 31–86 years). All patients had received at least one prior VEGFR-targeted TKI and had radiographic progression within 6 months after the most recent dose. Previous systemic therapy primarily consisted of sunitinib (62%), pazopanib (43%), and axitinib (16%). The primary endpoint of PFS was assessed on the first 375 patients enrolled in the trial. In this portion of the study, 187 patients were randomized to cabozantinib and 188 received everolimus. The median PFS almost doubled from 3.8 months (95% CI 3.7–5.4) with everolimus to 7.4 months (95% CI: 5.6–9.1) with cabozantinib, representing a 42% reduction in the risk of progression or death (P<0.001). Cabozantinib was superior to everolimus for PFS across all subgroups. Objective tumor responses were observed in 21% of the cabozantinib group compared to 5% of patients treated with everolimus. When further assessed by an independent radiology process, the median PFS across all enrolled patients was 7.4 months for the cabozantinib arm vs 3.9 months for the everolimus arm, corresponding to a 48% reduction in the rate of disease progression or death for cabozantinib as compared to everolimus (HR =0.52, 95% CI 0.43–0.64, P<0.001). The objective response rate was 17% for cabozantinib and 3% for everolimus. In the secondary endpoint of the trial, the entire study population of 658 patients showed a median overall survival of 21.4 months (95% CI: 18.7–not estimable) with cabozantinib and 16.5 months (95% CI: 14.7–18.8) with everolimus (HR =0.66, 95% CI 0.53–0.83; P=0.00026). The pivotal results of the METEOR trial led to the approval of cabozantinib by the FDA for the treatment of advanced RCC in 2016.