Cabozantinib (cabo), formerly known as XL184, has recently shown unprecedented activity against bone metastases in prostate cancer patients in a phase II trial. Cabo is a dual, potent inhibitor of the tyrosine kinases MET and VEGFR2. It's an oral drug developed by Exelixis for a variety of cancers and is currently in phase III for medullary thyroid cancer (MTC), and in phase II for metastatic castration-resistant prostate cancer (CRPC). Several phase III trials in CRPC are currently slated to begin at the end of 2011 or in early 2012. Cabo is the first MET inhibitor to be evaluated in prostate cancer.
Cabozantinib Targets Key Pathways in Cancer Progression and Metastasis
Chemical structure of CabozantinibAs a MET and VEGFR2 inhibitor, cabo inhibits both metastasis and angiogenesis. MET is known to be up-regulated in many tumor types and is thought to facilitate metastasis. MET expression has been observed in both primary and metastatic prostate carcinomas with higher MET levels observed in bone metastases. The ligand for MET, hepatocyte growth factor (HGF) is overexpressed in prostate cancer. HGF plasma levels are a prognosis marker for prostate cancer, with increased plasma levels of HGF observed to be associated with decreased overall survival in CRPC. Both MET and HGF are up-regulated by the androgen signaling pathway in prostate cancer, according to preclinical studies. Additionally, there is evidence that both MET and VEGFR signaling pathways have a crucial role in the function of osteoblasts and osteoclasts, cells in the bone microenvironment that are often found to be dysregulated during bone metastases onset and progression.
Prostate Cancer Phase II Results
The metastatic castration-resistant prostate cancer (CRPC) results presented at ASCO 2011 were longer-term interim data from a phase II adaptive randomized discontinuation trial (RDT) of 31 patients. 14 patients with CRPC randomized to cabo showed stabilization of metastatic bone lesions on bone scan and relief of bone pain in the majority of patients. Patients treated with cabo were able to reduce or eliminate the use of narcotic analgesic medication taken to relieve bone pain.
The randomized discontinuation phase of the study showed a statistically significant improvement in median progression-free survival (PFS) with a hazard ratio of 0.13 (P = .0007). This hazard ratio corresponds to an 87% reduction in risk of progression. Randomized patients were un-blinded due to a high rate of observed clinical activity.
A total of 171 patients were part of the trial, including 17 placebo-randomized patients in the RTD portion of the study. Including only the 154 cabo-treated patients, median PFS was 29 weeks, and was similar for both docetaxel(Drug information on docetaxel)-naïve and pretreated patients (24 and 29 weeks, respectively). Furthermore, a partial or complete resolution of bone scan was seen in 82 (76%) of patients, 23 patients (21%) had stable disease, and three patients (3%) had progressive disease in bone. All patients with a bone scan resolution were more likely to remain free of disease progression for 6 months (61% vs 35%) after starting treatment and had tumor regression (78% vs 58%) and bone pain relief compared with those who did not achieve bone scan resolution.
Traditionally, the response rate of solid tumors is measured as the response of soft tissue organs and not bone metastases. Based on this criteria, the 12-week disease control rate for soft tissue lesions was 68%, with 136 patients (80%) reporting stable disease and seven (4%) having a partial response. The safety data was consistent with previous studies.
Previous interim results in prostate cancer were presented at the European Organisation for Research and Treatment of Cancer (EORTC) conference in November of 2010 and at the American Society of Clinical Oncology (ASCO) Gastrointestinal (GI) Cancers Symposium in February of 2011.
Significance of the Prostate Cancer Bone Metastases Data
The high rate of activity seen with prostate cancer bone metastases has not been seen previously with either approved or experimental agents. While the initial 20-patient data was viewed with skepticism, the longer term and larger cohort results that were presented at ASCO show that cabo has a real effect on bone metastases as well as markers of bone metastases. However, it is important to note that there are currently no standard metrics for evaluating bone metastases because of the fact that no agent has yet had a meaningful effect on bone metastases in cancer.
There are an estimated 220,000 annual cases of prostate cancer in the United States and almost 15% of patients eventually progress after an initial treatment of surgery, radiation therapy, or observation for slow-growing disease. Patients that progress typically receive androgen deprivation therapy which blocks male sex hormones that stimulate prostate cancer cell growth. The vast majority of patients that receive this treatment progress to develop bone metastases, the main cause of morbidity and mortality in CRPC patients. The current standard of care only provides a 2–5 month benefit in survival.
Bone metastases cause a disruption of normal bone remodeling. These bone lesions often lead to increased skeletal fractures, spinal cord compression, and severe bone pain. Bone scans are a way to visualize these lesions. Additionally, increased blood levels of ALP and CTx, markers for both osteoblast and osteoclast activity, respectively, are associated with shorter overall survival.
Additional Studies of Cabo in Other Tumor Types
Thyroid Cancer
In May of this year, phase I trial data in advanced solid tumors or lymphoma were published in the Journal of Clinical Oncology, including data on the safety of the drug and tumor response among 85 patients. Thirty-seven patients in the study had medullary thyroid cancer (MTC) and the published data includes genotyping, pharmacokinetic, and pharmacodynamic biomarker results. Ten of the 37 MTC patients in the phase I trial had a partial response, with 5 patients showing a partial response at their first radiologic assessment. Seventeen patients had at least a 30% decrease in their tumor burden from baseline. Stable disease of at least 6 months (ranging from 6.4 to 31.1 months) was seen in 25 of the 37 patients with MTC. A phase III trial in MTC is ongoing and no interim results have yet been announced. However, according to Exelixis, the trial is close to achieving its required number of progression events for unblinding. Initially, data from this potentially registrational trial were expected in the second half of 2011, but the results have been pushed back by three months, so data is expected sometime in the fall of 2011, with a potential filing in early 2012.
A competing oral inhibitor, vandetinib from Astra Zeneca, has also shown substantial activity and was approved earlier this year.
Ovarian Cancer
At ASCO, data was also reported for a phase II ovarian cancer trial. The ovarian cancer results were longer-term follow up data in patients with advanced epithelial ovarian cancer, primary peritoneal carcinoma, or fallopian tube carcinoma, half of whom had platinum refractory/resistant ovarian cancer (platinum-free interval of 6 months or less). 57% of patients had received two or more prior platinum therapies and some patients had other lines of treatment such as VEGF pathway inhibitors or toptotecan. Cabo shows promising activity in these patients independent of prior response to platinum-based therapies. The best overall response rate was 24% (16 partial responses and 1 complete response), including patients with platinum refractory disease. The 12 week disease control rate was 53%. These results show the broader potential of Cabo for non-bone metastasis cancers, as bone metastases are quite rare in ovarian cancers.
Safety Data
Adverse events (AEs) seen at the maximum tolerated dose of 175 mg per day were palmar plantar erythrodysesthesia (PPE), AST/ALT elevations, lipase elevation, and mucositis. AEs have been consistent among all cancer types tested and include diarrhea, fatigue, decreased appetite, nausea, PPE syndrome, rash, increased AST, vomiting, and mucosal inflammation, including grade 3 and 4 AEs. Two grade 5 AEs, an enterocutaneous fistula and an intestinal perforation, were attributed to cabo in the phase II ovarian cancer cohort and 1 unexplained death in the prostate cancer study at week 33. Other medical events including infrequent grade 3 and 4 AEs include hemorrhage, venouse thrombosis, gastrointestinal perforation, and arterial thrombosis.
The success of cabo still awaits results of larger late-stage trials. The main outstanding questions will be the durability of the response vs tolerability, and whether the clinical profile is distinguished from other oncology treatments in development for prostate, ovarian, and thyroid cancers. It will be interesting to learn the mechanism of progression in prostate cancer bone metastases patients who were treated with cabo, to gain insight into the mechanisms of resistance and to facilitate identification of predictive biomarkers of response to treatment.
Exelexis has submitted the protocol for the first cabo phase III prostate cancer trial, called Study 306, to the U.S. Food and Drug Administration (FDA) with a primary endpoint of pain reduction and bone scan response. The company has requested a Special Protocol Assessment (SPA) for the trial which is a validation of the trial design and endpoints. Feedback from the FDA is expected as early as September 2011, and the trial is expected to begin by the end of 2011. A second phase III CRPC trial is scheduled to start in 2012 and will evaluate the impact of cabo on overall survival in CRPC patients. Whether cabo will be compared to placebo or an approved prostate cancer drug such as abiraterone acetate (Zytiga) or cabazitaxel (Jevtana) has not yet been announced. A third cabo phase III trial, also expected to begin in 2012, will evaluate cabo in the prevention of bone metastases in earlier-stage, non-metastatic CRPC patients. There are currently no drugs that are approved for this novel indication.
Cabo is also in clinical trials for brain, melanoma, breast, non–small-cell lung, hepatocellular, and kidney cancer.
Other Bone Metastases Treatments in Development
Positive data indicating a survival advantage in prostate cancer patients whose cancer has spread to the bone was released for Alpharadin, an oral treatment developed by Algeta and Bayer. Full phase III data for Alpharadin is expected to be presented at the ECCO/ESMO Stockholm Congress September 23–27th. The phase III ALSYMPCA trial is an international, double-blind, randomized, placebo-controlled trial evaluating 922 PRPC patients with symptomatic bone metastases. The median overall survival was 14 months, compared to 11.2 months for placebo with a hazard ratio of 0.699 (P = .0022). Safety data on Alpharadin has not yet been released. Based on phase II data, the safety profile is comparable to cabo, with constipation and mild neutropenia as the most frequent AEs.
