Cabozantinib or XL184 (Exelixis, Inc), a Novel Multi-targeted oral inhibitor which simultaneously targets MET and VEGFR2, key kinases involved in the development and progression of many cancers, showed strong responses in patients with various advanced cancers in a Phase II trial. The findings will be presented on Sunday, June 5, 2011 at the 47th Annual Meeting of the American Society of Clinical Oncology(ASCO).

The drug demonstrated particularly high rates of disease control for advanced prostate, ovarian and liver cancers, which are historically resistant to available therapies. The drug also fully or partially eliminated bone metastases in patients with breast and prostate cancers and melanoma.

Improving outcomes
A number of preclinical models have shown that treatment with selective inhibitors of VEGF signaling can result in tumors that are more invasive and aggressive compared to control treatment. In preclinical studies, upregulation of MET has been shown to occur in concert with development of invasiveness after selective anti-VEGF therapy, and may constitute a mechanism of acquired or evasive resistance to agents that target VEGF signaling without inhibiting MET. Accordingly, treatment with cabozantinib in similar preclinical studies resulted in tumors that were less invasive and aggressive compared to control or selective anti-VEGF treatment. Therefore, cabozantinib has the potential for improving outcomes in a range of indications, including those where selective anti-VEGF therapy has shown minimal or no activity.

Treatment-resistant tumors
?Cabozantinib appears to have significant effects on several treatment-resistant tumors, as well as impressive effects on bone metastases. In addition, these effects are associated with rapid improvement in pain, a reduction in opiate narcotic requirements and improvement in anemia,? said lead author Michael S. Gordon, MD, a medical oncologist at Pinnacle Oncology Hematology, a community-based medical practice in Scottsdale, AZ. ?The implications of these results are very exciting?it is unusual to find a targeted therapy, absent of a molecular mutation in tumors, that works in bony disease and has this activity.?

Novel trial design
To be eligible for the study, patients had to have advanced, progressive solid tumors, with or without bone metastases. Of 398 evaluable patients (of 483 enrolled in the trial), 39 percent had bone metastases at baseline. Patients received cabozantinib over 12 weeks. The trial was designed as a ?discontinuation? trial, in which those who had partial responses stayed on the drug; those with stable disease were randomized to cabozantinib or placebo; and patients with progressive disease were removed from the trial. This novel type of clinical trial design more quickly evaluates the disease-stabilizing activity of growth-inhibitory agents like cabozantinib, compared to the traditional model of randomizing all patients to either the experimental arm or placebo.

Among 398 patients evaluable with all types of cancer included in the trial, the response rate was 9% (34 of 398). The highest disease control rates (partial response and stable disease) at week 12 were 76% for liver cancer (22 of 29 patients), 71% for prostate cancer (71 of 100 patients), and 58% for ovarian cancer (32 of 51 patients).

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Significant pain relief
Fifty-nine of 68 patients with bone metastases (including patients with breast and prostate cancers and melanoma) experienced either partial or complete disappearance of the cancer on bone scans, often with significant pain relief and other improved cancer-related symptoms.

The reduction of bone metastases and pain relief was an unexpected finding in this study, Gordon said. Independent review by radiologists confirmed that bone metastases disappeared in the majority of patients who had bone metastases when they entered the study. The majority of these patients had castration-resistant prostate cancer (CRPC), but patients with breast cancer and melanoma also had disappearance of bone metastases. Bone metastases greatly contribute to morbidity and mortality in patients with these types of cancer, which typically spread to the bone.

Ovarian Cancer
Due to these results, the study has been expanded to include more CRPC patients. Similarly, the high rate of lasting responses in ovarian cancer patients led researchers to also expand the study to evaluate the drug?s effect on patients with a particularly resistant form of the disease known as platinumresistant/refractory ovarian cancer.

This study expansion results will help determine the design of future Phase III trials, which will assess whether the drug extends patients lives or has other longer-term benefits among patients with specific cancer types. At present, cabozantinib is being investigated for use as a single agent. Additional studie will evaluate the efficacy and tolerability of appropriate combinations with other agents for future indications.

The most common grade three or above adverse events were fatigue (9%) and hand-foot syndrome (8%). Dose reductions were required in 41% of patients due to side effects; 12% were removed from the trial for adverse events.

For more information:
Study authors: Gordon MS, Vogelzang NJ, Schoffski P, Daud A, Spira AI, et al.
Abstract title: Cabozantinib (XL184) has activity in both soft tissue and bone: Results of a phase II randomized discontinuation trial (RDT) in patients (pts) w/ advanced solid tumors.
Session Date and Time: Sunday, June 5, 2011, 12:00-12:15 PM CDT
Abstract: # 3010

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