Last week, Exelixis (EXEL) presented updated results for its lead agent cabozantinib (also known as XL184 or "cabo"). Cabo had become a closely watched agent last year after demonstrating unique and unprecedented activity in prostate cancer patients, leading to either partial or complete resolution of bone scans in 19 out of 20 patients. This effect had never been seen with any of the approved or investigational agents for prostate cancer, leading to widespread enthusiasm but also some skepticism.
Following last week's data, it is now safe to say cabo has a real effect on bone metastases. The data set included 100 response evaluable patients, 62 of whom were evaluable for bone response. 85% of these patients experienced partial or complete resolution of their bone scans (the bone mets shrank or disappeared), 13% had stabilization and 2% (1 patient) had progression. Cabo had a profound effect on bone pain as well as markers for bone metabolism, implying the drug also has potential utility for treating bone related complications.
It is important to note that traditionally, bone metastases are not included in response evaluation for solid tumors, as standard response criteria apply only to tumors in other organs (soft tissue disease). Based on those criteria, cabo led to a modest response rate of 6%, with the majority of patients (82%) achieving stable disease as their best response.
Bone metastases are a hallmark of many types of cancer (lung, prostate, breast, renal) and in many cases lead to death either directly or indirectly. In addition, bone metastases are associated with severe quality of life issues such as fractures and pain, representing another unmet need. The clear (albeit less profound) effect XL184 has on soft tissue lesions adds a third layer of potential clinical benefit.
Patients with bone metastases are treated with two classes of drugs. Anti-cancer drugs act on soft tissue tumors but rarely shrink bone metastases. For the bone component, physicians can only offer drugs that treat symptoms and complications but none of them has a direct effect on existing bone mets. As the first drug that might treat bone mets rather than their symptoms, cabo has the potential to revolutionize treatment of cancer and complement existing regimens.
The bone mets effect appears to be broad, and not limited to prostate cancer. According to the company, similar bone scan resolutions have been observed in breast, lung and renal cancer patients. In all of these indications, cabo's immediate potential is in patients with existing bone metastases, a multi-billion opportunity worldwide. Cabo could also be beneficial as preventative treatment in patients who are at risk of developing bone mets, an even larger opportunity.
Cabo's complementary clinical profile puts it in a favorable position, as it is not necessarily competing with approved anti cancer drugs. Ideally, cabo should be added to existing therapies for achieving systemic effect on both soft tissue and bone lesions. Nevertheless, combining cabo with other agents is not trivial, as the drug has safety issues that might be a barrier for widespread adoption.
Path to registration
Exelixis decided to focus on prostate cancer, a reasonable choice given the large body of clinical evidence and the pivotal role bone metastasis has in this disease. The company plans to initiate 3 pivotal trials, each in a different patient population using a different pre-specified endpoint for approval.
Trial #1 -The first trial will focus on cabo's effect on bone scans and pain. Therefore, patients on this trial will have positive bone scans and inadequate pain control. The primary endpoint for this trial will be a composite endpoint of bone scan improvement and pain score, which is still not clearly defined.