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XGEVA (Denosumab) Approved as Treatment for Preventing Skeletal-Related Complications
The FDA just recently approved a new drug, denosumab (now christened with the marketed name XGEVA) as a treatment for patients with bone metastases from solid tumors such as lung cancer, breast cancer, and prostate cancer (in fact about three quarters of bone metastases are in these three cancer types). Dr. Sanborn previously described preliminary results of a trial of XGEVA, given as a subcutaneous (under the skin) injection every 4 weeks, compared with the current standard of Zometa (zoledronic acid), a bisphosphonate therapy that is also commonly administered every 4 weeks to patients with known bone metastases to prevent the development of future “skeletal-related events” (SREs), a defined collection of complications from bone metastases that includes a pathologic fracture (bone fracture caused by structural instability of a bone metastasis), need for surgery or palliative radiation to a bone met, initiation of narcotics to manage pain from a bone met, or an abnormally high serum calcium level (hypercalcemia) — a complication that often requires hospitalization to manage.
Amgen, the company that makes XGEVA, ran a series of three large randomized phase III trials that each compared XGEVA to Zometa: one in patients with bone mets from breast cancer, another for those with bone mets from prostate cancer, and the third a grab bag of patients with multiple myeloma (a cancer of blood cells that includes bone lesions) or solid tumors that aren’t breast or prostate cancer. These well-conducted studies gave drug and placebo in a double-blinded fashion: every four weeks, patients received XGEVA with an IV placebo of Zometa, or they received Zometa with a subcutaneous placebo injection — neither the doctor nor the patient knew which was the active drug and which was the placebo. All of these trials looked at the rate of developing SREs as the primary endpoint, have now been completed and reported in one form or another, and they were all strikingly similar in their outcome.
Bone Pain in Cancer
Bone pain is a specific cancer pain syndrome that also happens to be the most common cause of cancer pain. Cancer involvement of bone is also something that can be seen with numerous types of cancer. It is a type of somatic pain, which is “body-related” pain, as I mentioned in my Pain 101 post.
The more common bone sites for metastases include the spine, skull, humerus (upper arm), ribs, pelvis, and femur (hip bone). The more common cancers that cause bony metastases include lung, breast, prostate, and multiple myeloma. The incidence of bone involvement varies among these different cancers, but for example in lung cancer, up to 24% of patients have bony metastases. Bone pain in cancer also occurs as a complication of certain treatments, such as avascular necrosis (bone death in the large hip or shoulder bones) due to steroid treatments or osteoradionecrosis (bone death after radiation, particularly in the jaw bone). I will focus primarily on bone pain from metastases in this post.
Why do bone metastases cause pain? While the mechanisms are not completely understood, it is thought that cancer metastases disrupt the normal balance of bone building and bone resorption (bone breakdown); this imbalance contributes to the pain. The pain is usually constant and localized; it can sometimes “refer” or be felt in other adjacent locations. Patients often describe bone pain as an ache, versus the shooting electrical qualities of neuropathic pain, and it often gets worse with certain activity. Should the bone metastasis cause a fracture or damage a nerve, then the pain can become more complex and severe, with qualities of both somatic pain and neuropathic pain.
Bisphosphonates for Skeletal Metastases in Lung Cancer
In addition to local treatments such as surgery or radiation for more immediate and directed therapy for bone metastases, there is a commonly used and FDA-approved approach with Zometa, also known as zoledronate or zoledronic acid. It is one of a class of drugs known as bisphosphonates that can reduce the rate of progression with skeletal complications. They bind tightly to calcium and then distribute especially to sites of active bone remodeling, such as bone metastases. In addition to increasing calcium deposits in bone, bisphosphonates like Zometa and others inhibit cells called osteoclasts, which break down bone (and can have a normal function in remodeling during the healing process for bone).
More than 10 years ago, clinical trials with other bisphosphonates demonstrated reductions in the risk of future skeletal fractures and pain in patients with osteoporosis and cancer-related bone disease. A key trial, known as Zometa 011 (abstract here) evaluated Zometa at either 8 or 4 mg given IV every three weeks for 9 months, compared with a placebo in patients with bone metastases from lung cancer or another solid tumor. A total of 773 patients were enrolled, of whom 436 had lung cancer (378 with NSCLC, 58 with SCLC), representing by far the largest cancer type involved in the study. Participants also received supplemental calcium with vitamin D. In an earlier safety analysis, it was noted that patients on the higher dose of zometa were experiencing problematic declines in their kidney function over time, and the trial was modified to focus exclusively on the lower dose of 4 mg IV every three weeks. The trial was also modified to give the Zometa or placebo over 15 minutes instead of 5, since this had been found in other testing to be associated with lower risk of kidney problems. Continue reading
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