Cambridge, UK, (April, 2011) – Amgen has announced the publication of results from a pivotal Phase 3 study of 1,776 advanced cancer patients with different types of solid tumours (not including breast and prostate cancer) or multiple myeloma, which compared denosumab to Zometa® (zoledronic acid) in preventing skeletal-related events (SREs). The study, which appeared in the Journal of Clinical Oncologyi, found that denosumab was non-inferior to Zometa® in delaying or preventing first on-study SREs.
“When cancer progresses, bone is one of the most common sites to be affected by metastatic disease. Bone metastases can cause significant complications for patients including severe bone pain, fracture and spinal cord compression”, said Dr Gary Middleton, Consultant Medical Oncologist, Royal Surrey County Hospital. “Due to improvements in cancer care, patients are living longer and are therefore more likely to develop bony metastatic involvement during the course of their disease. It is therefore critical that we discover the most effective therapies to prevent or reduce the impact of this significant and debilitating problem. These treatments must be well tolerated and convenient as it is crucial that their use leads to significant improvements in quality of life.”
Denosumab, the first and only RANK Ligand inhibitor indicated for the prevention of SREs in patients with bone metastases from solid tumours was approved by the U.S. Food and Drug Administration on Nov. 18, 2010.ii The approval was based in part on results described in this publication. Denosumab is not indicated for the prevention of SREs in patients with multiple myeloma.iii Denosumab has not yet been approved in Europe.
Key Study ResultsFor the primary endpoint of this study, the median time to first on-study SRE (defined as fracture, radiation to bone, surgery to bone, or spinal cord compression) was 20.6 months for patients receiving denosumab and 16.3 months for patients receiving Zometa® (hazard ratio 0.84, 95 percent CI: 0.71-0.98), which is statistically significant for non-inferiority (p=0.0007).i Although numerically greater, the delay in the time to first SRE associated with denosumab was not statistically superior compared to Zometa® based upon the statistical testing strategy (adjusted p=0.06) (secondary endpoint). The time to first- and- subsequent SRE was also numerically greater but not statistically superior compared to Zometa® (hazard ratio 0.90, 95 percent CI: 0.77-1.04, p=0.14) (secondary endpoint).
In the study, hypocalcaemia occurred more frequently with denosumab, while osteonecrosis of the jaw (ONJ) occurred at similar rates in both groups.i Acute phase reactions after the first dose occurred more frequently in the Zometa® arm, as did renal adverse events and elevation in serum creatinine. No dose adjustments or dose withholding for renal function are required for denosumab.
Study DesignThis study was an international, randomised, double-blind, double-dummy, active-controlled study, in which advanced cancer patients with solid tumours or multiple myeloma were randomised to receive either subcutaneous denosumab 120 mg and intravenous placebo (N=886), or Zometa® administered intravenously a single 15 minute infusion at a dose of 4 mg (or equivalent creatinine clearance-adjusted dose in patients with baseline creatinine clearance ≤ 60 mL/min) every four weeks as per the labeled instructions (N=890).i All patients were strongly recommended to take daily calcium and vitamin D supplements. The primary endpoint was time to first on-study SRE.
Denosumab Important Safety Information iii
Denosumab can cause severe hypocalcaemia. Correct pre-existing hypocalcaemia prior to denosumab treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Advise patients to contact a healthcare professional for symptoms of hypocalcaemia.
Osteonecrosis of the jaw (ONJ) can occur in patients receiving denosumab. Patients who are suspected of having or who develop ONJ while on denosumab should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.
The most common adverse reactions in patients receiving denosumab were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction in patients receiving denosumab was dyspnea. The most common adverse reactions resulting in discontinuation of denosumab were osteonecrosis and hypocalcaemia.
Bone Metastases and Skeletal Related Events: Prevalence and ImpactBone metastases occur in more than 1.5 millioniv patients with cancer worldwide and are most commonly associated with cancers of the prostate, lung, and breast, with incidence rates as high as 75% of patients with metastatic disease.v
Approximately 50-70% of cancer patients with bone metastases will experience debilitating SREs.vi vii viii Events considered to be SREs include fractures, spinal cord compression, and severe bone pain that may require surgery or radiation.ix Such events can profoundly disrupt a patient’s life and can cause disability and pain.x xi
Denosumab and Amgen's Research in Bone BiologyThe denosumab development programme demonstrates Amgen's commitment to researching and delivering pioneering medicines to patients with unmet medical needs. Amgen is studying denosumab in numerous tumour types across the spectrum of cancer-related bone diseases.
In addition, denosumab is approved by the FDA and EMA for the treatment of osteoporosis in postmenopausal women and marketed as Prolia® ▼. xii xiii
Denosumab Skeletal Related Events Regulatory StatusDenosumab was approved by the FDA for the prevention of SREs in patients with bone metastases from solid tumours on Nov. 18, 2010.ii
Amgen has also submitted marketing applications for denosumab in the European Union, Australia and Switzerland. In Japan, Amgen is working with its licensing partner, Daiichi-Sankyo Company, Limited and a marketing application was submitted.
DMO-GBR-AMG-102-2011
Date of preparation: March 2011
