Potential risk of new primary malignancy with Xgeva®

HSA would like to inform healthcare professionals about a pooled safety analysis which showed an increased rate of new primary malignancy (NPM) in patients with advanced malignancies treated with Xgeva® (denosumab) compared to zoledronic acid. However, the incidence and event rates for any NPM were low and the absolute difference in event rates were small. No treatment-related pattern in individual cancers or cancer groupings was apparent.

Xgeva® (Amgen Singapore Manufacturing Pte. Ltd.) is a human monoclonal antibody (IgG2) that has been registered in Singapore since March 2012. It is indicated for the prevention of skeletal related events (e.g. pathological fracture, spinal cord compression) in adults with bone metastases from solid tumour, as well as the treatment of adults and skeletally mature adolescents with giant cell tumour of bone that is unresectable or where surgical resection is likely to result in severe morbidity.

Xgeva® targets and binds with high affinity and specificity to the receptor activator of nuclear factor kappa-B ligand (RANKL), a membrane protein essential for the formation, function and survival of osteoclasts. The binding of Xgeva® with RANKL interferes with the RANKL and RANK receptor signalling pathway, thereby decreasing bone resorption and cancer-induced bone destruction.

Influence of RANK modulation on the immune system1, 2

The RANKL/RANK signalling pathway regulates diverse physiological functions and organ development in the body. Besides its role in the regulation of bone homeostasis, the inhibition of the RANKL/RANK signalling pathway has also been hypothesised to play a role in immune modulation. RANK and RANKL are expressed on a variety of immune cells, such as dendritic cells, monocytes, and both T and B lymphocytes. The RANKL has been shown to play a role in preventing apoptosis in monocytes and dendritic cells, as well as in activating the antigen-presenting functions of monocytes to T cells. Hence, it has been postulated that inhibition of the RANK/RANKL signalling pathway might potentially lead to impairment of immune surveillance mechanisms, thereby predisposing susceptible patients to an increased risk of malignancy.

Review by the European Medicines Agency3,4

During a routine review of Xgeva® safety data in February 2018, the European Medicines Agency (EMA) noted that NPM was reported more frequently in patients with advanced malignancies involving bone treated with Xgeva® (120mg once monthly) compared to zoledronic acid (4 mg once monthly). In a pooled analysis of four Phase 3 studies that used zoledronic acid as a comparator, NPM occurred in 54 (1.5%) of 3,691 patients treated with Xgeva® (median exposure: 13.8 months; range: 1.0 to 51.7 months), and in 33 (0.9%) of 3,688 patients treated with zoledronic acid (median exposure: 12.9 months; range: 1.0 to 50.8 months) (risk ratio: 1.64, 95% CI 1.07 – 2.52). The cumulative incidence at one year was 1.1% for Xgeva® and 0.6% for zoledronic acid.

Review of the available information did not identify any treatment-related pattern in individual cancers or cancer groupings. Although the absolute differences in event rates were small, and a clear causal mechanism has not been identified, the EMA considered that the involvement of Xgeva® and a potential mechanism related to impaired immune surveillance could not be excluded. Consequently, the European Union (EU) product information for Xgeva® was updated to include information about the imbalance in NPM observed from clinical studies. A Dear Healthcare Professional Letter was also issued in the EU to inform healthcare professionals about this potential risk.

Local situation and HSA’s advisory

To date, HSA has not received any local adverse event report of NPM associated with the use of Xgeva®. The Singapore package insert for Xgeva® is in the process of being updated to include information about the incidence of NPM reported from the pooled safety analysis. Healthcare professionals are encouraged to take into consideration the above safety information when assessing the benefit-risk of Xgeva® therapy for their patients.

References 

1. Curr Oncol Rep (2010) 12: 80-6

2. World J Orthop (2012) 3: 142-50

3. https://www.gov.uk/drug-safety-update/denosumab-xgeva-for-advanced-malignancies-involving-bone-study-data-show-new-primary-malignancies-reported-more-frequently-compared-to-zoledronate

4. https://assets.publishing.service.gov.uk/media/5b2ccd01ed915d587f69eec5/Xgeva-DHPC-1605_signed.pdf