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XGEVA (denosumab)

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Clinical Studies of XGEVA®

Clinical efficacy of XGEVA® (denosumab) compared to zoledronic acid

Three pivotal, phase III, randomized, double-blind studies have been conducted to assess the clinical efficacy of XGEVA® in preventing skeletal-related events (SREs) in adults with advanced malignancies involving bone.[CHMP AR, p. 48]

Studies of clinical efficacy in adults with advanced malignancies involving bone

In these studies, XGEVA® was compared with zoledronic acid, the primary objective being to determine if XGEVA® was noninferior to zoledronic acid in preventing SREs.

SREs are defined as one or more of the following: pathological fracture, radiation to bone, spinal cord compression or surgery to bone.

Patients in the XGEVA® group received 120 mg of XGEVA® every four weeks. Concomitant calcium and vitamin D supplementation were strongly recommended. Patients with a life expectancy of less than six months, patients with previous or current osteonecrosis of the jaw (ONJ) and patients with previous or current bisphosphonate treatment were excluded from the studies. In addition to SREs, data were collected on disease progression, overall survival, analgesic use, quality of life and healthcare utilization. The maximum duration of treatment in these studies was 30–41 months. Due to the severe nature of metastatic cancer, dropout rates were high in both groups (54–80%), which is similar to other oncology studies in these patients.[CHMP AR, pp. 48-51, 54, 58, 60-62]

The first study involved 2,046 patients with breast cancer and bone metastases. Male breast cancer patients were also included. XGEVA® was superior to zoledronic acid for the delay or prevention of SREs, reducing the risk by 18% compared with zoledronic acid.[CHMP AR, pp. 48-49, 58]

The second study involved 1,901 patients with castration-resistant prostate cancer and bone metastases. Again, XGEVA® was superior to zoledronic acid for the delay or prevention of SREs, reducing the risk by 18% compared with zoledronic acid.[CHMP AR, p. 58; SmPC, p. 9]

The third study was conducted in 1,776 patients with advanced solid malignant tumours and bone metastases (excluding breast and prostate cancer), or multiple myeloma. Approximately 40% of study participants had non-small cell lung cancer, 10% had multiple myeloma, and the remainder had other solid tumour types. XGEVA® was noninferior to zoledronic acid for the delay or prevention of SREs. XGEVA® lowered the risk of SREs by 16%, but this reduction did not reach statistical significance for superiority.[CHMP AR, pp. 48, 57-58]

A post-hoc analysis in patients with other solid tumours or multiple myeloma examined overall survival for the 3 tumour types used for stratification (non-small cell lung cancer, multiple myeloma, and other). Overall survival was longer for XGEVA® in non-small cell lung cancer (hazard ratio [95% CI] of 0.79 [0.65, 0.95]; n=702) and longer for zoledronic acid in multiple myeloma (hazard ratio [95% CI] of 2.26 [1.13, 4.50]; n=180) and similar between XGEVA® and zoledronic acid in other tumour types (hazard ratio [95% CI] of 1.08 (0.90, 1.30); n=894).[SmPC, p. 11]

In all three studies, the percentage decrease in the bone turnover markers uNTX/Cr and BSAP were greater (p<0.0001) following 3 months of XGEVA® treatment compared with zoledronic acid.[CHMP AR, p. 64]

XGEVA® reduced the risk of developing a SRE, and developing multiple SREs (first and subsequent) in patients with bone metastases from solid tumours.[SmPC, p. 10]

XGEVA® (DENOSUMAB) HAS PROVEN SUPERIORITY OVER ZOLEDRONIC ACID FOR THE PREVENTION OF SKELETAL-RELATED EVENTS (SREs) IN PATIENTS WITH BONE METASTASES FROM BREAST AND CASTRATION-RESISTANT PROSTATE CANCER, REDUCING THE RISK OF DEVELOPING THE FIRST ON-STUDY SRE BY 18% COMPARED WITH ZOLEDRONIC ACID.[CHMP AR, p. 58] 

Studies of clinical efficacy in adults and skeletally mature adolescents with giant cell tumour of bone

Two phase II, open-label, single-arm studies have been conducted to assess the efficacy of XGEVA® in patients with giant cell tumour of bone (n=529). The first study involved 37 adult patients with histologically confirmed unresectable or recurrent giant cell tumour of bone. The second study included 507 adults or skeletally mature adolescents with giant cell tumour of bone and evidence of measurable active disease. Overall, XGEVA® achieved objective tumour responses in 71.6% of patients in these two studies.[SmPC, pp. 11-12]