th median reductions of approximately 80% for uNTx/Cr occurring within 1 week regardless of prior bisphosphonate therapy or baseline uNTx/Cr level. In the phase III clinical trials, median reductions of approximately 80% were maintained in uNTx/Cr after 3 months of treatment in 2075 XGEVA-treated advanced cancer patients naïve to IV-bisphosphonate.
Immunogenicity
In clinical studies, neutralising antibodies have not been observed for XGEVA. Using a sensitive immunoassay < 1% of patients treated with denosumab for up to 3 years tested positive for non neutralising binding antibodies with no evidence of altered pharmacokinetics, toxicity, or clinical response.
Clinical efficacy in patients with bone metastases from solid tumours
Efficacy and safety of 120 mg XGEVA SC every 4 weeks or 4 mg zoledronic acid (dose-adjusted for reduced renal function) IV every 4 weeks were compared in three randomised, double blind, active controlled studies, in IV-bisphosphonate naïve patients with advanced malignancies involving bone: adults with breast cancer (study 1), other solid tumours or multiple myeloma (study 2), and castrate-resistant prostate cancer (study 3). Patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure, were not eligible for inclusion in these studies. The primary and secondary endpoints eva luated the occurrence of one or more skeletal related events (SREs).
XGEVA reduced the risk of developing a SRE, and developing multiple SREs (first and subsequent) in patients with bone metastases from solid tumours (see table 2).
Table 2: Efficacy results in patients with advanced malignancies involving bone
Study 1
breast cancer
Study 2
other solid tumours** or multiple myeloma
Study 3
prostate cancer
Combined
advanced cancer
XGEVA
zoledronic acid
XGEVA
zoledronic acid
XGEVA
zoledronic acid
XGEVA
zoledronic acid
N
1026
1020
886
890
950
951
2862
2861
First SRE
Median time (months)
NR
26.4
20.6
16.3
20.7
17.1
27.6
19.4
Difference in median time (months)
NA
4.2
3.5
8.2
HR (95% CI) / RRR (%)
0.82 (0.71, 0.95) / 18
0.84 (0.71, 0.98) / 16
0.82 (0.71, 0.95) / 18
0.83 (0.76, 0.90) / 17
Non-inferiority / Superiority p-values
< 0.0001† / 0.0101†
0.0007† / 0.0619†
0.0002† / 0.0085†
< 0.0001 / < 0.0001
Proportion of subjects (%)
30.7
36.5
31.4
36.3
35.9
40.6
32.6
37.8
First and subsequent SRE*
Mean number/patient
0.46
0.60
0.44
0.49
0.52
0.61
0.48
0.57
Rate ratio (95% CI) / RRR (%)
0.77 (0.66, 0.89) / 23
0.90 (0.77, 1.04) / 10
0.82 (0.71, 0.94) / 18
0.82 (0.75, 0.89) / 18
Superiority p-value
0.0012†
0.1447†
0.0085†
< 0.0001
SMR per Year
0.45
0.58
0.86
1.04
0.79
0.83
0.69
0.81
First SRE or HCM
Median time (months)
NR
25.2
19.0
14.4
20.3
17.1
26.6
19
