Key safety concerns with Denosumab ( Xgeva ) included in the Warnings and Precautions section of the existing product labeling involve the risks of osteonecrosis of the jaw ( ONJ ) and hypocalcemia. One additional concern regarding this bone-targeted drug is whether Denosumab may shift the pattern of metastases to non-bony areas. An exploratory analysis showed that a higher number of patients developed an extra-osseous progression event in the Denosumab arm ( 184 versus 156, including lymph node progression ); however, Denosumab-treated patients were undergoing disease related follow-up for a longer period of time ( due to longer BMFS ).
Severe hypocalcemia ( corrected serum calcium less than 7 mg/dL or less than 1.75 mmol/L ) occurred in 1.3% of patients treated with Denosumab and 0% of patients receiving placebo. The incidence observed in the Denosumab group was lower than that observed in Study 20050103, the prostate cancer trial which served ( in part ) as a basis for the existing Xgeva ( SRE ) indication.
Osteonecrosis, or avascular necrosis of the jaw ( ONJ ) is a pathological process associated with pain, swelling, exposed bone, local infection, and pathologic fracture of the jaw. Risk factors for developing ONJ include treatment with Denosumab, bisphosphonates, duration of bisphosphonate exposure, cancer and anti-cancer therapy, dental extractions, dental implants, poorly fitting dentures, glucocorticoids, smoking, and pre-existing dental disease. The mechanism by which ONJ develops is not well understood. Osteonecrosis of the jaw presents as exposed necrotic bone typically involving the maxilla or mandible. It is not known whether osteonecrosis is the primary process that becomes secondarily infected or if osteonecrosis represents primary osteomyelitis that becomes exacerbated.
The definition of ONJ used by Amgen ( a lesion occurring in the oral cavity as an area of exposed alveolar or palatal bone where gingival or alveolar mucosa is normally found, associated with non-healing after appropriate care by 8 weeks in a patient without prior history of radiation to the head, face, or mouth; the lesion can be asymptomatic, or oral/orofacial fistulas suspicious for underlying ONJ can be present ) was accurate and consistent with the medical literature.
In order to identify all ONJ events in Study 20050147, adverse events considered possible manifestations of osteonecrosis of the jaw were identified using pre-specified search criteria and sent for adjudication by a panel of independent experts blinded to treatment group, who used predefined criteria for establishing a diagnosis of osteonecrosis of the jaw. Reported adverse events were identified by searches of the safety databases using a predefined list of MedDRA search terms and via clinical review of oral examination case report forms and the verbatim terms used to report adverse events. Oral examinations were conducted for each patient every 6 months during the treatment phase of the study.
Including follow-up of patients through the extended blinded treatment phase, the overall incidence of osteonecrosis of the jaw confirmed by the adjudication committee was 5.4% in Denosumab-treated patients [ 4.6% ( 33 patients ) in Denosumab-treated patients compared to no events in patients receiving placebo during the primary analysis phase ]. The overall incidence of osteonecrosis of the jaw was higher than that observed with Denosumab treatment in Study 20050103 ( the randomized trial that evaluated Denosumab versus Zoledronic acid for the prevention of SREs ); and the median duration of exposure was longer for Study 20050147 as compared to Study 20050103 ( 19.3 months vs. 11.9 months, respectively ). Median time to onset of osteonecrosis of the jaw was 21 months.
An assessment of patients through the cut-off date for the primary efficacy analysis showed that 30% of patients with ONJ events ( 10 patients ) required no surgical treatment; 21 ( 64% ) required limited surgical procedures ( debridement, sequestrectomy, and curettage ) and 2 required bone resection. One patient suffered cardiac arrest, seizures, and post-cardiac arrest coma related to complications of lower jaw osteomyelitis / osteonecrosis of the jaw.
The increased risk of osteonecrosis of the jaw observed in Study 20050147 compared to 20050103 is concerning given the context that Denosumab is approved for patients with prostate cancer metastatic to bone. These results suggest the possibility that the risk of osteonecrosis of the jaw increases with increasing exposure to Denosumab as Xgeva, and that continued long-term exposure may increase the ONJ rate to a level that off-sets the risk-benefit profile for the SRE indication in patients with prostate cancer. Indeed, the 120-day safety update to the sBLA reported an additional 6 patients with ONJ events out of 100 patients who received Denosumab ( in the denosumab arm ) in the open-label extension phase of Study 20050147.
The incidence rates of adverse events other than osteonecrosis of the jaw and hypocalcemia, including other serious adverse events, fatal adverse events, and Grade 3-5 adverse events were similar between treatment groups. ( Xagena )
Source: FDA, 2012