Denosumab Approved in China for Prevention of Skeletal-Related Events in Bone Metastases From Solid Tumors, Myeloma

November 23, 2020 - The China National Medical Products Administration (NMPA) has approved denosumab (Xgeva) for the prevention of skeletal-related events (SREs) in patients with bone metastases from solid tumors and in those with multiple myeloma, according to BeiGene, Ltd.¹

The regulatory decision was based on data from 4 randomized clinical trials that enrolled over 7000 patients: NCT00321464, NCT00330759, NCT00321620, and NCT01345019.

Results from these trials showed that denosumab delayed the time to the first SRE compared with zoledronic acid in patients with bone metastases from breast cancer, castration-resistant prostate cancer (CRPC), and other solid tumors like non–small cell lung cancer. Moreover, in those with lyic lesions from multiple myeloma, the agent had noninferiority to zoledronic acid in delaying the time to the first SRE.

“We began commercializing [denosumab] in China in July of this year and are excited to offer it for prevention of skeletal-related events, which can be caused by bone metastases from solid tumors and multiple myeloma and can include pathologic fractures, spinal cord compression, as well as the need for surgery or radiation to the bone,” Xiaobin Wu, PhD, general manager of China and president of BeiGene, stated in a press release. “This approval provides us with an opportunity to offer these patients in China a new medicine to help prevent SREs and is an important addition to our expanding oncology product portfolio.”

In a phase 3 trial (NCT00321464), investigators set out to determine whether denosumab would be noninferior to zoledronic acid when used in patients with bone metastases who had advanced breast cancer.^2,3

In the trial, participants were randomized to receive either subcutaneous denosumab at a dose of 120 mg and intravenous (IV) placebo (n = 1026) or IV zoledronic acid at 4 mg adjusted for creatinine clearance and subcutaneous placebo (n = 1020) every 4 weeks. The primary end point of the trial was time to first SRE.

Results showed that denosumab was superior to zoledronic acid in terms of delaying time to first SRE on trial (HR, 0.82; 95% CI, 0.71-0.95; P =.01) and time to first and subsequent SREs on trial (rate ratio, 0.77; 95% CI, 0.66-0.89; P =.001). Moreover, with denosumab the reduction in bone turnover markers was more significant. The agent was also found to be well tolerated.

Another phase 3 trial (NCT00330759) examined whether denosumab is noninferior to zoledronic acid in the treatment of patients with bone metastases and advanced cancer and multiple myeloma.^4,5

In the trial, participants were given either subcutaneous denosumab at 120 mg monthly or IV zoledronic acid at 4 mg, which was adjusted for creatinine clearance. The key end points in the trial comprised times to first on-study SRE, first-and-subsequent SREs, and pain worsening.

Results demonstrated that again, denosumab resulted in a substantial delay in time to first SRE on trial versus zoledronic acid (HR, 0.81; 95% CI, 0.68-0.96) and time to first-and-subsequent SREs (RR, 0.85; 95% CI, 0.72-1.00). The agent also led to a significant delay in the time to development of moderate or severe pain (HR, 0.81; 95% CI, 0.66-1.00), pain worsening (HR, 0.83; 95% CI, 0.71-0.97, and worsening pain interference in patients who had no or mild pain at baseline (HR, 0.77; 95% CI, 0.61-0.96).

In a third phase 3 trial (NCT00321620) examined whether denosumab was noninferior to zoledronic acid when used as a treatment for patients with hormone-refractory prostate cancr who also had bone metastases.^6,7

Here, patients with CRPC, 1 or more bone metastases, and no previous IV bisphosphonate use were given either subcutaneous denosumab at 120 mg or IV zoledronic acid at 4 mg, adjusted for creatinine clearance; this was given in a blinded fashion every 4 weeks.

Data indicated that fewer patients in the denosumab arm experienced a first symptomatic skeletal event compared with those in the zoledronic arm, at 25.4% and 30.4%, respectively (HR, 0.78; 95% CI, 0.66-0.93; P <.01). The same thing was true with regard to first SRE, at 35.9% versus 40.6%, respectively (HR, 0.82; 95% CI, 0.71-0.95; P <.01). The median estimate of time to first SSE for denosumab had not been reached versus 24.2 months with zoledronic acid (HR, 0.78; 95% CI, 0.66-0.93; P <.01).

A fourth phase 3 trial (NCT01345019) also set out to examine whether denosumab is noninferior to zoledronic acid in the treatment of patients with bone disease, this time, from multiple myeloma.^8,9

Patients with symptomatic newly diagnosed multiple myeloma who had at least 1 documented lytic bone lesion were randomized 1:1 to receive subcutaneous denosumab at 120 mg plus IV placebo every 4 weeks or IV zoledronic acid at 4 mg plus subcutaneous placebo every 4 weeks. Both arms were also given investigator’s choice of first-line antimyeloma treatment. The primary objective of this trial was noninferiority of denosumab to zoledronic acid in terms of time to first SRE in the full analysis dataset.

The trial was found to meet its primary end point, proving the noninferiority of denosumab to zoledronic acid for time to first SRE (HR, 0.98; 95% CI, 0.85-1.14; P =.010). With regard to safety, the most common grade 3 or higher treatment-emergent toxicities in the investigational and control arms included neutropenia (15% vs 15%, respectively), thrombocytopenia (14% vs 12%), anemia (12% vs 10%), febrile neutropenia (11% vs 10%), and pneumonia (8% vs 8%). Renal toxicity was experienced by 10% of those who received denosumab versus 17% of those given zoledronic acid, with 17% versus 12%, respectively, experiencing hypocalcemia.

“Amgen is accelerating our oncology pipeline for patients in China with difficult-to-treat cancers through our collaboration with BeiGene,” My Linh Kha, vice president and general manager of Amen Japan Asia-Pacific, added in the release. “We congratulate our teams and celebrate the approval of this new indication of [denosumab] for the prevention of skeletal-related events. With the approval of [denosumab] in this new indication, we are excited about the positive health impact it may have for patients in China.”

In January 2018, the FDA approved denosumab for the prevention of SREs in patients with multiple myeloma based on data from the aforementioned phase 3 trial (NCT01345019) performed in this patient population. A few months later, in April 2018, the RANK ligand inhibitor was approved in Europe for use in the same indication.

References

1. BeiGene announces the approval of Xgeva (denosumab) in China for the prevention of skeletal-related events in patients with bone metastases from solid tumors and in patients with multiple myeloma. News release. November 19, 2020. Accessed November 22, 2020. https://bit.ly/3lWHmrI.
2. A study comparing denosumab vs zoledronic acid for the treatment of bone metastases in breast cancer subjects. ClinicalTrials.gov. Updated October 17, 2018. Accessed November 22, 2020. https://clinicaltrials.gov/ct2/show/NCT00321464.
3. Stopeck AT, Lipton A, Body J-J, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol. 2010;28(35):5132-5139. doi:10.1200/JCO.2010.29.7101
4. Study of denosumab vs zoledronic acid to treat bone metastases in subjects with advanced cancer or multiple myeloma. ClinicalTrials.gov. Updated August 31, 2018. Accessed November 22, 2020. https://clinicaltrials.gov/ct2/show/NCT00330759.
5. Henry D, Vadhan-Raj S, Hirsh V, et al. Delaying skeletal-related events in a randomized phase 3 study of denosumab versus zoledronic acid in patients with advanced cancer: an analysis of data from patients with solid tumors. Support Care Cancer. 2014;22(3):679-687. doi:10.1007/s00520-013-2022-1
6. Study of denosumab vs zoledronic acid to treat bone metastases in men with hormone-refractory prostate cancer. ClinicalTrials.gov. Updated August 29, 2018. Accessed November 22, 2020. https://clinicaltrials.gov/ct2/show/NCT00321620.
7. Klotz L, Smith MR, Coleman RE, et al. Symptomatic skeletal events (SSE) in patients with advanced prostate cancer: results from a phase III trial of denosumab for the prevention of skeletal-related events. J Clin Oncol. 2014;32(suppl 15):5075. doi:10.1200/jco.2014.32.15_suppl.5075
8. Denosumab compared to zoledronic acid in the treatment of bone disease in patients with multiple myeloma. ClinicalTrials.gov. Updated March 31, 2020. Accessed November 22, 2020. https://clinicaltrials.gov/ct2/show/NCT01345019.
9. Raje N, Terpos E, Willenbacher W, et al. Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study. Lancet Oncol. 2018;19(3):370-381. doi:10.1016/S1470-2045(18)30072-X