The combination of a targeted antiangiogenic agent and denosumab (Xgeva) appears to significantly increase the risk for osteonecrosis of the jaw in patients with metastatic renal cell carcinoma (mRCC), French investigators cautioned.
Among 41 patients with RCC metastatic to bone treated with an antiangiogenic agent and denosumab, 7 (17%) developed osteonecrosis of the jaw (ONJ). All seven received the combination in the first line, reported Aline Guillot, MD, from the Institut de cancérologie Lucien Neuwirth in Saint-Priest-en-Jarez, France, and her colleagues.
“The incidence of ONJ was high in this real-life population of patients with mRCC treated with antiangiogenic therapies combined with denosumab. This toxicity signal should warn physicians about this combination in the mRCC population,” they wrote in Clinical Genitourinary Cancer.
Previous studies have shown that the combination of another bone-targeted therapy – zoledronic acid – with antiangiogenic tyrosine kinase inhibitors (TKIs) such as sunitinib (Sutent) is associated with increased risk for ONJ. In addition, ONJ with the combination of denosumab and antiangiogenic therapies “has been noticed but never estimated,” the authors noted.
To evaluate the incidence of hypocalcemia and ONJ in patients with RCC metastatic to bone treated with denosumab and a TKI or mammalian target of rapamycin inhibitor, the investigators gathered data retrospectively from 10 French centers.
They identified 25 men and 16 women with a median age of 62 years (range, 54-68 years). Of this group, 40 received denosumab in the first line in combination with either sunitinib (31 patients), pazopanib (6), everolimus (Afinitor and generics; 2), and temsirolimus (Torisel and generics; 1). The median duration of first-line therapy was 12 months.
Denosumab was given in the second line with axitinib (Inlyta) to nine patients, with everolimus to nine, and with sunitinib to three patients. The median duration of second-line therapy was 3 months.
Skeletal-related events occurred in 41% of patients prior to receiving denosumab and in 61% (25 patients) after denosumab. The events included clinical fracture, bone pain requiring radiation, and spinal compression.
Of the seven patients who developed ONJ, six received denosumab and sunitinib in the first line and one received denosumab plus temsirolimus, with a median duration of treatment of 11.8 months. Three of these patients also received denosumab in the second line with either axitinib, everolimus, or sunitinib, with a median duration of 9.8 months. Data on second-line therapy for the remaining four patients with ONJ were not available.
The investigators noted that the 17% incidence of ONJ was higher than the 10% rate seen in a study of patients with mRCC treated with a TKI and a bisphosphonate (Acta Clin Belg. 2018 Apr;73(2):100-9), and the 1.8% incidence seen in an analysis of three phase 3 trials in cancer patients with bone metastases (Ann Oncol. 2012 May;23(5):1341-7).
Although the etiology of ONJ is unknown, patient education and oral hygiene may reduce the risk in patients treated with denosumab and a TKI.
“The benefit of denosumab in this setting in regard [to] toxicity needs to be demonstrated in a prospective trial,” they wrote.
No conflicts of interest or disclosures were reported.
SOURCE: Guillot A et al. Clin Genitourin Cancer. 2018 Sep 6. doi: 10.1016/j.clgc.2018.08.006.