Emanuela Palmerini, MD
More than one-third of patients with resectable giant cell tumor of bone (GCTB) avoided surgery and nearly half had less morbidity with surgery when treated with denosumab (Xgeva), according to results of an open-label phase II study.
After a minimum of 12 months of follow-up, 37% of 245 patients avoided surgery, and 44% had downstaging of planned surgical procedures. The recurrence rate after surgery was 27%.
An additional 250 patients with unresectable disease were treated with denosumab; they had an estimated 5-year progression-free survival (PFS) rate of 88%.
Denosumab was generally well tolerated, and the most common adverse events (AEs) were consistent with the drug’s known safety profile, explained Emanuela Palmerini, MD, during the 2017 ESMO Congress in Madrid. The frequency of osteonecrosis of the jaw increased with exposure to denosumab, reaching 8% at 5 years in patients with unresectable disease.
“In resectable patients, 80% had improvement with neoadjuvant denosumab,” said Palmerini, a medical oncologist at the Instituto Ortopedico Rizzoli in Bologna, Italy. “In unresectable patients, denosumab provides excellent long-term disease control.”
GCTB is a histologically benign condition that often develops into an aggressive skeletal tumor. Surgery is the only curative option for the condition but is often associated with severe morbidity and loss of function. Moreover, the rate of local recurrence after surgery is as high as 50%, Palmerini noted.
The rationale for treating GCTB with the RANK ligand inhibitor denosumab came from evidence that RANKL mediates processes that lead to formation and progression of activated osteoclast precursors to osteoclasts, to activated giant cells.
The phase II trial was designed to evaluate the safety and efficacy of denosumab in patients with resectable and unresectable GCTB. Investigators at 27 international sites enrolled a total of 532 patients.
The trial had planned 3 interim analyses after accrual of 50, 100, and 200 patients with a minimum follow-up of 6 months. The primary analysis, results of which were presented at the meeting, occurred after the final patient enrolled reached 12 months of follow-up.
The study population comprised 3 cohorts: 267 patients with unresectable GCTB, 253 patients with resectable disease, and 12 patients incorporated from a preliminary study of denosumab in GCTB.
Patients with unresectable GCTB received subcutaneous denosumab at 120 mg every 4 weeks with loading doses, which was continued for as long as a patient derived clinical benefit. In the cohort of surgical candidates, patients received neoadjuvant denosumab at the same dosage. Patients who underwent successful complete resection received a maximum of 6 doses of adjuvant denosumab, also at 120 mg every 4 weeks. The 12 rollover patients continued denosumab at the 120-mg dose for as long as they continued to benefit from treatment.
The primary endpoint of the trial was the safety of denosumab, defined by the type, frequency, and severity of AEs that occurred in each cohort. The key secondary endpoints were time to disease progression for patients with unresectable GCTB, and the proportion of patients with resectable disease who avoided surgery for at least 6 months.
The study population had a median age of 33 and an age range of 13 to 83, and 5% of the patients were adolescents. Two-thirds of patients in the unresectable cohort had prior surgery for GCTB, as did 37% of patients in the cohort with resectable disease.
The safety analysis showed that 34.8% of patients had grade 3/4 AEs, most often hypophosphatemia (4.6%), osteonecrosis of the jaw (2.7%), and extremity pain (2.3%). Additionally, 26.2% of patients had serious AEs, and 8.7% had AEs leading to discontinuation of treatment. AEs of particular interest (all grades) included osteonecrosis of the jaw (5.3%), atypical femur fracture (0.8%), new malignancy in GCTB (1.9%), and grade ≥3 hypercalcemia following denosumab discontinuation (0.8%).
Palmerini reported that 7% of patients in the unresectable cohort discontinued denosumab because of investigator-assessed disease progression. Additionally, 135 patients in the cohort discontinued with no evidence of progression. Subsequently, 34 of the 135 (25%) had GCTB recurrence after a median of 39 months off denosumab. Overall, the patients with unresectable disease had a 5-year PFS rate of 88%.
The 157 patients who underwent surgery had a 3-year event-free survival of 59% (95% CI, 0.49-0.70). The 27% recurrence rate included 34% after curettage and 12% after resection.
A final analysis is anticipated in November 2017, after the last main study patient enrolled achieves 5 years of follow-up.
Palmerini E, Blay J, Cesne AL, et al. Long-term efficacy of denosumab in giant cell tumor of bone: results of an open-label phase 2 study. In: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA56.
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