14 CLINICAL TRIALS

14.1 Bone Metastasis from Solid Tumors

The safety and efficacy of Xgeva for the prevention of skeletal-related events in patients with bone metastases from solid tumors was demonstrated in three international, randomized (1:1), double-blind, active-controlled, noninferiority trials comparing Xgeva with zoledronic acid. In all three trials, patients were randomized to receive 120 mg Xgeva subcutaneously every 4 weeks or 4 mg zoledronic acid intravenously (IV) every 4 weeks (dose adjusted for reduced renal function). Patients with creatinine clearance less than 30 mL/min were excluded. In each trial, the main outcome measure was demonstration of noninferiority of time to first skeletal-related event (SRE) as compared to zoledronic acid. Supportive outcome measures were superiority of time to first SRE and superiority of time to first and subsequent SRE; testing for these outcome measures occurred if the main outcome measure was statistically significant. An SRE was defined as any of the following: pathologic fracture, radiation therapy to bone, surgery to bone, or spinal cord compression.

Study 20050136 (NCT00321464) enrolled 2046 patients with advanced breast cancer and bone metastasis. Randomization was stratified by a history of prior SRE (yes or no), receipt of chemotherapy within 6 weeks prior to randomization (yes or no), prior oral bisphosphonate use (yes or no), and region (Japan or other countries). Forty percent of patients had a previous SRE, 40% received chemotherapy within 6 weeks prior to randomization, 5% received prior oral bisphosphonates, and 7% were enrolled from Japan. Median age was 57 years, 80% of patients were White, and 99% of patients were women. The median number of doses administered was 18 for denosumab and 17 for zoledronic acid.

Study 20050244 (NCT00330759) enrolled 1776 adults with solid tumors other than breast and castrate-resistant prostate cancer with bone metastasis and multiple myeloma. Randomization was stratified by previous SRE (yes or no), systemic anticancer therapy at time of randomization (yes or no), and tumor type (non-small cell lung cancer, myeloma, or other). Eighty-seven percent were receiving systemic anticancer therapy at the time of randomization, 52% had a previous SRE, 64% of patients were men, 87% were White, and the median age was 60 years. A total of 40% of patients had non-small cell lung cancer, 10% had multiple myeloma, 9% had renal cell carcinoma, and 6% had small cell lung cancer. Other tumor types each comprised less than 5% of the enrolled population. The median number of doses administered was 7 for both denosumab and zoledronic acid.

Study 20050103 (NCT00321620) enrolled 1901 men with castrate-resistant prostate cancer and bone metastasis. Randomization was stratified by previous SRE, PSA level (less than 10 ng/mL or 10 ng/mL or greater) and receipt of chemotherapy within 6 weeks prior to randomization (yes or no). Twenty-six percent of patients had a previous SRE, 15% of patients had PSA less than 10 ng/mL, and 14% received chemotherapy within 6 weeks prior to randomization. Median age was 71 years and 86% of patients were White. The median number of doses administered was 13 for denosumab and 11 for zoledronic acid.

Xgeva delayed the time to first SRE following randomization as compared to zoledronic acid in patients with breast or castrate-resistant prostate cancer (CRPC) with osseous metastases (Table 2). In patients with bone metastasis due to other solid tumors or lytic lesions due to multiple myeloma, Xgeva was noninferior to zoledronic acid in delaying the time to first SRE following randomization.

Overall survival and progression-free survival were similar between arms in all three trials.

Table 2. Efficacy Results for Xgeva Compared to Zoledronic Acid
	Study 20050136 Metastatic Breast Cancer				Study 20050244 Metastatic Solid Tumors or Multiple Myeloma				Study 20050103 Metastatic CRPCa
	Xgeva N = 1026		Zoledronic Acid N = 1020		Xgeva N = 886		Zoledronic Acid N = 890		Xgeva N = 950		Zoledronic Acid N = 951
First On-study SRE
Number of Patients who had SREs (%)	315 (30.7)		372 (36.5)		278 (31.4)		323 (36.3)		341 (35.9)		386 (40.6)
Components of First SRE
Radiation to Bone	82 (8.0)	119 (11.7)		119 (13.4)		144 (16.2)		177 (18.6)		203 (21.3)
Pathological Fracture	212 (20.7)	238 (23.3)		122 (13.8)		139 (15.6)		137 (14.4)		143 (15.0)
Surgery to Bone	12 (1.2)	8 (0.8)		13 (1.5)		19 (2.1)		1 (0.1)		4 (0.4)
Spinal Cord Compression	9 (0.9)	7 (0.7)		24 (2.7)		21 (2.4)		26 (2.7)		36 (3.8)
Median Time to SRE (months)	NRb	26.4		20.5		16.3		20.7		17.1
Hazard Ratio (95% CI)	0.82 (0.71, 0.95)			0.84 (0.71, 0.98)				0.82 (0.71, 0.95)
Noninferiority p-value	< 0.001			< 0.001				< 0.001
Superiority p-valuec	0.010			0.060				0.008
First and Subsequent SREd
Mean Number/Patient	0.46		0.60		0.44		0.49		0.52		0.61
Rate Ratio (95% CI)	0.77 (0.66, 0.89)				0.90 (0.77, 1.04)				0.82 (0.71, 0.94)
Superiority p-valuee	0.001				0.145				0.009
a CRPC = castrate-resistant prostate cancer. b NR = not reached. c Superiority testing performed only after denosumab demonstrated to be noninferior to zoledronic acid within trial. d All skeletal events postrandomization; new events defined by occurrence ≥ 21 days after preceding event. e Adjusted p-values are presented.

14.2 Multiple Myeloma

The efficacy of Xgeva for the prevention of skeletal-related events in newly diagnosed multiple myeloma patients with treatment through disease progression, was evaluated in Study 20090482 (NCT01345019), an international, randomized (1:1), double-blind, active-controlled, noninferiority trial comparing Xgeva with zoledronic acid. In this trial, patients were randomized to receive 120 mg Xgeva subcutaneously every 4 weeks or 4 mg zoledronic acid intravenously (IV) every 4 weeks (dose adjusted for reduced renal function). Patients with creatinine clearance less than 30 mL/min were excluded. In this trial, the main efficacy outcome measure was noninferiority of time to first skeletal-related event (SRE). Additional efficacy outcome measures were superiority of time to first SRE, time to first and subsequent SRE, and overall survival. An SRE was defined as any of the following: pathologic fracture, radiation therapy to bone, surgery to bone, or spinal cord compression.

Study 20090482 enrolled 1718 newly diagnosed multiple myeloma patients with bone lesions. Randomization was stratified by a history of prior SRE (yes or no), the anti-myeloma agent being utilized/planned to be utilized in first-line therapy (novel therapy-based or non-novel therapy-based [novel therapies include bortezomib, lenalidomide, or thalidomide]), intent to undergo autologous PBSC transplantation (yes or no), stage at diagnosis (International Staging System I or II or III) and region Japan (yes or no). At study enrollment, 96% of the patients were receiving or planning to receive novel therapy-based first-line anti-myeloma therapy, 55% of the patients intended to undergo autologous PBSC transplantation, 61% of patients had a previous SRE, 32% were at ISS stage I, 38% were at ISS stage II and 29% were at ISS Stage III, and 2% were enrolled from Japan. Median age was 63 years, 82% of patients were White, and 46% of patients were women. The median number of doses administered was 16 for Xgeva and 15 for zoledronic acid.

Xgeva was noninferior to zoledronic acid in delaying the time to first SRE following randomization (HR = 0.98, 95% CI, 0.85-1.14). The results for overall survival (OS) were comparable between Xgeva and zoledronic acid treatment groups with a hazard ratio of 0.90 (95% CI: 0.70, 1.16).

Table 3. Efficacy Results for Xgeva Compared to Zoledronic Acid
	Study 20090482 Multiple Myeloma
	Xgeva N = 859	Zoledronic Acid N = 859
First On-study SRE
Number of Patients who had SREs (%)	376 (43.8)	383 (44.6)
Components of First SRE
Radiation to Bone	47 (5.5)	62 (7.2)
Pathological Fracture	342 (39.8)	338 (39.3)
Surgery to Bone	37 (4.3)	48 (5.6)
Spinal Cord Compression	6 (0.7)	4 (0.5)
Median Time to SRE (months) (95% CI)	22.8 (14.7, NEa)	24 (16.6, 33.3)
Hazard Ratio (95% CI)	0.98 (0.85, 1.14)
a NE = not estimable

14.3 Giant Cell Tumor of Bone

The safety and efficacy of Xgeva for the treatment of giant cell tumor of bone in adults or skeletally mature adolescents were demonstrated in two open-label trials [Study 20040215 (NCT00396279) and Study 20062004 (NCT00680992)] that enrolled patients with histologically confirmed measurable giant cell tumor of bone that was either recurrent, unresectable, or for which planned surgery was likely to result in severe morbidity. Patients received 120 mg Xgeva subcutaneously every 4 weeks with a loading dose on Days 8 and 15 of the first cycle of therapy. Patients who discontinued Xgeva then entered the safety follow-up phase for a minimum of 60 months. Retreatment with Xgeva while in safety follow-up was allowed for patients who initially demonstrated a response to Xgeva (e.g., in the case of recurrent disease).

Study 20040215 was a single-arm, pharmacodynamic, and proof of concept trial conducted in 37 adult patients with unresectable or recurrent giant cell tumor of bone. Patients were required to have histologically confirmed giant cell tumor of bone and radiologic evidence of measurable disease from a computed tomography (CT) or magnetic resonance imaging (MRI) obtained within 28 days prior to study enrollment. Patients enrolled in Study 20040215 underwent CT or MRI assessment of giant cell tumor of bone at baseline and quarterly during Xgeva treatment.

Study 20062004 was a parallel-cohort, proof of concept, and safety trial conducted in 535 adult or skeletally mature adolescent patients with histologically confirmed giant cell tumor of bone and evidence of measurable active disease. Study 20062004 enrolled 19 patients who were 12-16 years of age [see Use in Specific Populations (8.4)]. Patients enrolled into one of three cohorts: Cohort 1 enrolled 268 patients with surgically unsalvageable disease (e.g., sacral or spinal sites of disease, or pulmonary metastases); Cohort 2 enrolled 252 patients with surgically salvageable disease where the investigator determined that the planned surgery was likely to result in severe morbidity (e.g., joint resection, limb amputation, or hemipelvectomy); Cohort 3 enrolled 15 patients who previously participated in Study 20040215. Patients underwent imaging assessment of disease status at intervals determined by their treating physician.

A retrospective interim analysis concluded by an independent review committee evaluated objective response in 187 patients enrolled and treated in Study 20040215 and Study 20062004 for whom baseline and at least one post-baseline radiographic assessment were available (27 of 37 patients enrolled in Study 20040215 and 160 of 270 patients enrolled in Cohorts 1 and 2 of Study 20062004). The primary efficacy outcome measure was objective response rate using Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1.

The overall objective response rate (RECIST 1.1) was 25% (95% CI: 19, 32). All responses were partial responses. The estimated median time to response was 3 months. In the 47 patients with an objective response, the median duration of follow-up was 20 months (range: 2-44 months), and 51% (24/47) had a duration of response lasting at least 8 months. Three patients experienced disease progression following an objective response.

14.4 Hypercalcemia of Malignancy

The safety and efficacy of Xgeva was demonstrated in an open-label, single-arm trial [Study 20070315 (NCT00896454)] that enrolled 33 patients with hypercalcemia of malignancy (with or without bone metastases) refractory to treatment with intravenous bisphosphonate therapy. Patients received Xgeva subcutaneously every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy.

In this trial, refractory hypercalcemia of malignancy was defined as an albumin-corrected calcium of > 12.5 mg/dL (3.1 mmol/L) despite treatment with intravenous bisphosphonate therapy in 7-30 days prior to initiation of Xgeva therapy. The primary outcome measure was the proportion of patients achieving a response, defined as corrected serum calcium (CSC) ≤ 11.5 mg/dL (2.9 mmol/L), within 10 days after Xgeva administration. Efficacy data are summarized in Figure 1 and Table 4. Concurrent chemotherapy did not appear to affect response to Xgeva.

Table 4. Efficacy in Patients with Hypercalcemia of Malignancy Refractory to Bisphosphonate Therapy
	N = 33	Proportion (%) (95% CI)
All Responders (CSC ≤ 11.5 mg/dL) by Day 10	21	63.6
		(45.1, 79.6)
All Responders by Day 57	23	69.7
		(51.3, 84.4)
Complete Responders (CSC ≤ 10.8 mg/dL) by Day 10	12	36.4
		(20.4, 54.9)
All Complete Responders by Day 57	21	63.6
		(45.1, 79.6)

Median time to response (CSC ≤ 11.5 mg/dL) was 9 days (95% CI: 8, 19), and the median duration of response was 104 days (95% CI: 7, not estimable). Median time to complete response (CSC ≤ 10.8 mg/dL) was 23 days (95% CI: 9, 36), and the median duration of complete response was 34 days (95% CI: 1, 134).