Incidence Of Skeletal-related Events Research Articles

A phase Ib study of JMT103, a receptor activator of NF-kB ligand (RANKL) antibody, in patients (pts) with bone metastases from solid tumors.

e15190 Background: JMT103 is a human IgG4 monoclonal antibody against RANKL and blocks the RANK signaling in osteoclasts, thus suppressing bone resorption. This phase Ib study aims to demonstrate the activity of JMT103 in bone metastases patients with solid tumors. Methods: In this randomized, multi-center, open-label, phase Ib study, adult pts with bone metastases from solid tumors were enrolled and randomized at a 1:1:1 ratio to receive JMT103 subcutaneously at 120mg every 4 weeks (Q4W, Cohort 1), 120mg every 8 weeks (Q8W, Cohort 2) and 180mg Q8W (Cohort 3) up to 49 weeks. The primary endpoint was the percent change from baseline to week 13 in creatinine-adjusted urinary N-telopeptide (uNTx/Cr). Secondary endpoints included safety, anti-drug antibodies (ADA) positivity, the percentage of patients who experienced on-study skeletal-related events (SREs), and ≥ 2-point decreases in pain with Brief Pain Inventory – Short Form. Results: At database lock (Mar. 31, 2023), 295 pts were enrolled; 293 were treated with JMT103 and eligible for efficacy and safety evaluation (96 pts in Cohort 1, 97 pts in Cohort 2, and 100 pts in Cohort 3). The median age was 58 years (Interquartile range [IQR] 51, 66), and the primary tumor types were mainly breast (145, 50%) and prostate cancer (44, 15%). At week 13, the median (IQR) percent change in uNTx/Cr was - 80% (- 93%, - 50%) in Cohort 1, - 73% (- 94%, - 34%) in Cohort 2, and - 76% (- 92%, - 40%) in Cohort 3, respectively. The incidence of SREs in the three cohorts was 3%, 6%, and 7%, respectively. Among the 33 pts in Cohort 1, 35 pts in Cohort 2, and 37 pts in Cohort 3 with baseline pain scores ≥ 2, 61% in Cohort 1, 46% in Cohort 2, and 54% in Cohort 3 experienced ≥ 2-point decreases in pain at the first post-treatment visit (Day 15). For ADA analysis, only 1 (1%) pt in Cohort 2 with a negative result at baseline tested positive after treatment. The table shows the overall summary of the safety profile. Most of TRAEs were low in grade and resolved quickly. The most common TRAEs (any grade) were hypocalcemia (68, 23%), hypophosphatemia (67, 23%), and increased aspartate transaminase (35, 12%). Among the 40 cases of grade-5 TEAE, only 1 was reported as a TRAE (pneumonia); the rest were unrelated to JMT103. Conclusions: Our study demonstrated a promising efficacy of JMT103 in reducing bone metabolism biomarker and a good safety profile with low immunogenicity. Clinical trial information: NCT04630522 . [Table: see text]

Incidence and prevention of skeletal‐related events in multiple myeloma patients: A population‐based real‐world experience

AbstractNovel treatments in multiple myeloma (MM) could influence the incidence of skeletal‐related events (SREs). We aimed to examine the incidence of SRE and the preventive use of osteoclast inhibitors (OIs) in a cohort of MM patients in the era of modern treatment. In this real‐world retrospective study, we included 199 patients with a diagnosis of MM between January 1, 2010, and December 31, 2019, with follow‐up at St. Olavs University Hospital. Data was extracted from The Myeloma Registry of Central Norway. SREs occurred in 46% of patients at baseline and 55.8% during follow‐up. Excluding baseline SREs, the incidence rate was 29 (95% confidence interval: 26–33) per 100 person years. 48% experienced > 1 SRE. The incidence of SREs was highest at baseline followed by a gradual increase in each subsequent line of treatment. The first two years after diagnosis 80% received bisphosphonates (BPs). The proportion of recommended dosage was 46%. Only two cases (1.2%) of symptomatic hypocalcemia and one case (0.6%) of osteonecrosis of the jaw were identified. SREs are still a common problem in an era of novel treatment. Cumulative dosage of BPs was lower than recommended, and treatment with BPs was safe in this population.

Efficacy, Safety, and Population Pharmacokinetics of MW032 Compared With Denosumab for Solid Tumor–Related Bone Metastases

The bioequivalence of denosumab biosimilar has yet to be studied in a 53-week, multicenter, large-scale, and head-to-head trial. A clinically effective biosimilar may help increase access to denosumab in patients with solid tumor-related bone metastases. To establish the biosimilarity of MW032 to denosumab in patients with solid tumor-related bone metastases based on a large-scale head-to-head study. In this 53-week, randomized, double-blind, phase 3 equivalence trial, patients with solid tumors with bone metastasis were recruited from 46 clinical sites in China. Overall, 856 patients were screened and 708 eligible patients were randomly allocated to receive either MW032 or denosumab. Patients were randomly assigned (1:1) to receive MW032 or reference denosumab subcutaneously every 4 weeks until week 49. The primary end point was percentage change from baseline to week 13 of natural logarithmic transformed urinary N-telopeptide/creatinine ratio (uNTx/uCr). Among the 701 evaluable patients (350 in the MW032 group and 351 in the denosumab group), the mean (range) age was 56.1 (22.0-86.0) years and 460 patients were women (65.6%). The mean change of uNTx/uCr from baseline to week 13 was -72.0% (95% CI, -73.5% to -70.4%) in the MW032 group and -72.7% (95% CI, -74.2% to -71.2%) in the denosumab group. These percent changes corresponded to mean logarithmic ratios of -1.27 and -1.30, or a difference of 0.02. The 90% CI for the difference (-0.04 to 0.09) was within the equivalence margin (-0.13 to 0.13); the mean changes of uNTx/uCr and bone-specific alkaline phosphatase (s-BALP) at each time point were also similar during 53 weeks. The differences of uNTx/uCr change were 0.015 (95% CI, -0.06 to 0.09), -0.02 (95% CI, -0.09 to 0.06), -0.05 (95% CI, -0.13 to 0.03) and 0.001 (95% CI, -0.10 to 0.10) at weeks 5, 25, 37, and 53, respectively. The differences of s-BALP change were -0.006 (95% CI, 0.06 to 0.05), 0.00 (95% CI, -0.07 to 0.07), -0.085 (95% CI, -0.18 to 0.01), -0.09 (95% CI, -0.20 to 0.02), and -0.13 (95% CI, -0.27 to 0.004) at weeks 5, 13, 25, 37 and 53, respectively. No significant differences were observed in the incidence of skeletal-related events (-1.4%; 95% CI, -5.8% to 3.0%) or time to first on-study skeletal-related events (unadjusted HR, 0.86; P = .53; multiplicity adjusted HR, 0.87; P = .55) in the 2 groups. MW032 and denosumab were biosimilar in efficacy, population pharmacokinetics, and safety profile. Availability of denosumab biosimilars may broaden the access to denosumab and reduce the drug burden for patients with advanced tumors. ClinicalTrials.gov Identifier: NCT04812509.

Skeletal-Related Events in Patients With Multiple Myeloma: A Comprehensive Retrospective Cohort Study.

Multiple myeloma (MM) patients are at risk of skeletal-related events (SREs) like spinal cord compression, pathologic fractures, bone surgery, and radiation to bone. Real-world data regarding SREs in MM are limited. We conducted a large, retrospective, nationwide cohort study using the Korean Health Insurance Review and Assessment Service (HIRA) database from 2007 to 2018. Over a 12-year study period, we identified 6,717 patients who developed symptomatic MM. After a median follow-up of 35.1 months (interquartile range [IQR], 20.8-58.2 months), 43.6% of these patients experienced SREs, and 39.6% had four or more SREs. One in five patients (20.0%) experienced pathologic fractures within the first year of follow-up. The median time to first SRE was 9.6 months (IQR, 1.2-25.8 months), with 3.0 months in the group with prior SREs and 19.8 months in the group without prior SREs. During follow-up, 78.5% of patients received bisphosphonates. Multiple logistic regression analysis revealed several factors associated with an increased risk of SREs, including being female (odds ratio [OR], 1.44), aged 50 or older (OR, 1.87), having cerebrovascular disease (OR, 1.34), undergoing first-line chemotherapy regimens not containing bortezomib or lenalidomide (OR, 1.49), and being in the group with prior SREs and bisphosphonate use (OR, 5.63), compared to the group without prior SREs and without bisphosphonate use. This population-based study is the first to report the incidence and risk factors of SREs in Korean MM patients, which can be used to assess their bone health.

Efficacy and safety of bone management agents administered at 12 weeks vs. 4 weeks in patients with bone metastases: A systematic review.

Bone modifying agents (BMAs) have been used to prevent skeletal-related events (SRE) in cancer patients with bone metastases. In this meta-analysis, efficacy and adverse events (AEs) were studied based on a de-escalation strategy in which the BMA dosing interval was prolonged from 4 to 12 weeks. PubMed, Cochrane, ICHUSHI, and CINAHL were searched for articles on BMA dosing intervals from outcomes measured were the incidence of SRE and related various AEs. A quantitative meta-analysis was performed using a random-effects model to calculate relative risk ratios (RRs) and 95% confidence intervals (CIs). The meta-analysis included three randomized controlled studies (RCTs) of Zoledronic acid hydrate (ZA) (n = 2663) and six RCTs (n = 141) on BMA other than ZA. There was no difference in the incidence of SREs when comparing the dosing frequency of 12 versus 4 weeks for BMA (RR = 1.21, 95% CI [0.82-1.78], p = 0.33). Further, AEs related to treatment discontinuation were significantly less frequent with ZA given every 12 weeks than when given every 4 weeks (RR = 0.51 [0.30-0.89], p = 0.02). In particular, renal dysfunction leading to grade ≥3 or discontinuation of treatment with ZA occurred significantly less frequently with every 12-week dosing (RR = 0.33 [0.12-0.91], p = 0.33). This meta-analysis showed no influence of BMA de-escalation on the incidence of SRE; nevertheless, AEs appeared to reduce with the de-escalated usage of ZA.

Retrospective analysis of the relationship between time to anti-resorptive therapy and incidence of skeletal related events in patients with multiple myeloma.

8048 Background: Patients with multiple myeloma (MM) often have bone disease at diagnosis and are at risk of developing skeletal related events (SRE) (pathological fractures, spinal cord compression, and/or need for radiotherapy or surgery to bone). It is well established that for patients with lytic bone lesions at diagnosis, the use of anti-resorptive agents lead to a lower incidence of SREs. However, it is common for initiation of anti-resorptive therapy to be delayed. Recent studies have demonstrated that anti-resorptive therapy is underutilized in patients with MM. However, the effect of time to initiation of anti-resorptive agent after diagnosis of MM on SREs has not been well studied. Herein, we conducted a multi-center retrospective analysis to determine if time to anti-resorptive agent has an adverse impact on the risk of SREs. Methods: We performed a retrospective cohort study using our Electronic Health Record system to identify patients with newly diagnosed MM between July 1st, 2016 and June 30th, 2019 at two large academic centers. Patients previously treated or patients not treated with anti-resorptive therapy were excluded. The study’s primary endpoint was hazard ratio of developing a SRE based on time to anti-resorptive therapy. The relationship between incidence of SREs and time to anti-resorptive therapy, gender, age, International Staging System (ISS) stage at diagnosis, and prior SRE present at diagnosis was analyzed by using a multivariable Cox proportional hazards model. The cutoff point of anti-resorptive therapy delay was based on the recursive partitioning of univariable Cox model. Results: 759 patients were included in the study (Thomas Jefferson University: n = 232; The Ohio State University: n = 527). Median age at diagnosis is 60.2 years (IQR: 12.4 years). 57% of patients were male. 77.9% and 20.3% of patients identified as white and black respectively. 210 patients (27.7%) were noted to have osteopenia, 45 (5.9%) had osteoporosis, 229 (30.2%) were vitamin D deficient, and 319 (42%) were obese at diagnosis. A skeletal related event was present at diagnosis in 338 (45.1%) of patients. 180 (34%) patients received anti-resorptive agents within 31 days. A delay in initiating anti-resorptive agents of greater than 31 days from diagnosis had an increased risk for SRE with a hazard ratio 1.654 (1.054~2.598; p-value: 0.029). Conclusions: This large multicenter retrospective study demonstrated that time to anti-resorptive therapy MM patients has a significant impact on the risk of SRE. Given many of the challenges in starting anti-resorptive therapy in a timely manner, this study emphasizes the need for inter-professional, multi-disciplinary collaborations to streamline the workflow and start therapy within the first month of diagnosis. Ongoing efforts are underway to develop quality improvement processes to achieve this goal.

Randomized phase II study of zoledronate dosing every four versus eight weeks in patients with bone metastasis from lung cancer (Hanshin Cancer Group0312)

BackgroundZoledronic acid (ZA) reduces the incidence of skeletal-related events (SREs) in patients with bone metastases from solid tumors. However, the optimal dosing interval of ZA for patients with lung cancer is uncertain. MethodsWe conducted a randomized, open-label, feasibility phase 2 trial at eight Japanese hospitals. Patients with bone metastases from lung cancer were randomly assigned to receive either 4 mg of ZA every four weeks (4wk-ZA) or every eight weeks (8wk-ZA). The primary endpoint was the time to the first SRE and the rate and types of SREs after one year. SREs were defined as pathologic bone fracture, bone radiation therapy or surgery, and spinal cord compression. Secondary endpoints were the SRE incidence at six months, pain assessment, changes in analgesic consumption, serum N-telopeptide, toxicity, and overall survival. ResultsBetween November 2012 and October 2018, 109 patients were randomly assigned to the 4wk-ZA group (54 patients) and the 8wk-ZA group (55 patients). The number of patients who received chemotherapy or molecular-targeted agents was 30 and 23 and 18 and 16 in the 4wk-ZA and 8wk-ZA groups, respectively. The median time to the first SRE could not be calculated because of a low SRE. The time to the first SRE of all patients did not differ between the groups (P = 0.715, HR = 1.18, 95% CI = 0.48, 2.9). The SRE rate of all patients after 12 months was 17.6% (95% CI = 8.4, 30.9%) in the 4wk-ZA and 23.3% (95% CI = 11.8, 38.6%) in the 8wk-ZA group, without significant differences between the groups. There was no difference in any secondary endpoint between groups, and these endpoints did not differ among treatment modalities. ConclusionsAn eight-week ZA interval does not increase the SRE risk for patients with bone metastasis from lung cancer and could be considered clinically.

Impact of somatic DNA repair mutations on bone-related efficacy endpoints in patients with metastatic castration-resistant prostate cancer (mCRPC): A retrospective analysis.

214 Background: Up to 80% of mCRPC have bone metastases and about 25% of metastatic prostate cancer harbor mutations in DNA damage repair defects (DDR). DDR gene mutations are a negative prognostic factor, being associated with short metastasis-free survival and cancer-specific survival. We analyzed the impact of somatic mutations in DDR genes on bone-related efficacy endpoints in mCRPC. Methods: We retrospectively analyzed the mutational status of mCRPC patients per FoundationOne analysis in tissue biopsy or, when it was not possible, in liquid biopsy (performed at the onset of mCRPC). We evaluated the impact of DDR gene mutations on bone-related efficacy endpoints at the time of mCRPC diagnoses, by dividing patients in two main groups (mutated DDR, specifically, mutations in at least one of BRCA1/2, ATM, FANCA, ATR, CHEK2, RAD51, PALB2, and CDK12 genes: group A; wild-type DDR: group B). We investigated differences between the two groups in terms of time from bone metastases onset to death, skeletal metastatic tumor burden (sites and number of lesions), skeletal-related events (SRE) incidence, and time to first on-study SRE. Results: Of the 131 patients with mCRPC enrolled, 115 had bone metastases. Clinical data distribution, according to molecular profile, is presented. There is no difference in terms of sites of metastases and time from bone metastases onset to death between the 2 groups. Mutated DDR status was associated with bone metastases volume (p = 0.0325), but did not affect SRE incidence and time to SRE onset. Conclusions: In our analysis, mutated DDR status was associated with higher bone metastases volume, although a not detrimental effect on the other bone-related efficacy endpoints was observed. [Table: see text]

Efficacy and safety of nivolumab in bone metastases from renal cell carcinoma: Results of the GETUG-AFU26-NIVOREN multicentre phase II study

IntroductionBone metastases (BM) in renal cell carcinoma (RCC) are associated with a poor prognosis based on retrospective studies evaluating antiangiogenic agents. Few data are available regarding immune checkpoint inhibitors (ICI) in patients with bone metastatic RCC. NIVOREN is a multicentre prospective study in which patients were treated with nivolumab after the failure of antiangiogenic agents. We aim to assess the impact of BM on prognosis, and the efficacy and safety of nivolumab in patients enrolled in the NIVOREN trial. Materials and methodsAll patients with BM at inclusion were included in our study. The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), objective response rate (ORR), safety, and skeletal-related events (SRE). ResultsAmong 720 patients treated with nivolumab, 194 presented BM at inclusion. The median follow-up was 23.9 months. Median OS was 17.9 months in patients with BM versus 26.1 months in patients without BM (p = 0.0023). The difference was not statistically significant after adjustment (p = 0.0707). The median PFS was shorter in patients with BM even after adjustment (2.8 versus 4.6 months, p = 0.0045), as well as the ORR (14.8% versus 23.3%). SRE occurred for 36% of patients with BM. A post-hoc analysis evaluating the impact of bone-targeting agents (BTA) on SRE incidence showed a significant benefit of BTA on the incidence of SRE (OR = 0.367, CI95% [0.151–0.895]). ConclusionNivolumab is associated with shorter PFS, and lower ORR in RCC patients with BM. Our study suggests that BTA in association with immunotherapy decreases the incidence of SRE.

A Retrospective Analysis of Denosumab for the Treatment of Bone Metastases in Chinese Patients With Breast Cancer.

Denosumab entered the Chinese market for the first time in 2020. Since it is a short period of time, there is a lack of data on its effectiveness and safety in Chinese people. The objective of this study was to evaluate the effectiveness and safety of denosumab in delaying skeletal-related events (SREs) in patients with breast cancer metastatic to bone. The study retrospectively analyzed data from breast cancer patients with bone metastases (BM) who were treated with denosumab in the First Affiliated Hospital of Nanjing Medical University from September 2020 to January 2022. The primary endpoint was SRE incidence at 1 year after receiving denosumab treatment. The secondary endpoints included time to first on-study SRE and safety. Descriptive analysis was utilized to display clinicopathological features. The Kaplan-Meier method was used to estimate the median time to first on-study SRE in total population and subgroups. Logistic regression analysis and χ2 test were employed to determine the potential factors influencing the occurrence of SREs. Fifty breast cancer patients with BM were enrolled in our study, and 54.0% of the patients had 5 or more metastatic bone lesions. After a median follow-up of 17.00 months, 24% of the patients developed SREs at 1 year after receiving denosumab treatment, and the median time to first on-study SREs was not reached. Five or more metastatic bone lesions were an independent risk factor for SRE occurrence (odds ratio = 6.06, 95% CI: 1.09-33.54, P = .039). The adverse events (AEs) associated with denosumab mainly included hypocalcemia (68.0%), periodontitis (28.0%), and myalgia (14.0%). Only 3 cases of grade III/IV AEs were reported, and no serious AEs occurred. Denosumab was effective and well tolerated in Chinese breast cancer patients with BM.

Skeletal-Related Events After Surgery With or Without Radiotherapy for Bone Metastases to Weight-Bearing Bones.

Introduction In patients with metastatic disease involving weight-bearing bones, postoperative radiotherapy (PORT) is commonly administered following surgical stabilization of an impending or confirmed pathologic fracture to reduce the risk of a seeded local recurrence. The goalwas to re-evaluate the beneficial effect of PORT in a modern cohort of patientsand determine any potential clinical predictors of skeletal-related events (SREs) which were defined as a pathologic fracture or the necessity for radiation or surgery to the affected bone. Methods Consecutive patients undergoing surgical stabilization of metastatic disease to weight-bearing bones of the extremities between 2012 and 2019 were reviewed. Patient, disease, and treatment factors were abstracted. The cumulative incidenceof SREs was determined using competing risks methodology; overall survival (OS) was estimated using the Kaplan-Meier method. Results A total of 82 patients were identified, 74% of whom had undergone intramedullary nail fixation and 26% internal fixation or replacement. The femur was the most commonly involved bone (94%).A majority (78%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 1-2. Bone-strengthening agents were given to 38% and PORT to 54%. The median PORT dose was 30 Gy in 10 fractions and the median percent coverage of surgical hardware was 100% (range, 25-100). SREs occurred in 10 of 82 patients. There were no differences between no RT and RT groups for the two-year cumulative incidence of SREs (8.2% vs 11.5%, p=0.59) or two-year cumulative incidence of local failure (10.8% vs4.6%, p=0.53). The only identified predictors of SREs were the use of bone-strengthening agents (hazard ratio [HR] 0.22, 95% confidence interval [CI] 0.05-1.06, p=0.06) and malnutrition (HR 3.69, 95% CI 0.91-14.93, p=0.07). For patients treated with PORT, a biologically effective dose or percent coverage of surgical hardware was not associated with SREs. Conclusion In this series, the addition of PORT following surgery for metastatic disease involving weight-bearing bones does not significantly affect the rate of SREs. The use of bone-strengthening agents appears protective, and malnourished patients appear particularly at high risk for future SRE.

Incidence of Skeletal-Related Events Among Multiple Myeloma Patients: A Nationwide Population-Based Cohort Study

Incidence of Skeletal-Related Events Among Multiple Myeloma Patients: A Nationwide Population-Based Cohort Study

Multi-Institutional Prospective Observational Study of Radiotherapy for Metastatic Bone Tumor

<h3>Purpose/Objective(s)</h3> To evaluate patient characteristics and radiotherapy treatments and outcomes in bone metastasis in Japan. <h3>Materials/Methods</h3> Patients for whom radiotherapy for bone metastasis was planned at 26 institutions in Japan between December 2020 and March 2021 were consecutively registered in this prospective, observational study. The number of registrations per facility was limited to 10. Study measures included patient characteristics, pain relief, skeletal-related events (SREs), overall survival, and incidence of radiation-related adverse events. Pain was evaluated by using a numerical rating scale (NRS) from 0 to 10. <h3>Results</h3> Two hundred thirty-two patients were registered; 224 patients and 302 lesions were fully analyzed. Primary sites were lung (36% of patients), breast (15%), and other (49%). ECOG-performance status (PS) was 0 in 23%, 1 in 38%, 2 in 22%, 3 in 13%, and 4 in 4%; 59% of patients had spinal metastases and 84% had painful lesions (at least NRS 2). The biologically effective dose (BED) assuming α/β=10 was <20 Gy (in 27%), 20 to <30 Gy (24%), 30 to <40 Gy (36%), and ≥40 Gy (13%); 9% of patients were treated by stereotactic body radiotherapy (SBRT). For ECOG-PS 3 or 4, 61% of patients were treated with a low BED (<30 Gy); 41% of those with ECOG-PS 0 or 1 were treated with a low BED (<30 Gy). Grade 3 adverse events occurred in 4% and no grade 4 or 5 toxicity was reported. Pain relief was achieved in 52% at 2 months and 58% at 6 months. Use of systemic chemotherapy or hormonal therapy was significantly related to good pain response at 2 months (<i>P</i> = 0.006), but no other factor was associated with pain response. Cumulative incidence of SREs was 6.5% (95% CI 3.1–9.9) at 6 months; no factor was significantly associated with SREs. Among 132 patients with spinal lesions, 10% were classified as Bilsky grade 3; 18% of patients were not ambulatory at baseline; 50% of evaluable patients in this group were able to walk at 2 months. The 6-month overall survival rate was 70.2% (95% CI 64.2–76.9). Good ECOG-PS, ambulatory status at baseline, no other bone metastases, high BED, and SBRT use were significantly related to better overall survival. <h3>Conclusion</h3> We report real-world details of radiotherapy in bone metastasis. BED is not related to pain relief or SRE incidence, but high BED or SBRT were selected for long survivors.

Incidence of Post-denosumab Rebound Hypercalcaemia in Bony-Metastatic Breast Cancer.

Denosumab reduces incidence of skeletal related events in patients with bony-metastatic breast cancer, however cessation is associated with a rebound phenomenon which, rarely, has been associated with hypercalcaemia. We aimed to identify the incidence of post-denosumab cessation rebound hypercalcaemia amongst patients with breast cancer-related bony metastases. We performed a single-centre retrospective cohort analysis to determine the incident of rebound hypercalcaemia amongst patients treated with antiresorptive agents for bony metastatic breast cancer between 2016-2020. 22,320 outpatient encounters were reviewed, which identified 97 patients with bonymetastatic disease treated with antiresorptive therapy. Of the 21 patients who had denosumab ceased, six (28.6%) developed hypercalcaemia. Interval between last denosumab dose and onset of hypercalcaemia was a median 7.5 (range 2-13) months. There was a significant difference in both denosumab treatment duration as well as total treatment dose exposure between patients who developed hypercalcaemia post-denosumab cessation (median 41 months, 40 doses) and those who remained normocalcaemic (median 10 months, 5 doses), p = 0.009. In our study, hypercalcaemia occurred between two and thirteen months after denosumab cessation. Greater denosumab treatment duration as well as total denosumab dose exposure was associated with higher risk of hypercalcaemia after denosumab cessation. Hormonal therapy or previous bisphosphonate treatment was not seen to impact upon development of hypercalcaemia. Rebound hypercalcaemia is a rare but important diagnosis to consider in patients experiencing hypercalcaemia after denosumab cessation.

Determination of direct treatment costs of patients with metastatic and nonmetastatic castration-resistant (mCRPC, nmCRPC) and metastatic hormone-sensitive (mHSPC) prostate cancer in Colombia.

e18838 Background: The purpose of this study was to determine the direct costs associated with the management of patients with metastatic castration resistant (mCRPC), non-metastatic (nmCRPC) and metastatic hormone-sensitive (mHSPC) prostate cancer in the Colombian healthcare system. Methods: First, a literature review was carried out to identify the main clinical recommendations for the treatment and follow-up of patients with prostate cancer at local and international levels. Subsequently, a participation process was developed with clinical experts, through a modified Delphi panel, to validate the natural history of the disease, and identify treatment options, skeletal-related events management, resource utilization, and distribution of patients within stages. Based on the above, a cost analysis model was performed, using Colombian health technology assessment agency recommendations, to calculate direct cost of treatment for mCRPC, nmCRPC and mHSPC from payer’s perspective. Exchange rate used was USD $1 = COP $4,000. Finally, the results were estimated considering the cost per patient per year. Results: According to the cost analysis of each stage, in the non-metastatic castration resistant stage (nmCRPC) the associated yearly cost of a patient was lower than in the metastatic castration resistant stage (mCRPC) (USD $8,581 versus $24,590, respectively), with a difference of USD $16,008. The metastatic hormone-sensitive stage (mHSPC) had a lower yearly cost than the metastatic castration-resistant stage (mCRPC) (USD $15,030 versus $24,590, respectively), with a difference of USD $ 9,559. The event that generated the greatest impact on the cost is the incidence of skeletal-related events associated with disease metastasis (55%). The deterministic sensitivity analysis on key variables, such as the percentage of patients who responded to treatment and the incidence of skeletal-related events, showed consistency of results. Conclusions: Delaying or stopping disease progression to mCRPC could more than halve annual treatment costs for patients. Given the findings, advanced metastatic castration resistant stages demand more resource utilization associated with disease management. The Colombian healthcare system would benefit from risk management strategies that implement timely interventions associated with early diagnosis and screening. In this way, the resource utilization in health sector's institutions would be directly impacted through budget optimization, obtaining better results focused on the national follow-up indicators of the prostate cancer patient cohort.

Newly Diagnosed Multiple Myeloma Patients with Skeletal-Related Events and Abnormal MRI Pattern Have Poor Survival Outcomes: A Prospective Study on 370 Patients.

Contemporary information is sparse on the frequency of skeletal-related events (SREs) in multiple myeloma (MM) patients at a population-based level in the era of novel agents. In this context, we conducted this single-center, prospective, observational study to determine the incidence of SREs among newly diagnosed MMs (NDMM) and to explore the possible correlations with disease characteristics, imaging finding, and patient prognosis. A total of 370 patients with available baseline MRIs were included. Among them, 208 (56%) presented with at least one SRE at diagnosis. Fractures were the most common reported SREs (48%). The incidence of SREs at diagnosis was higher in patients with osteolytic lesions, abnormal MRI pattern, hypercalcemia, and at least 60% bone marrow infiltration by plasma cells. Importantly, the patients with normal MRI pattern, who did not present with SREs at diagnosis, had statistically significant improved median OS in comparison with the patients who had abnormal MRI patterns and/or the presence of SREs at diagnosis (9.3 vs. 6.6 years, p = 0.048). Our data, which represent one of a few systematic reports on the incidence and characteristics of SREs in the era of novel agents, was indicative of a high incidence of SREs at the time of MM diagnosis. Early detection of myeloma bone disease and tailored patient management are essential to optimize patient outcomes.

Uptake of bone-modifying agents in patients with HER2+ metastatic breast cancer with bone metastases - prospective data from a multi-site Australian registry.

International practice guidelines recommend administration of bone-modifying agents (BMA) in metastatic breast cancer (MBC) patients with bone metastases to reduce skeletal-related events (SRE). Optimal delivery of BMA in routine clinical practice, including agent selection and prescribing intervals, remains unclear. To describe real-world practice of Australian breast oncologists. Prospective data from February 2015 to July 2020 on BMA delivery to MBC patients with bone metastases was analysed from Treatment of Advanced Breast Cancer in the Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Australian Patient (TABITHA), a multi-site Australian HER2+ MBC registry. Of 333 HER2+ MBC patients, 171 (51%) had bone metastases at diagnosis, with a mean age of 58.1 years (range, 32-87). One hundred and thirty (76%) patients received a BMA, with 90 (69%) receiving denosumab and 40 (31%) receiving a bisphosphonate. Patients who received a BMA were more likely to have received concurrent first-line systemic anti-HER2 therapy (95% vs 83%; P = 0.04), to present with bone-only metastases at diagnosis (24% vs 7%; P = 0.02) and less likely to have visceral metastases (51% vs 71%; P = 0.03). Ten of 40 (25%) bisphosphonate patients and 45 of 90 (50%) denosumab patients received their BMA at the recommended 4-weekly interval. Prescribing intervals varied over time. Adverse events reported were consistent with clinical trial data. Three-quarters of Australian HER2+ MBC patients with bone metastases receive a BMA, often at different schedules than guidelines recommend. Further studies, including all MBC subtypes, are warranted to better understand clinicians' prescribing rationale and potential consequences of current prescribing practice on SRE incidence.

Risk factors associated with skeletal-related events following discontinuation of denosumab treatment among patients with bone metastases from solid tumors: A real-world machine learning approach

BackgroundClinical practice guidelines recommend the use of bone-targeting agents for preventing skeletal-related events (SREs) among patients with bone metastases from solid tumors. The anti-RANKL monoclonal antibody denosumab is approved for the prevention of SREs in patients with bone metastases from solid tumors. However, real-world data are lacking on the impact of individual risk factors for SREs, specifically in the context of denosumab discontinuation. PurposeWe aim to identify risk factors associated with SRE incidence following denosumab discontinuation using a machine learning approach to help profile patients at a higher risk of developing SREs following discontinuation of denosumab treatment. MethodsUsing the Optum PanTher Electronic Health Record repository, patients diagnosed with incident bone metastases from primary solid tumors between January 1, 2007, and September 1, 2019, were evaluated for inclusion in the study. Eligible patients received ≥ 2 consecutive 120 mg denosumab doses on a 4-week (± 14 days) schedule with a minimum follow-up of ≥ 1 year after the last denosumab dose, or an SRE occurring between days 84 and 365 after denosumab discontinuation. Extreme gradient boosting was used to develop an SRE risk prediction model evaluated on a test dataset. Multiple variables associated with patient demographics, comorbidities, laboratory values, treatments, and denosumab exposures were examined as potential factors for SRE risk using Shapley Additive Explanations (SHAP). Univariate analyses on risk factors with the highest importance from pooled and tumor-specific models were also conducted. ResultsA total of 1,414 adult cancer patients (breast: 40%, prostate: 30%, lung: 13%, other: 17%) were eligible, of whom 1,133 (80%) were assigned to model training and 281 (20%) to model evaluation. The median age at inclusion was 67 (range, 19–89) years with a median duration of denosumab treatment of 253 (range, 88–2,726) days; 490 (35%) patients experienced ≥ 1 SRE 83 days after denosumab discontinuation. Meaningful model performance was evaluated by an area under the receiver operating curve score of 77% and an F1 score of 62%; model precision was 60%, with 63% sensitivity and 78% specificity. SHAP identified several significant factors for the tumor-agnostic and tumor-specific models that predicted an increased SRE risk following denosumab discontinuation, including prior SREs, shorter denosumab treatment duration, ≥ 4 clinic visits per month with at least one hospitalization (all-cause) event from the baseline period up to discontinuation of denosumab, younger age at bone metastasis, shorter time to denosumab initiation from bone metastasis, and prostate cancer. ConclusionThis analysis showed a higher cumulative number of SREs, prior SREs relative to denosumab initiation, a higher number of hospital visits, and a shorter denosumab treatment duration as significant factors that are associated with an increased SRE risk after discontinuation of denosumab, in both the tumor-agnostic and tumor-specific models. Our machine learning approach to SRE risk factor identification reinforces treatment guidance on the persistent use of denosumab and has the potential to help clinicians better assess a patient’s need to continue denosumab treatment and improve patient outcomes.

Efficacy and safety of nivolumab in renal cell carcinoma patients with BONE metastases: Results of the GETUG: AFU 26 nivoren multicenter phase II study.

342 Background: Bone metastases (BM) in renal cell carcinoma (RCC) are associated with a poor prognosis based on retrospective studies in which patients were treated with antiangiogenic agents. Since the development of immune checkpoint inhibitors, few data are available regarding the prognosis impact of BM or the efficacy and safety of checkpoint inhibitors in patients with bones metastatic RCC. GETUG-AFU26-NIVOREN (NIVOREN) is a French multicenter prospective study in which patients were treated with nivolumab after failure of one or more antiangiogenic tyrosine kinase inhibitors. We therefore aim to evaluate the impact of BM on prognosis, and the efficacy and safety of nivolumab in patients with BM enrolled in NIVOREN trial. Methods: All adult patients with BM at inclusion were included in our study. The primary endpoint of this ancillary study was overall survival (OS). Secondary endpoints were progression-free survival (PFS), objective response rate (ORR), safety, and skeletal-related events (SRE) in patients with BM. Clinical data were collected prospectively, except for SRE data which were collected retrospectively in a complementary consent report form. Results: Among 720 patients treated with nivolumab in the NIVOREN study, 194 had BM at inclusion. After a median follow-up of 23.9 months, the median OS was 17.9 months in patients with BM versus 26.1 months in patients without BM (HR = 1.42 CI95% [1.13-1.79], p = 0.0023). After adjustment on sex, age, IMDC group and line of treatments, the difference was not significant (HR = 1.24, CI95% [0.98-1.56], p = 0.0707). The median PFS was shorter in patients with BM even after adjustment (2.8 versus 4.6 months, HR = 1.30 CI95% [1.08-1.56]), as well as the ORR (14.8% versus 23.3%). The safety profile was similar between patients with or without BM at inclusion. The incidence of SRE in the BM population was 36% during the treatment period with nivolumab. A post-hoc analysis evaluating the impact of bone-targeting agents in association with nivolumab on SRE incidence was performed. There was a statistically significant benefit in patients treated with bone-targeting agents on the incidence of SRE (OR = 0.367, CI95% [0.151-0.895], p = 0.0276). Conclusions: Nivolumab is associated with shorter OS, PFS, and lower ORR in patients with BM. Our study confirms, in the era of immunotherapy that patients with BM are associated with poorer prognosis and suggests that association with bone-targeting agents decreases the incidence of SRE. Clinical trial information: 2015-004117-24.

Use of Denosumab after Zoledronic Acid in Patients with Multiple Myeloma: Real-World Experience from 2015 to 2019 at Yale Cancer Center

Introduction:Skeletal-related events (SREs) can cause significant morbidity and adversely impact quality of life in patients with multiple myeloma (MM). The bisphosphonate zoledronic acid (ZOL) has historically been the most widely used agent to prevent and treat SREs in this population. In 2018, a landmark trial by Raje et al showed that denosumab (DEN), a monoclonal antibody against the receptor activator of nuclear factor-kappa B ligand (RANKL), was non-inferior to ZOL in time to SREs. The use of DEN has since been incorporated into official guidelines and there has been a significant uptake of DEN use in clinical practice, with some patients being switched from ZOL to DEN. Currently, there is a lack of data on the clinical and biological impact of the use of DEN following prior exposure to ZOL in patients with MM. Some have suggested that the use of DEN in patients extensively treated with ZOL may over-suppress bone turnover and recommend the use of bone resorption markers such as C-terminal telopeptide (CTX) to guide this treatment decision. In this observational study, we describe the reasons for the switch in use of these bone-modifying agents (BMAs) and evaluate the incidence of SREs in a selected population of MM patients who received both agents during their course of treatment.Methods:This retrospective study included all MM patients that were treated at Yale Cancer Center including Smilow Cancer Hospital and Smilow Care Centers between January 1, 2015 and August 1, 2019. Patient demographics, date of diagnosis, location of main treatment center, and dates and doses of receipt of all BMAs, including ZOL and DEN, were extracted from the electronic medical record. For patients who were switched from one class of BMA to another, we used manual chart review to extract the switch date, reason for switch, estimated glomerular filtration rate (eGFR), and dates and types of all SREs sustained thereafter.Results:We identified 658 patients who received BMAs for MM during the study period. Among these, 499 (75.8%) received ZOL only, 91 (13.8%) received DEN only, and 68 (10.3%) received ZOL and DEN during their treatment course. Of this last group, 63 were switched from ZOL to DEN. The most common reasons for switching from ZOL to DEN were as follows: change in eGFR (57.1%), physician preference (19%), ZOL intolerance (12.7%), and recalcitrant hypercalcemia (11.1%). Among patients switched due to change in eGFR, the median eGFR at time of switch was 34 mL/min/1.73m2 (range, 4->60). For switches made due to physician preference only, the date of switch was a median of 6 months (range, 2-16) following the FDA approval of DEN for MM indication in 2018. The median number of doses of ZOL (either 4mg, 3.5mg, 3.3mg, or 3mg) received before switch was 11 (IQR, 3.5-18) and the median number of doses of DEN (120mg) received after switch was 5 (2.5-9). Among patients who were switched from ZOL to DEN, 24/63 (38%) developed a new fracture at some time during treatment with either therapy, whereas 5/63 (7.9%) developed a new fracture after the switch to DEN. Time from ZOL initiation to new fracture was 16 months (range, 1-73) for any fracture and 38 months (range, 2-62) for long bone fractures. The median time to a new fracture after switch from ZOL to DEN was 5 months (range, 1-11). None of the patients who were switched from ZOL to DEN due to hypercalcemia developed new fractures during the study period. Out of all patients who received BMAs, 32/658 (4.9%) underwent serum CTX level testing to guide use of therapy.Conclusions:After the approval of DEN for MM as an alternative to ZOL, we observed that the most common reasons for switch of ZOL to DEN at our cancer center were due to changes in patient renal function or for bisphosphonate intolerance. The use of serum CTX to guide switch in therapy was uncommon in clinical practice and should be encouraged more. In a selected cohort of patients who were switched from ZOL to DEN, the time to new SRE was shorter than historically reported with DEN only. These data highlight the need for prospective studies on the efficacy of DEN in MM patients who have previously been exposed to ZOL. [Display omitted] DisclosuresNeparidze: Eidos Therapeutics: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Research Funding; Janssen: Research Funding.