Denosumab Research Articles

Risk factors associated with onset of medication-related osteonecrosis of the jaw in patients treated with denosumab

ObjectivesWhile risk factors of bisphosphonate (BP) associated osteonecrosis of the jaw have been properly analyzed, studies focusing on risk factors associated with denosumab (DNO) are sparse. The purpose of this study was to identify risk factors influencing the onset of medication-related osteonecrosis of the jaw (MRONJ) in patients receiving antiresorptive treatment (ART) with DNO by comparing patients suffering from MRONJ and patients without MRONJ. Multiple variables were evaluated including the impact of a previous BP intake.Materials and methodsA retrospective single-center cohort study with patients receiving DNO was conducted. One-hundred twenty-eight patients were included and divided into three groups: I (control, n = 40) receiving DNO with absence of MRONJ; group II (Test 1, n = 46), receiving DNO with presence of MRONJ; and group III (Test 2, n = 42) sequentially receiving BP and DNO with presence of MRONJ. Patients’ medical history, focusing on the identification of MRONJ risk factors, was collected and evaluated. Parameters were sex, age, smoking habit, alcohol consumption, underlying disease (cancer type, osteoporosis), internal diseases, additional chemo/hormonal therapy, oral inflammation, and trauma.ResultsThe following risk factors were identified to increase MRONJ onset significantly in patients treated with DNO: chemo/hormonal therapy (p = 0.02), DNO dosage (p < 0.01), breast cancer (p = 0.03), intake of corticosteroids (p = 0.04), hypertension (p = 0.02), diabetes mellitus (p = 0.04), periodontal disease (p = 0.03), apical ostitis (p = 0.02), and denture use (p = 0.02). A medication switch did not affect MRONJ development (p = 0.86).ConclusionsMalignant diseases, additional chemotherapy, DNO dosage, and oral inflammations as well as diabetes mellitus and hypertension influence MRONJ onset in patients treated with DNO significantly.Clinical relevancePatients receiving ART with DNO featuring aforementioned risk factors have a higher risk of MRONJ onset. These patients need a sound and regular prophylaxis in order to prevent the onset of MRONJ under DNO treatment.

Characterization of M Cells in Tear Duct-Associated Lymphoid Tissue of Mice: A Potential Role in Immunosurveillance on the Ocular Surface.

The ocular mucosal tissues are exposed to potentially harmful foreign antigens in the air and tear fluid. The tear duct-associated lymphoid tissue (TALT) may contribute to immune surveillance in the eye region. Follicle-associated epithelium (FAE) of TALTs is classified as stratified squamous epithelium and consists of squamous epithelial cells arranged in layers on the basement membrane. In contrast, most mucosa-associated lymphoid tissue is covered by a monolayer of epithelium containing microfold (M) cells. Therefore, antigen uptake and the presence of M cells in TALT are not fully understood. The present study found that a small population of FAE cells in the TALT expressed intestinal M-cell markers, namely Sox8, Tnfaip2, GP2, and OPG. This cell population was identified as functional M cells because of their uptake capacity of luminal nanoparticles. In addition, RANKL, which is essential for M-cell differentiation, was expressed by stroma-like cells at the subepithelial region and its receptor RANK by the FAE in the TALT. The administration of RANKL markedly increased the number of Sox8+ M cells. In contrast, deficiency in OPG, an endogenous inhibitor of RANKL, increased the number of M cells in the TALT. These data demonstrate that the RANKL-RANK axis is essential for M-cell differentiation in the TALT. Furthermore, immunization via eye drops elicited the production of antigen-specific antibodies in tears, which was enhanced by RANKL administration. Thus, TALT M cells play an important role in the immunosurveillance of the eye region.

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.

P40.08 Bone-Targeted Agents Improve Survival in High Bone Tumor Burden Advanced Non-Small-Cell-Lung Cancer Patients Treated With PD-(L)1 Inhibitors

Bone-targeted agents (BTA) prevent skeletal-related events in cancer patients (pts) treated with chemotherapy (CT) with no significant impact on overall survival (OS). Among BTA, denosumab (DN) improved OS compared to zoledronic acid (ZA) in a subgroup analysis of advanced non-small-cell lung cancer (aNSCLC) pts with bone metastases (BM), while in the SPLENDOUR trial the addition of DN to 1st-line CT in aNSCLC did not improve survival. Currently, the impact of BTA in immune-checkpoint inhibitors (ICIs) treated aNSCLC with BM is unclear.

Immunization With RANKL Inhibits Osteolytic Bone Metastasis in Breast Cancer.

Breast cancer cells often metastasize to bone. Accumulating evidence suggests that inhibiting the receptor activator of nuclear factor-κB ligand (RANKL) not only leads to reduced bone metastasis of breast cancer but also has antitumoral effects. Here, we used mutant receptor activator of nuclear factor-κB ligand (RANKLM) as a vaccine for active immunization to induce antibodies for immunotherapy of bone metastatic cancer. We investigated whether anti-RANKL antibodies inhibit osteolytic bone metastasis in vitro and in a murine model. MC3T3 cells stimulated by MDA-MB-231 culture medium secreted growth differentiation factor-15 (GDF-15), which induced the nuclear factor-κB signaling cascade. In addition, RANKLM treatment-induced reduction of intraosseous growth of MDA-MB-231 cells correlated with decreased GDF-15 expression, a reduced number of osteolytic lesions, and slower tumor progression. In addition, vaccination with RANKLM led to significant improvement in overall survival and skeletal metastasis in tumor-bearing mice. Induction of anti-RANKL antibodies by RANKLM decreased GDF-15 production by deactivating nuclear factor-κB signaling, which in turn inhibited metastasis of MDA-MB-231 cells to bone. Taken together, the results demonstrate a role for RANKLM immunization in preventing bone metastasis of breast cancer.

1327P Impact of bone targeted agents (BTA) in advanced non-small cell lung cancer (aNSCLC) patients (pts) with high bone tumor burden (HBTB) treated with PD(L)1 inhibitors (ICIs)

BTA use in cancer pts with bone metastases (BM) can prevent skeletal related events. A subgroup analysis of aNSCLC pts showed an overall survival (OS) benefit with denosumab (DN) compared to zoledronic acid (ZA), while in the SPLENDOUR trial the addition of DN to 1st line chemotherapy did not improve OS. Currently, the impact of BTA in ICI treated BM aNSCLC remains unclear.

Anticancer Profiling of Gambogic Acid as a Target Specific RANKL Inhibitor in Osteosarcoma Cell Line

Osteosarcoma is a common cancer type among the youth population and usually develops in growing bones. Approximately twenty percent of osteosarcoma cases show tendency to metastases and patients with osteosarcoma have a low survival rate after treatment. RANK/RANKL/OPG key regulator triad of bone remodeling play critical roles in tumourigenesis of osteosarcoma. Anti-proliferative activity of the gambogic acid was determined in Saos-2 cell line by XTT assay. To understand the anticancer activities of the gambogic acid, molecular docking calculations were also performed with RANK-RANKL complex. The expression levels of the RANKL and OPG was measured at gene and protein level with RT-PCR and ELISA assays. Its potential anti-invasive property in-vitro against osteosarcoma cells was evaluated using wound healing assay. Experimental assays indicated that gambogic acid suppressed cell proliferation, cell migration, and decreased protein expression ratio of RANKL/OPG in Saos-2 cells. Gambogic acid binds to RANK-RANKL complex with Kd value of 549.38 nM and with estimated free energy of binding -8.54 kcal/mol. Gambogic acid is found to be significant drug template for target specific osteosarcoma treatment.

Medication-Related Osteonecrosis of the Jaw—A Continuing Issue

Introduction: Medication-related osteonecrosis of the jaw (MRONJ) is a condition that is becoming more common in the everyday practice of both dental and maxillofacial surgeons. Materials and methods: This paper aims to provide a comprehensive and easy to read by clinicians presentation of comprehensive, accessible, and up-to-date data on MRONJ. The individual chapters focus on the etiology, epidemiology, diagnosis, prevention, treatment, and recurrence of MRONJ. Results and discussion: It has been observed over the years that among drugs that increase the risk of the disease, apart from bisphosphonates, angiogenesis inhibitors and anti-RANKL monoclonal antibodies should also be included. A thorough physical and subjective examination, periodic correction of dental prostheses, and an adequate preparation for even the simplest of procedures in the oral cavity area can prevent or minimize the risk of MRONJ. Conclusions: It is extremely difficult to treat once it occurs and oftentimes is a recurring problem that leads to a multitude of symptoms that gradually decrease the quality of a patient’s life.

The real-world effectiveness of anti-RANKL antibody denosumab on the clinical fracture prevention in patients with rheumatoid arthritis: The ANSWER cohort study.

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by localized and generalized bone loss. The risk of fractures is doubled in patients with RA. Denosumab, an anti-RANKL monoclonal antibody, is used for those with osteoporosis at high risk fracture and it has inhibitory effect of progressive bone erosion in patients with RA. While the increase in bone mineral density by denosumab has been reported in patients with RA, preventive effect of fracture by denosumab remains unknown. This study aimed to evaluate the efficacy of denosumab in treating clinical fracture risk in patients with RA. Patients with RA who received denosumab treatment between 2013 and 2019 were retrospectively evaluated using the ANSWER (Kansai Consortium for the Well-Being of Rheumatic Disease Patients) cohort data. Fracture rates were evaluated between 0 and 6 months (reference period) versus > 6 months (post-reference period) of denosumab use. A total of 873 patients with RA received denosumab, and their characteristics were as follows: 88% females, mean age 68 years, and average disease duration 14.5 years. The hazard rates of all clinical fractures were 0.69 (per 100 person-years) in the reference period and 0.35 in the post-reference period, indicating a 49.2% decrease (p = 0.03). Denosumab suppresses the risk of clinical fractures in patients with RA.

The Roadmap of RANKL/RANK Pathway in Cancer.

The receptor activator of the nuclear factor-κB ligand (RANKL)/RANK signaling pathway was identified in the late 1990s and is the key mediator of bone remodeling. Targeting RANKL with the antibody denosumab is part of the standard of care for bone loss diseases, including bone metastases (BM). Over the last decade, evidence has implicated RANKL/RANK pathway in hormone and HER2-driven breast carcinogenesis and in the acquisition of molecular and phenotypic traits associated with breast cancer (BCa) aggressiveness and poor prognosis. This marked a new era in the research of the therapeutic use of RANKL inhibition in BCa. RANKL/RANK pathway is also an important immune mediator, with anti-RANKL therapy recently linked to improved response to immunotherapy in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). This review summarizes and discusses the pre-clinical and clinical evidence of the relevance of the RANKL/RANK pathway in cancer biology and therapeutics, focusing on bone metastatic disease, BCa onset and progression, and immune modulation.

Does denosumab offer survival benefits? -Our experience with denosumab in metastatic non-small cell lung cancer patients treated with immune-checkpoint inhibitors.

BackgroundImmune checkpoint inhibitors (ICIs) have revolutionized the treatment of non-small-cell lung cancer (NSCLC). Denosumab is a humanized monoclonal antibody to RANK ligand used to prevent skeletal-related events of bone metastases in solid tumors. We are reporting the clinical outcomes in our NSCLC patients who received RANKL inhibitor in combination with ICIs.MethodsThis observational study used retrospective data from a tertiary cancer center from 2015–2020. Stage IV non-small cell lung cancer patients who received denosumab within 30 days of ICIs (pembrolizumab, nivolumab, atezolizumab, ipilimumab) were included. Kaplan-Meier curves were obtained for survival analysis.ResultsWe identified 69 patients and all had skeletal metastases, and 37.7% had brain metastases. Median OS was 6.3 months and median PFS was 2.8 months, with overall response rate (ORR) of 18.8% and disease control rate (DCR) of 40.6%. Median OS in patients with concomitant denosumab and ICIs more than 3 months was 11.5 months, comparing to 3.6 months in patients with <3 months of concomitant therapy (P=0.0005). OS and PFS did not differ with respect to brain metastases or number of skeletal metastases. However, the duration of ICIs and denosumab overlap was associated with improved OS and PFS. Among the 18.8% of patients who achieved complete response (CR) and partial response (PR), six-month survival rate was 100% and one-year survival rate was 69.2%. Most of the patients tolerated denosumab well, and hypocalcemia was the most commonly reported side effect.ConclusionsPatients receiving combination therapy did not perform poorly comparing to published studies despite of poor prognostic features such as brain metastases and numerous skeletal metastases. Although we did notice potential benefit of the longer duration of concomitant use of ICI and denosumab, future prospective clinical trials are needed to evaluate the synergistic effect of RANKL inhibitors/ICI and if duration of RANKL inhibitors matters.

Serial cellular events in bone formation initiated by calcium phosphate ceramics

To better understand the biological mechanisms triggered by osteoinductive materials in vivo, we evaluated the timeline of cellular responses to osteoinductive materials subcutaneously implanted in FVB mice. More F4/80-positive macrophages were present in osteoinductive tri-CaP ceramic (TCP) with submicron surface topography (TCPs) than non-osteoinductive TCP with micron surface topography (TCPb) at week 1. Moreover, TCPs (but not TCPb) significantly enhanced osteoclastogenesis, and induced macrophages to polarize from M1 to M2 in the first week. The time sequence and relevance of macrophages and osteoclasts responses involved in bone formation was then evaluated through peri-implant injection of specific chemicals in mice implanted with osteoinductive TCPs. Day-1 injection of clodronate liposomes (LipClod) depleted macrophages, inhibited macrophage polarization to M2, blocked osteoclastogenesis and bone formation, while the day-6 injection was less effective. Anti-RANKL antibody (aRANKL) did not affect macrophage colonization but inhibited osteoclastogenesis. Injection of aRANKL before week 2 aborted bone formation in TCPs, while injection at week 4 partially inhibited bone formation. The overall data show that following ectopic implantation, osteoinductive materials allow macrophage colonization in hours to days, macrophage polarization to M2 in days (within 7 days), osteoclastogenesis in weeks (e.g. in 2 weeks) and bone formation thereafter (after 4 weeks). The serial cellular events verified herein bring a new insight on material-induced bone formation and pave the way to further explore the mechanisms triggered by osteoinductive materials. Statement of significanceA series of key cellular events triggered by osteoinductive calcium phosphate ceramic was revealed: macrophages colonized within hours to days, polarization of M2 macrophages occurred within 7 days, osteoclastogenesis mainly occurred in weeks (e.g. in 2 weeks) and bone formation finally arose thereafter (after 4 weeks). Moreover, such time sequence of cellular events was confirmed with specific chemicals (clodronate liposomes and anti-RANKL antibody). The findings verified herein bring a new insight on material-induced bone formation and pave the way to further explore the mechanisms triggered by osteoinductive materials.

New Target for Precision Medicine Treatment of Giant-Cell Tumor of Bone: Sunitinib Is Effective in the Treatment of Neoplastic Stromal Cells with Activated PDGFRβ Signaling.

Simple SummaryThe purpose of this study was to analyze differential cell signaling in response to denosumab treatment to identify and subsequently inhibit molecular targets in the neoplastic stromal cell population, which poses a risk for tumor recurrence. Using phosphoprotein arrays, a distinct signaling profile was detected in GCTB tissues treated with denosumab, a specific RANKL antibody, which coincided with the RTK profile in derived cell lines. PDGFRβ was selected as a promising receptor target, and its inhibition by the small-molecule inhibitor sunitinib resulted in potent inhibition of cell proliferation in vitro. The addition of sunitinib to denosumab resulted in the disappearance of both multinuclear giant cells and neoplastic stromal cells, as reported here. Thus, sunitinib could become an effective addition to denosumab in the treatment of GCTB with activated PDGFRβ.Giant-cell tumor of bone (GCTB) is an intermediate type of primary bone tumor characterized by locally aggressive growth with metastatic potential. The aim of this study was to identify new druggable targets among the cell signaling molecules involved in GCTB tumorigenesis. Profiles of activated signaling proteins in fresh-frozen tumor samples and tumor-derived cell lines were determined using phosphoprotein arrays. Analysis of the obtained data revealed epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor beta (PDGFRβ) as potential targets, but only the PDGFR inhibitor sunitinib caused a considerable decrease in stromal cell viability in vitro. Furthermore, in the case of a 17-year-old patient suffering from GCTB, we showed that the addition of sunitinib to the standard treatment of GCTB with the monoclonal antibody denosumab resulted in the complete depletion of multinucleated giant cells and mononuclear stromal cells in the tumor tissue. To summarize, the obtained data showed that a specific receptor tyrosine kinase (RTK) signaling pattern is activated in GCTB cells and plays an important role in the regulation of cell proliferation. Thus, activated RTKs and their downstream signaling pathways represent useful targets for precision treatment with low-molecular-weight inhibitors or with other types of modern biological therapy.

Effects of RANKL inhibition on promoting healing of bone erosion in rheumatoid arthritis using HR-pQCT: a 2-year, randomised, double-blind, placebo-controlled trial

ObjectiveTo evaluate the effects of denosumab on erosion healing at 2–4 metacarpophalangeal (MCP) head as determined by high-resolution peripheral quantitative CT (HR-pQCT) in patients with rheumatoid arthritis (RA) with stable...

Anti-RANKL monoclonal antibody and bortezomib prevent mechanical unloading-induced bone loss.

Bone loss is a major health concern for astronauts during long-term spaceflight and for patients during prolonged bed rest or paralysis. It is essential to develop therapeutic strategies to combat the bone loss occurring in people afflicted with disuse atrophy on earth as well as in astronauts in space, especially during prolonged missions. Although several drugs have been demonstrated for treating postmenopausal osteoporosis or bone-related diseases, their effects on microgravity-induced bone loss are still unclear. Here, we employed the hindlimb-unloading (HLU) tail suspension model and compared the preventive efficiencies of five agents including alendronate (ALN), raloxifene (Rox), teriparatide (TPTD), anti-murine RANKL monoclonal antibody (anti-RANKL) and proteasome inhibitor bortezomib (Bzb) on mechanical unloading-induced bone loss. Bone mineral density (BMD) was measured by quantitative computed tomography. The osteoblastic and osteoclastic activity were measured by serum ELISA, histology analysis, and histomorphometric analysis. Compared to the control, ALN and anti-RANKL antibody could restore bone mass close to sham levels by inhibiting bone resorption. Bzb could increase the whole bone mass and strength by inhibiting bone resorption and promoting bone formation simultaneously. Meanwhile, Rox did not affect bone loss caused by HLU. TPTD stimulated cortical bone formation but the total bone mass was not increased significantly. We demonstrated for the first time that anti-RANKL antibody and Bzb had a positive effect on preventing mechanical unloading-induced bone loss. This finding puts forward the potential use of anti-RANKL and Bzb on bone loss therapies or prophylaxis of astronauts in spaceflight.

Pharyngeal spreading of peri-implant infections under antiresorptive/antiangiogenic therapy

ObjectivesTo assess the influence of antiresorptive/antiangiogenic therapy on the spreading of peri-implant infections in the pharyngeal region.Material and methodsThis analysis was based on tissue biopsies obtained from a total of twenty-five albino rats having either received (1) amino-bisphosphonate (Zoledronate) (Zo) (n=4), (2) RANKL inhibitor (Denosumab) (De) (n=4), (3) antiangiogenic medication (Bevacizumab) (Be) (n=4), (4) Zo+Be (n=3), (5) De+Be (n=5), or (6) no medication (Co) (n=5). Drug administration was repeated at 12 weeks. Chronic-type peri-implant infections were induced at titanium implants located in the upper jaws. The surface area (%) of infiltrated connective tissue (ICT) and CD68-positive cells was assessed within the lateral pharyngeal/retropharyngeal connective tissue zone.ResultsMean (±SD) and median ICT% values and CD68 counts were markedly highest in the De+Be (11.10±6.04; 11.81; 95% CI − 3.89; 26.11) and De (5.70±5.06; 6.19; 95% CI − 2.34; 13.75) groups, reaching statistical significance for De CD68 counts over the Co (0.18±0.25; 0.18; 95% CI −2.14; 2.51) group. In both De+Be and De groups, the ICTs were occasionally associated with an ulceration of the epithelial compartment.ConclusionsInduced peri-implant infections were not associated with any inflammatory lesions in pharyngeal tissues. While these findings were similar under Zo and Be medication, De and De+Be had a marked effect on ICT and CD68 values. The clinical relevance of these adverse findings needs further investigation.

Denosumab

Denosumab

Efficacy and safety of JMT103 in patients with giant cell tumor of bone: A multicenter, single-arm, open-label, phase Ib/II study.

11526 Background: JMT103 is a novel, fully humanized IgG4 monoclonal antibody targeting RANKL, inhibiting osteoclastogenesis and osteoclast-mediated bone resorption. A multicenter, single-arm, open-label, phase Ib/II study was conducted to evaluate the efficacy and safety of JMT103 in patients (pts) with Giant cell tumor of bone (GCTB). Methods: Eligible pts (ECOG: 0-2) were adults with pathologically confirmed unresectable GCTB or their planned surgery is associated with severe morbidity. Pts with active dental or jaw condition requiring oral surgery, other anti-tumor therapies, anti-RANKL antibody or concurrent use of bisphosphonates were excluded. 2 mg/kg JMT103 was administrated subcutaneously every 4 weeks with a loading dose on days 8 and day 15 of the first 4 week of therapy. The primary endpoint was tumor response, defined as elimination of at least 90% giant cells or objective response of the target lesion assessed by radiologic imaging as per Modified Inverse Choi density/size (ICDS) or the Modified European Organization for Research and Treatment of Cancer (EORTC) criteria within 12 weeks. Secondary endpoints included safety profile, change of pain score using Brief Pain Inventory-Short Form, and suppression of bone-resorption biomarkers. Results: 38 pts (14 males) were enrolled between June 3 and December 24, 2020. The median age was 31 years (range 18-57). Lesions sites included lower extremities (39.5%), upper extremities (31.6%), spine (21.1%) and pelvis (13.2%). Among 32 pts with at least 1 efficacy evaluation within 12 weeks, 26 (81.3%, 95% CI: 63.6-92.8) had a tumor response by at least one response criteria. All 7 pts who underwent histological assessments had a tumor response. 25 of 32 pts assessed by radiology had a tumor response. As per ICDS criteria, 23 of 32 (71.9%) had a response; as per EORTC criteria, 15 of 17 (88.2%) had a response. 21 of 26 (80.8%) pts who complained of pain at baseline experienced reduced pain during the treatment. The median reductions in bone-resorption biomarkers were 71.8% (IQR 67.7-82.4) for uNTx/Cr (p &lt; 0.001) and 81.4% (IQR 68.3-84.7) for sCTx (p &lt; 0.001) at day 8. Of all 38 pts who were included in safety analyses, treatment-related adverse events (TRAEs) occurred in 14 pts. The most common TRAEs were hypophosphatemia (18.4%), hypocalcemia (7.9%) and blood bilirubin increased (7.9%). 1 patient (2.6%) was reported a grade 3 AE but it was not related to the treatment; other AEs were grade 1–2. Conclusions: JMT103 demonstrated encouraging anti-tumor efficacy and manageable safety profile in pts with unresectable GCTB or at high risk of severe morbidity after surgery. Clinical trial information: NCT04255576.

Does denosumab offer survival benefits? Our experience with denosumab in metastatic non-small cell lung cancer patients treated with immune-checkpoint inhibitors.

e21039 Background: Lung cancer is the leading cause of cancer-related death in the United States. Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of non-small-cell lung cancer (NSCLC). Denosumab is a humanized monoclonal antibody to RANK ligand used to prevent skeletal-related events of bone metastases in solid tumors. In preclinical and some clinical studies, denosumab have shown to have some anti-tumor properties. We are reporting the clinical outcomes in our NSCLC patients who received RANKL inhibitor in combination with ICIs. Methods: This observational study used retrospective data from a tertiary cancer center from 2015-2020. Stage IV non-small cell lung cancer patients who received denosumab within 30 days of ICIs (pembrolizumab, nivolumab, atezolizumab, ipilimumab) were included. Median overall survival (OS), progression free survival (PFS), best radiographic responses were obtained. Univariate, multivariate analyses and logistic regression analyses were done, and Kaplan-Meier curves were obtained for survival analysis. Results: We identified 69 patients and all had skeletal metastasis, and 37.7% had brain metastases. Median duration of concomitant use of denosumab and ICI was 1.5 months. Median OS was 6.3 months and median PFS was 2.8 months. Overall response rate was 18.8% and disease control rate was 40.6%. Median OS in patients with concomitant denosumab and ICIs more than 3 months was 11.5 months, comparing to 3.6 months in patients with &lt; 3 months of concomitant therapy (P=0.0005). OS and PFS did not differ with respect to brain metastases or number of skeletal metastases. However, the duration of ICIs and denosumab overlap was associated with improved OS and PFS. Among the 18.8% of patients who achieved complete response (CR) and partial response (PR), six-month survival rate was 100% and one-year survival rate was 69.2%. Conclusions: Patients receiving combination therapy did not perform poorly despite of poor prognostic features such as brain metastases and numerous skeletal metastases. Although we did notice potential benefit of the longer duration of concomitant use of ICI and denosumab, future prospective clinical trials are needed to evaluate the synergistic effect of RANKL inhibitors/ICI and if duration of RANKL inhibitors matters.

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

1567 Background: The anti-RANKL monoclonal antibody denosumab has been shown to be superior to the bisphosphonate zoledronate for the prevention of skeletal-related events (SREs) in patients with incident bone metastases (BM) from solid tumors (ST). Clinical guidelines recommend the use of a bone-targeting agent for SRE prevention for ≥ 2 years. However, real-world treatment patterns in the U.S. suggest that the denosumab treatment duration is often &lt; 1 year. Applying a machine learning approach, we sought to identify risk factors associated with SRE incidence following cessation of denosumab to help inform optimal clinical SRE prevention strategies. Methods: Using the Optum PanTher Electronic Health Record repository, patients diagnosed with incident BM from a primary ST between 1 Jan 2007 and 1 Sep 2019 were evaluated for inclusion in the study. Eligible patients had to receive ≥ 2 consecutive 120 mg denosumab doses on an every 4-week (± 14 days) schedule and have a minimum follow-up ≥ 1 year after the last denosumab dose or an SRE occurring between days 84 and 365 after denosumab cessation. Extreme gradient boosting was used to develop an SRE risk prediction model evaluated on a test dataset. Impact and relative importance of available medical, clinical, and treatment factors on SRE risk following denosumab cessation were extracted from the model using Shapley additive explanations (SHAP). Univariate analyses on risk factors with the highest importance from pooled and tumor-specific models were also conducted. Results: A total of 1,414 patients (breast, n = 563 [40%]; prostate, 421 [30%]; lung, 180 [13%]; other cancers, 250 [17%]) met inclusion criteria, with a median of 253 (min, 88; max, 2726) days of denosumab treatment; 490 (35%) experienced ≥ 1 SRE following denosumab cessation. With a meaningful model performance based on an area under the receiver operating characteristic (AUROC) score of 77%, SHAP identified several significant factors that predicted an increased SRE risk following denosumab cessation, including prior SREs, shorter denosumab treatment duration, and a higher number of clinic visits as the top-ranked factors (Table). Conclusions: A machine learning approach to SRE risk factor identification may help clinicians better assess the individualized patient’s need for denosumab treatment persistence and improve patient outcomes. Results from tumor-specific groups will be presented at the meeting.[Table: see text]