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Risk Factors for Hypocalcemia in Patients with Cancer Receiving Denosumab
Annals of Oncology 25 (Supplement 4): iv517–iv541, 2014 doi:10.1093/annonc/mdu356.34
1513P
RISK FACTORS FOR HYPOCALCEMIA IN PATIENTS WITH CANCER RECEIVING DENOSUMAB
Aim: The potent RANK ligand inhibitor denosumab (Dmab) can cause hypocalcemia (hypoCa). Patients ( pts) with inadequate intake of Ca and vitamin D are at increased risk for hypoCa. Additional baseline risk factors for hypoCa in pts with metastatic bone disease (MBD) were evaluated to aid clinical risk assessment for this adverse event. Methods: A post hoc analysis used data from three identically designed, randomized, blinded phase 3 trials comparing monthly dosing of 4 mg zoledronic acid (ZA) to 120 mg Dmab in pts with MBD to identify lab events of grade≥2 hypoCa (CTCAE: <8.0–7.0 mg/dL;<2.0–1.75 mmol/L). Pt characteristics evaluated included: gender, race (white vs non-white), tumor type, bone lesion type (osteolytic, osteoblastic, mixed), baseline calculated creatinine clearance (CrCl), # of bone mets, and baseline bone-specific alkaline phosphatase (BSAP) and urinary N-telopeptide (uNTx) levels. Results: The overall incidence of lab grade≥2 hypoCa events in those treated with Dmab was equal to or greater than in those treated with ZA and occurred in 12.4% of
Table: 1513P Baseline Factor
Hazard 95% CI Ratio
P-value
> 2 bone mets BSAP>median (20.77 μg/L) BSAP>median vs≤median > 2 bone mets ≤ 2 bone mets Interaction of baseline BSAP and # of bone mets uNTX>50 nmol/mmol Interaction of baseline uNTX and # of bone mets
1.329 2.078
(1.044, 1.692) 0.021 (1.579, 2.734) <.0001
4.236 1.773
(2.117, 8.479) (1.312, 2.395) 0.021
1.316
(1.031, 1.680) 0.027 0.21
Conclusions: The risk of hypoCa after Dmab for MBD is associated with the # of bone mets and elevated bone turnover markers, especially high BSAP with>2 mets. BSAP may indicate the potential for deposition of Ca in undermineralized matrix. Pts with high bone turnover may be more susceptible to hypoCa when osteoclasts are rapidly inhibited, particularly when Ca and vitamin D intake is insufficient. Disclosure: J. Body: Consultant for and received research funding from Amgen; received honoraria from Amgen and Novartis; H.G. Bone: Consultant for and received honoraria from Amgen and Novartis; C. van Poznak: Received research funding from Amgen and Novartis; R.H. De Boer: Consultant for and received honoraria from Novartis; received research funding and other remuneration from Amgen and Novartis; A. Stopeck: Consultant for Amgen; honoraria from Amgen and GlaxoSmithKline; research funding from Amgen and Novartis; K. Fizazi: Consultant for Amgen and Novartis; honoraria from Amgen; D.H. Henry: Consultant for and received research funding and honoraria from Amgen, Ortho Biotech, and Watson; T. Ibrahim: Consultant for Amgen; A. Lipton: Honoraria and research funding from Amgen; F. Saad: Consultant for and received research funding and honoraria from Amgen and Novartis; N.D. Shore: Consultant for Amgen, Astellas, Bayer, Dendreon, Janssen, and Medivation; T. Takano: Consultant for and received honoraria from Daiichi-Sankyo; H. Wang: Employee of and owns stock or stock options in Amgen; O. L. Bracco: Employee of and owns stock or stock options in Amgen; A. Balakumaran: Employee of and owns stock or stock options in Amgen; P.J. Kostenuik: Employee of and owns stock or stock options in Amgen. All other authors have declared no conflicts of interest.
© European Society for Medical Oncology 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from https://academic.oup.com/annonc/article-abstract/25/suppl_4/iv529/2242200 by guest on 25 October 2019
J. Body1, H.G. Bone2, C. van Poznak3, R.H. De Boer4, A. Stopeck5, R. Damião6, K. Fizazi7, D.H. Henry8, T. Ibrahim9, A. Lipton10, F. Saad11, N.D. Shore12, T. Takano13, H. Wang14, O.L. Bracco15, A. Balakumaran16, P.J. Kostenuik17 1 Medicine, Centre Hospitalier Universitaire Brugmann University, Brussels, BELGIUM 2 Endocrinology, Michigan Bone and Mineral Clinic, Detroit, MI, USA 3 Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA 4 Department of Medical Oncology, Royal Melbourne Hospital, Parkville, VIC, AUSTRALIA 5 Clinical Breast Cancer Program, University of Arizona Cancer Center, Tucson, AZ, USA 6 Urology, Hospital Universitario Pedro Ernesto, Rio de Janeiro, BRAZIL 7 Department of Cancer Medicine, Institut Gustave Roussy, University of Paris Sud, Villejuif, FRANCE 8 Joan Karnell Cancer Center, Pennsylvania Hospital, Philadelphia, PA, USA 9 Oncology, IRCCS-Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, ITALY 10 Division of Hematology/oncology, Pennsylvania State University, Milton S Hershey Medical Center, Hershey, PA, USA 11 Surgery, University of Montreal Hospital Center, Montreal, QC, CANADA 12 Urology, Carolina Urologic Research Center, Myrtle Beach, SC, USA 13 Dept. of Medical Oncology, Toranomon Hospital, Tokyo, JAPAN 14 Global Biostatistical Science, Amgen, Thousand Oaks, CA, USA 15 Safety, Amgen, Thousand Oaks, CA, USA 16 Global Development, Amgen, Thousand Oaks, CA, USA 17 Metabolic Disorders, Amgen, Thousand Oaks, CA, USA
Dmab-treated pts. Baseline pt characteristics with the greatest incidence of hypoCa include: male gender (15.4%), prostate cancer (20.5%), small cell lung cancer (18.0%), and CrCl 30 –<60 ml/min (15.5%). The risk of developing hypoCa was increased in pts with>2 bone mets and those with higher BSAP or uNTx levels (Table). Osseous lesion type did not significantly increase the risk of developing hypoCa (P ≥ 0.23).
abstracts
supportive care
1513P
RISK FACTORS FOR HYPOCALCEMIA IN PATIENTS WITH CANCER RECEIVING DENOSUMAB
Aim: The potent RANK ligand inhibitor denosumab (Dmab) can cause hypocalcemia (hypoCa). Patients ( pts) with inadequate intake of Ca and vitamin D are at increased risk for hypoCa. Additional baseline risk factors for hypoCa in pts with metastatic bone disease (MBD) were evaluated to aid clinical risk assessment for this adverse event. Methods: A post hoc analysis used data from three identically designed, randomized, blinded phase 3 trials comparing monthly dosing of 4 mg zoledronic acid (ZA) to 120 mg Dmab in pts with MBD to identify lab events of grade≥2 hypoCa (CTCAE: <8.0–7.0 mg/dL;<2.0–1.75 mmol/L). Pt characteristics evaluated included: gender, race (white vs non-white), tumor type, bone lesion type (osteolytic, osteoblastic, mixed), baseline calculated creatinine clearance (CrCl), # of bone mets, and baseline bone-specific alkaline phosphatase (BSAP) and urinary N-telopeptide (uNTx) levels. Results: The overall incidence of lab grade≥2 hypoCa events in those treated with Dmab was equal to or greater than in those treated with ZA and occurred in 12.4% of
Table: 1513P Baseline Factor
Hazard 95% CI Ratio
P-value
> 2 bone mets BSAP>median (20.77 μg/L) BSAP>median vs≤median > 2 bone mets ≤ 2 bone mets Interaction of baseline BSAP and # of bone mets uNTX>50 nmol/mmol Interaction of baseline uNTX and # of bone mets
1.329 2.078
(1.044, 1.692) 0.021 (1.579, 2.734) <.0001
4.236 1.773
(2.117, 8.479) (1.312, 2.395) 0.021
1.316
(1.031, 1.680) 0.027 0.21
Conclusions: The risk of hypoCa after Dmab for MBD is associated with the # of bone mets and elevated bone turnover markers, especially high BSAP with>2 mets. BSAP may indicate the potential for deposition of Ca in undermineralized matrix. Pts with high bone turnover may be more susceptible to hypoCa when osteoclasts are rapidly inhibited, particularly when Ca and vitamin D intake is insufficient. Disclosure: J. Body: Consultant for and received research funding from Amgen; received honoraria from Amgen and Novartis; H.G. Bone: Consultant for and received honoraria from Amgen and Novartis; C. van Poznak: Received research funding from Amgen and Novartis; R.H. De Boer: Consultant for and received honoraria from Novartis; received research funding and other remuneration from Amgen and Novartis; A. Stopeck: Consultant for Amgen; honoraria from Amgen and GlaxoSmithKline; research funding from Amgen and Novartis; K. Fizazi: Consultant for Amgen and Novartis; honoraria from Amgen; D.H. Henry: Consultant for and received research funding and honoraria from Amgen, Ortho Biotech, and Watson; T. Ibrahim: Consultant for Amgen; A. Lipton: Honoraria and research funding from Amgen; F. Saad: Consultant for and received research funding and honoraria from Amgen and Novartis; N.D. Shore: Consultant for Amgen, Astellas, Bayer, Dendreon, Janssen, and Medivation; T. Takano: Consultant for and received honoraria from Daiichi-Sankyo; H. Wang: Employee of and owns stock or stock options in Amgen; O. L. Bracco: Employee of and owns stock or stock options in Amgen; A. Balakumaran: Employee of and owns stock or stock options in Amgen; P.J. Kostenuik: Employee of and owns stock or stock options in Amgen. All other authors have declared no conflicts of interest.
© European Society for Medical Oncology 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from https://academic.oup.com/annonc/article-abstract/25/suppl_4/iv529/2242200 by guest on 25 October 2019
J. Body1, H.G. Bone2, C. van Poznak3, R.H. De Boer4, A. Stopeck5, R. Damião6, K. Fizazi7, D.H. Henry8, T. Ibrahim9, A. Lipton10, F. Saad11, N.D. Shore12, T. Takano13, H. Wang14, O.L. Bracco15, A. Balakumaran16, P.J. Kostenuik17 1 Medicine, Centre Hospitalier Universitaire Brugmann University, Brussels, BELGIUM 2 Endocrinology, Michigan Bone and Mineral Clinic, Detroit, MI, USA 3 Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA 4 Department of Medical Oncology, Royal Melbourne Hospital, Parkville, VIC, AUSTRALIA 5 Clinical Breast Cancer Program, University of Arizona Cancer Center, Tucson, AZ, USA 6 Urology, Hospital Universitario Pedro Ernesto, Rio de Janeiro, BRAZIL 7 Department of Cancer Medicine, Institut Gustave Roussy, University of Paris Sud, Villejuif, FRANCE 8 Joan Karnell Cancer Center, Pennsylvania Hospital, Philadelphia, PA, USA 9 Oncology, IRCCS-Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, ITALY 10 Division of Hematology/oncology, Pennsylvania State University, Milton S Hershey Medical Center, Hershey, PA, USA 11 Surgery, University of Montreal Hospital Center, Montreal, QC, CANADA 12 Urology, Carolina Urologic Research Center, Myrtle Beach, SC, USA 13 Dept. of Medical Oncology, Toranomon Hospital, Tokyo, JAPAN 14 Global Biostatistical Science, Amgen, Thousand Oaks, CA, USA 15 Safety, Amgen, Thousand Oaks, CA, USA 16 Global Development, Amgen, Thousand Oaks, CA, USA 17 Metabolic Disorders, Amgen, Thousand Oaks, CA, USA
Dmab-treated pts. Baseline pt characteristics with the greatest incidence of hypoCa include: male gender (15.4%), prostate cancer (20.5%), small cell lung cancer (18.0%), and CrCl 30 –<60 ml/min (15.5%). The risk of developing hypoCa was increased in pts with>2 bone mets and those with higher BSAP or uNTx levels (Table). Osseous lesion type did not significantly increase the risk of developing hypoCa (P ≥ 0.23).
abstracts
supportive care