Non-Small-Cell Lung Cancer: New Treatment Approaches for Metastatic Bone Disease This program is supported by an educational donation from

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clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Faculty Vera Hirsh, MD, FRCP(C) Associate Professor Department of Medical Oncology McGill University Montreal, Canada Howard (Jack) West, MD Medical Director Thoracic Oncology Program Swedish Cancer Institute Seattle, Washington

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Disclosures Vera Hirsh, MD, FRCP(C), has disclosed that she has received consulting fees from Amgen, AstraZeneca, Boehringer Ingelheim, and Roche. Howard (Jack) West, MD, has no significant financial relationships to disclose.

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Overview  Bone Metastases in Patients With Lung Cancer  Bone-Targeted Therapy for Lung Cancer: Bisphosphonates  Biochemical Markers of Bone Formation and Resorption  Antitumor Activity of Zoledronic Acid in NSCLC  Bone-Targeted Therapy for Lung Cancer: Denosumab

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Disease Bone metastases Fracture Hypercalcemia Surgery to bone (including cementoplasty) Radiation to bone Skeletal-related events Spinal cord compression Loss of autonomy Consequences Significant morbidity Bone pain Decreased survival Increased healthcare costs and resources Ultimate consequence Reduced quality of life Bone Metastases Have Debilitating Consequences Kinnane N. Eur J Oncol Nurs. 2007;11(suppl):S28-S31. Weinfurt KP, et al. Ann Oncol. 2005;16:

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer 5-Yr World Prevalence, Thousands [1] Incidence of Bone Metastases in Cancers [2] Median Survival, Mos [2-4] Myeloma Renal Melanoma Bladder Thyroid Lung Breast Prostate More lytic More blastic Metastatic Bone Disease Is Prevalent in Patients With Lung Cancer 1. Ferlay J, et al. IARC Globocan Coleman RE. Cancer Treat Rev. 2001;27: Coleman RE. Cancer. 1997;80(8 suppl): Zekri J, et al. Int J Oncol. 2001;19:

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Bone Metastases Are a Concern in the Lung Cancer Field  Recent advances in treatment have extended survival of patients with advanced lung cancer to approximately 1 yr –Patients are living long enough for the effects of tumor on bone to manifest in skeletal complications Median time to first SRE [1] Median survival: P + C [2] Median survival: P + C + B [2] 1.2* 10.3 † 12.3 † Mos 1. Delea TE, et al. Oncology. 2004;67: Sandler A, et al. N Engl J Med. 2006;14: *Median survival from diagnosis of bone metastases. † Median survival from lung cancer diagnosis.

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer SREs in NSCLC: Data From Placebo Arm of a Large Trial and 2 Retrospective Studies Brodowicz T, et al. Ann Oncol. 2012;[E-pub ahead of print]. Radiotherapy Spinal cord compression Fracture Surgery or hypercalcemia 0.9% 13.1% 12.2% 73.8% Patients Experiencing SREs (%) Rosen et al, 2004 (n = 250) Tsuya et al, 2007 (n = 70) Sekine et al, 2009 (n = 642) Total SREs Radiotherapy Spinal cord compression Fracture Surgery Hypercalcemia 22.0

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Type of SREType of Service Estimated Costs of Skeletal Complications in Patients With Lung Cancer Brodowicz T, et al. Ann Oncol. 2012;[E-pub ahead of print]. Radiotherapy Surgery Fracture Other $ % $471 4% $ % $ % Hospitalization Office visit Outpatient visit Other $ % $393 3% $ % $ %

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Tsuya A, et al. Lung Cancer. 2007;57: Mean Survival Time (Days) SREs (n = 25) No SREs (n = 31) NSCLC Pts With SREs Had ~ 50% Shorter Survival Than Pts Without SREs

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Mevalonate Geranylpyrophosphate + IPP FPP Geranylgeranyl diphosphate HMG-CoA FPP synthase Ras S Rho S NBPs inhibits FPP synthase, thus blocking the prenylation of small signaling proteins required for cell function and survival X Kavanagh KL, et al. Proc Natl Acad Sci U S A. 2006;103: Rondeau JM, et al. ChemMedChem. 2006;1: Kavanagh KL, et al. J Biol Chem. 2006;281: GGPP synthase Molecular Mechanisms of Action of Nitrogen-Containing Bisphosphonates

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer StudyAgentTrial designPatients, nOutcome Rosen et al, 2004 [1] ZOL (4 mg/mo vs placebo) RCT773 (n = 378 in NSCLC stratum)  in proportion of patients with ≥ 1 SRE (P =.039)  in skeletal morbidity rate (P =.012)  risk of SREs (P =.003)  median time to first SRE (P =.009) Piga et al, 1998 [2] Oral clodronate (1600 mg/day vs placebo) RCT17No SRE data Trends for less deterioration in KPS and lower pain  need for analgesics (P =.042) Kiagia et al, 2006 [3] Ibandronate (4 mg vs placebo) Open-label, single-arm 32No SRE data 75% of patients had  or stable analgesic use  serum calcium (P =.03)  ALP (P = NS) Kritikos et al, 2005 [4] Ibandronate, pamidronate ControlledIbandronate: 5 Pamidronate: 5 No SRE data  analgesic use and serum calcium (P ≤.05) Spizzo et al, 2009 [5] PamidronateRetrospective analysis 104No SRE data ↑ OS (P <.001) 1. Rosen LS, et al. Cancer. 2004;100: Piga A, et al. J Exp Clin Cancer Res. 1998;17: Kiagia M, et al. Anticancer Res. 2006;26: Kritikos K, et al. ASCO Abstract Spizzo G, et al. Anticancer Res. 2009;29: Bisphosphonate Efficacy in Patients With Lung Cancer

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer ZOL in Patients With Bone Metastases From NSCLC and Other Solid Tumors  All patients received daily oral vitamin D 400 IU and calcium 500 mg; 8-mg arm dose reduced to 4 mg for renal safety  Stratification based on NSCLC vs other solid tumor 09 mos: core analysis 21 mos: final analysis Patients with bone metastases (N = 773) Zoledronic acid 4 mg q3w (n = 257) Placebo q3w (n = 250) Zoledronic acid 8 mg q3w, reduced to 4 mg for renal safety (n = 266) Rosen LS, et al. Cancer. 2004;100:

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Tumor Typen% NSCLC37850 Small-cell lung cancer588 Renal cell carcinoma7410 Cancer unknown primary547 Head and neck172 Thyroid11~ 2 Other tumor types17823 Randomized, Placebo-Controlled Trial of Zoledronic Acid: Tumor Types Enrolled Rosen LS, et al. Cancer. 2004;100:

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Zoledronic Acid Reduced Percentage of Patients With Each SRE  Phase III trial of patients with bone mets from NSCLC/OST who received zoledronic acid or placebo every 3 wks for up to 21 mos –~ 50% of patients had NSCLC; ~ 7% of patients had SCLC Mean SREs/Yr P = Any SRE but HCM RT to Bone Fracture to Bone Surgery to Bone SCCHCM Patients (%) Zoledronic acid Placebo P <.05 Rosen LS, et al. Cancer. 2004;100:

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Time to First Palliative Radiation* Time to First Pathologic Fracture* Median Time to First SRE 236 days 155 days 294 days 161 days 132 days 93 days Zoledronic acid 4 mg (n = 257)Placebo (n = 250) P =.009 P =.020 P = days 133 days 39 days Zoledronic Acid Delayed Time to SREs in Patients With NSCLC/OST Rosen LS, et al. Cancer. 2004;100: *Medians not reached. Values given are for the respective 25% quartiles.

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Zoledronic Acid Reduced the Risk of Developing an SRE 1. Rosen LS, et al. Cancer. 2004;100: Belch A, et al. ASCO Abstract In favor of zoledronic acid In favor of placebo P Value Risk Ratio (Zoledronic Acid 4 mg vs Placebo) NSCLC + OST [1] NSCLC [2] Risk Reduction 31% 32%

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Zoledronic Acid Reduced the Risk of SREs in Patients With a History of SREs  In patients with a history of ≥ 1 SRE before the study –Risk of on-study SREs was increased by 41% vs patients with no previous SRE at study entry (P =.036) Hirsh V, et al. Clin Lung Cancer. 2004;6: In favor of zoledronic acid In favor of placebo P Value Risk Ratio (Zoledronic Acid 4 mg vs Placebo) Previous SRE (n = 347) No Previous SRE (n = 156) Risk Reduction 31% 23%

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer ZOL in Solid Tumors: Disease Progression and Survival in the Overall Trial Population Median Time to Result, DaysZOL 4 mg (n = 257) Placebo (n = 250) P Value Bone lesion progression Overall disease progression Death Rosen LS, et al. Cancer. 2004;100:

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Safety and Tolerability Profile of Zoledronic Acid  > 3.5 million patients treated worldwide in clinical practice [1] –> 3000 patients treated in randomized trials  Long-term study (mean treatment duration: 3.6 yrs) demonstrated zoledronic acid was generally well tolerated [2]  Safety profile of IV bisphosphonates –Transient and manageable flulike symptoms after initial infusions –Dose- and infusion rate–dependent effects on renal function –Osteonecrosis of the jaw—lower rate in lung cancer setting compared with reports in myeloma or breast cancer [3] 1. The Institute of Cancer Research Ali SM, et al. J Clin Oncol. 2001;19: Bamias A, et al. J Clin Oncol. 2005;23:

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer IV Bisphosphonate Effects on Renal Function: Prevention and Management  Changes in kidney function are related to C max –ie, the highest level of BP is in the blood –As a result, rate of infusion is the key factor in prevention of kidney problems –Rates faster than mg/min are associated with problems  Importantly, rate of infusion has no impact on prevention of skeletal complications –Efficacy related to AUC (how much remains in patient)  Zoledronic acid and pamidronate affect different parts of the kidney –Zoledronic acid: tubular –Pamidronate: glomerular  Reduce the risk of renal dysfunction –Monitor serum creatinine prior to each infusion –Make sure patient is hydrated at time of treatment

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Biochemical Markers of Bone Formation and Resorption  Collagen degradation –NTx (urine/serum)* –CTx  Collagen crosslinks: PYD and DPD crosslinks of type I collagen  Osteoclasts –TRAcP-5b –BSP  Liver/bone/gut: serum ALP  Osteoblasts  Maturation: serum bone-specific alkaline phosphatase  Mineralization: osteocalcin  Initiation of collagen production: serum P1NP Osteoclasts Osteoblasts Osteoid *Most commonly used for marker of resorption in clinical practice. Resorption Initiation of bone formation Coleman R, et al. Cancer Treat Rev. 2008;34:

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Elevated NTx Levels Associated With Incr. Risk of Negative Clinical Outcomes NSCLC/OST (NTX ≥ 100 vs NTx < 100 nmol/mmol Creatinine) Relative Risk 3 P Value 1.79 SREs Disease Progression Death <.001 NTx < 100 NTx ≥ 100 Brown JE, et al. J Natl Cancer Inst. 2005;97:59-69.

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Survival in Patients With NSCLC and Normal Baseline NTx Normal NTx 100 RR: 1.33 (CI: ; P =.223) ZOL (81 at risk, 68 died) Placebo (37 at risk, 26 died) Mos Since Randomization Proportion Alive (%) Hirsh V, et al. J Thorac Oncol. 2008;3:

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Survival in Pts With NSCLC and High BL NTx Who Received ZOL or Placebo Hirsh V, et al. J Thorac Oncol. 2008;3: Elevated NTx (> 64 nmol/mmol Cr) RR: 0.65 (CI: ; P =.025) ZOL (102 at risk, 91 died) Placebo (42 at risk, 41 died) Mos Since Randomization Proportion Alive (%)

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Risk Ratio Reduced risk of death for variableIncreased risk of death P Value No Narcotics Use ZOL vs Placebo Excellent/good ECOG PS Lymphocytes (per %  ) Other Significant Variables 43%  risk of death Hirsh V, et al. J Thorac Oncol. 2008;3: ZOL  Survival in Pts With NSCLC and High Baseline NTx: Multivariate Analysis

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Summary  In patients with cancer, increased levels of markers of bone resorption, such as urinary NTx, are associated with an increased risk of SREs, disease progression, and death  Zoledronic acid confers normalization of NTx in 81% of patients with metastatic NSCLC disease and elevated markers of bone resorption  Normalization of NTx in patients with elevated NTx at baseline reduced the risk of death from NSCLC by 48% Lipton A, et al. Cancer. 2008;113:

Antitumor Activity of Zoledronic Acid in NSCLC

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Days After Tumor Injection SC Li YY, et al. Lung Cancer. 2008;59: n = 5 Tumor Diameter (mm) 0 Control ZOL 3 x ZOL Survival (%) Days After Tumor Injection SC n = 8 Control 3 x ZOL ZOL ZOL Inhibits Tumor Growth and Prolongs Survival in Murine Model of NSCLC  3 doses of zoledronic acid (1 µg/kg sc) injected on Days 7, 14, 21

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer MetastasesArrest in Distant Capillary Micrometastases Decreases Matrix Invasion Inhibits Angiogenesis Primary Tumor ZOL May Inhibit Multiple Steps in Tumor Progression and Metastasis Mundy GR, et al. Nat Rev Cancer. 2002;2: Coleman R. Breast. 2007;16(suppl 3):S21-S27. Decreases Adhesion to Bone Synergy With Anticancer Drugs Induces Tumor Cell Apoptosis Stimulates Immune Surveillance Suppresses Tumor Growth DIRECT EFFECT INDIRECT EFFECT

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Chemo ± Zoledronic Acid in Stage IV NSCLC: Study Design  Bone pain and SREs assessed in both arms  Assessments in zoledronic acid arm –Urinary NTx, calcium, and creatinine; monitored at baseline and cycles 3, 6, 9, 12 –Recommended dental exam and advised preventive measures to decrease ONJ risk *Zoledronic acid 4 mg via 15-min infusion every 28 days during chemotherapy then every 21 days as maintenance therapy Zarogoulidis K, et al. Int J Cancer. 2009;125: Patients with stage IV NSCLC and bone-only metastases, ECOG PS 0-1 (N = 144) Treatment until PD or decline in PS Docetaxel/Carboplatin + Zoledronic Acid* (n = 87) Docetaxel/Carboplatin (n = 57) Bone pain Asymptomatic

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Chemo ± Zoledronic: Median Survival and TTP  Longer zoledronic acid therapy (determined by a greater number of treatment cycles) correlated with prolonged survival and TTP (P <.01 each) Zarogoulidis K, et al. Int J Cancer. 2009;125: SurvivalTTP 50% 578 days 384 days P < % P < days 150 days Cumulative Survival Survival (Days) Zoledronic acid No zoledronic acid Cumulative Survival TTP (Days) Zoledronic acid No zoledronic acid

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Phase III Study: Zoledronic Acid in Stage III NSCLC  Endpoints –Primary: PFS –Secondary: time to bone metastases; rate of bone metastases at 6, 12, 18, 24 mos; TTP; time to first SRE; survival at 12 and 24 mos; and bone sialoprotein expression in primary tumor (substudy) Patients with stage IIIA/IIIB NSCLC, no progression after primary therapy, and ≤ 8 mos from diagnosis to randomization (N = 437) Zoledronic Acid 4 mg q3-4w No Zoledronic Acid Treatment duration: 24 mos from study entry Patients with bone mets Zoledronic Acid 4 mg q3-4w Scagliotti GV, et al. Ann Oncol. 2012;23:

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Phase III Study of Zoledronic Acid in Stage III NSCLC: Results  Zoledronic acid did not significantly affect PFS or OS vs controls –Trend toward worse PFS in long-term follow-up –Few patients experienced bone metastases Scagliotti GV, et al. Ann Oncol. 2012;23: OutcomeZoledronic Acid (n = 226) Control (n = 211) PFS  Median, mos (95% CI) 9.0 ( )11.3 ( )  24-mo estimate, % (95% CI) 25.7 ( )36.0 ( ) OS  Median, mos (95% CI) 30.3 (25.0-NR)NR (29.3-NR)  12-mo estimate, % (95% CI) 81.8 ( )81.8 ( )  24-mo estimate, % (95% CI) 59.5 ( )63.6 ( )

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Phase IV Study (Z-NEXT Registry): Zoledronic Acid in Stage IIIB/IV NSCLC  Key endpoints –Patients with bone metastases –Time to SRE, proportion of patients with an SRE, time to symptomatic SRE in patients with asymptomatic bone metastases at baseline, correlation of urine NTx levels and development of SREs, OS –Patients without bone metastases –Explore the use of urinary NTx for early detection of bone metastases Treatment/follow-up duration: 24 mos Patients with bone mets Zoledronic acid 4 mg q3-4w Bone mets Discontinue registry No bone mets Repeat bone scan q3mos if NTx remains elevated Patients without bone mets Monitor monthly for rise in NTx for 2 yrs; bone scans to confirm progression to bone Patients with stage IIIB/IV unresectable NSCLC (Planned N = 300) ClinicalTrials.gov. NCT

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Potential Mechanisms for Improved Outcomes With Bisphosphonate Therapy Bisphosphonates  therapy options (preservation of function) Effects on cancer cells (alone or with chemo) Effects on “vicious cycle” (bone) and anticancer response  SRE-related mortality  SREs Anticancer effects Improved disease outcomes:  Delayed disease progression  Prolongs survival

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Summary  Bisphosphonates help reduce the risk of SREs in patients with bone metastases  Normalization of bone turnover markers leads to improved outcomes and longer survival in lung cancer  Zoledronic acid only bisphosphonate to show anticancer benefits across tumor types alone or combined with chemotherapy –Decreases tumor angiogenesis –Stimulates antitumor immune response –Directly decreases tumor growth, invasion, and metastasis –Induces tumor cell apoptosis

RANK Ligand Inhibition: Denosumab

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Denosumab: A RANK Ligand Inhibitor  RANK ligand is essential for osteoclast formation, function, and survival  Denosumab –Fully human monoclonal antibody to RANK ligand –IgG 2 immunoglobulin isotype –High affinity and specificity for human RANK ligand –No detectable binding to other key TNF family members –Administered via subcutaneous injection Bekker PJ, et al. J Bone Miner Res 2004;19: Boyle WJ, et al. Nature. 2003;423: Peterson, et al. J Bone Miner Res. 2003;18:S166. Abstract SA393.

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Phase III Study: Denosumab vs Zoledronic Acid for Bone Metastases in Adv Cancers  International, randomized, double-blind, active-controlled phase III study Zoledronic Acid 4 mg IV* and Placebo SC q4w (n = 890) Denosumab 120 mg SC and Placebo IV* q4w (n = 886) Adults with solid tumors and bone metastases (excluding breast and prostate) or multiple myeloma and no current or previous IV bisphosphonate administration for treatment of bone metastases (N = 1776) *Per protocol and zoledronic acid label, IV product dose adjusted for baseline creatinine and subsequent dose intervals determined by serum creatinine. Supplemental calcium and vitamin D recommended 1° Endpoint  Time to first on-study SRE (noninferiority) 2° Endpoints  Time to first on-study SRE (superiority)  Time to first and subsequent on-study SRE (superiority) Henry DH, et al. J Clin Oncol. 2011;29:

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Denosumab vs Zoledronic Acid: Baseline Characteristics Henry DH, et al. J Clin Oncol. 2011;29: CharacteristicDenosumab (n = 886) Zoledronic Acid (n = 890) Male, n (%)588 (66)552 (62) Median age, yrs6061 Primary tumor type, n (%)  NSCLC350 (39)352 (40)  Multiple myeloma87 (10)93 (10)  Other449 (84)455 (50) ECOG performance score of 0 or 1, n (%)748 (84)728 (82) Median time from first bone metastasis to randomization, mos 22 Previous SRE, n (%)440 (50)446 (50) Presence of visceral metastases, n (%)474 (54)448 (50)

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Denosumab vs Zoledronic Acid: Time to First On-Study SRE Henry DH, et al. J Clin Oncol. 2011;29: HR: 0.84 (95% CI: ; P =.0007 noninferiority) Adjusted P =.06 (NS for superiority) Kaplan-Meier Estimate of Median Mos Denosumab Zoledronic acid Study Mo Proportion of Subjects Without SRE Patients at Risk, n Zoledronic acid Denosumab

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Denosumab vs Zoledronic Acid: Time to First and Subsequent On-Study SREs* *Multiple event analysis. Henry DH, et al. J Clin Oncol. 2011;29: Rate ratio: 0.90 (95% CI: ; P =.14) Total Number of SREs Denosumab Zoledronic acid Study Mo Cumulative Mean Number of SREs 2730

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Denosumab vs Zoledronic Acid: Disease Progression (Exploratory Endpoint) Henry DH, et al. J Clin Oncol. 2011;29: HR: 1.00 (95% CI: ; P = 1.0) Denosumab Zoledronic acid Study Mo Overall Disease Progression (Proportion) Patients at Risk, n Zoledronic acid Denosumab

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Denosumab vs Zoledronic Acid: OS (Exploratory Endpoint) Henry DH, et al. J Clin Oncol. 2011;29: HR: 0.95 (95% CI: ; P =.43) Denosumab Zoledronic acid Study Mo OS (Proportion) Zoledronic acid Denosumab Patients at Risk, n

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Denosumab vs Zoledronic Acid: Time to First On-Study SRE (Solid Tumors Only) Henry DH, et al. ASCO Abstract HR: 0.81 (95% CI: ; P =.017 superiority endpoint) Kaplan-Meier Estimate of Median Time to SRE, Mos Denosumab Zoledronic acid Study Mo Proportion of Patients Without SREs Denosumab Zoledronic acid Patients at Risk, n

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Denosumab vs Zoledronic Acid: Time to First and Subsequent SREs (Solid Tumors) Henry DH, et al. ASCO Abstract Rate ratio 0.85 (95% CI: ; P =.048) Events, n Denosumab Zoledronic acid Study Mo Cumulative Mean Number of SREs

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Denosumab vs Zoledronic Acid: Adverse Events Henry DH, et al. J Clin Oncol. 2011;29: Event, n (%)Denosumab (n = 878) Zoledronic Acid (n = 878) Infectious AEs358 (40.8)349 (39.7) Infectious serious AEs128 (14.6)118 (13.4) Acute phase reaction (first 3 days)61 (6.9)127 (14.5) Renal AEs*  Increased blood creatinine  Renal failure 73 (8.3) 29 (3.3) 20 (2.3) 96 (10.9) 43 (4.9) 25 (2.8) Adjudicated positive ONJ †  Yr 1  Yr 2  Yr 3 10 (1.1) (0.5) (1.1) (1.1) 11 (1.3) (0.6) (0.9) (1.3) New primary malignancy5 (0.6)3 (0.3) *Includes blood creatinine increased, renal failure, renal failure acute, proteinuria, blood urea increased, renal impairment, urine output decreased, anuria, oliguria, azotemia, hypercreatininemia, creatinine renal clearance decreased, renal failure chronic, and blood creatinine abnormal. † P = 1.0 No patients developed neutralizing anti-denosumab antibodies.

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer ONJ: Prevention and Management  Prevention –Prior to initiation of denosumab or zoledronic acid –An oral exam should be performed by the prescriber –Dental examination and appropriate preventive dentistry should be considered –During treatment with denosumab or zoledronic acid –Good oral hygiene practices should be maintained –Patients should avoid invasive dental procedures  Management –Patients with suspected or confirmed ONJ should receive care by a dentist or an oral surgeon –Extensive dental surgery to treat ONJ may exacerbate the condition –Management can include oral rinses, antibiotics, dental debridement, palliative therapy, and clinical follow-up American Association of Oral and Maxillofacial Surgeons. Position paper on bisphosphonate-related osteonecrosis of the jaw.

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Denosumab-Associated Hypocalcemia: Prevention and Management  Prevention –Prior to initiation of denosumab –Preexisting hypocalcemia must be corrected –During treatment with denosumab –All patients, except those with hypercalcemia, should receive calcium ≥ 500 mg/day plus vitamin D ≥ 400 IU/day –Monitor calcium levels as necessary –Monitor levels more frequently when denosumab is administered with other drugs that can also lower calcium levels  Management –If hypocalcemia occurs, additional short-term calcium supplementation may be necessary –Administer calcium, magnesium, and vitamin D as necessary based on calcium levels Denosumab [package insert]

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Phase III Study of Denosumab vs Zoledronic Acid: Pain Endpoints  Pain worsening and improvement –Time to moderate/severe pain (> 4 in BPI-SF worst pain score) for those with no/mild pain (≤ 4 in BPI-SF worst pain score) at baseline –Proportion of patients with moderate/severe pain by study visit for those with no/mild pain at baseline –Time to clinically meaningful pain worsening (≥ 2-point increase in BPI-SF worst pain score) –Proportion of patients with clinically meaningful pain worsening by study visit –Time to clinically meaningful pain improvement (≥ 2-point increase in BPI-SF worst pain score)  Analgesic use –Proportion of patients shifting from no/mild analgesic use (AQA ≤ 2) at baseline to strong opioid analgesic use (AQA ≥ 3) by study visit Fallowfield L, et al. ESMO Abstract 7004.

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer BPI-SF: Pain Evaluation Tool  BPI-SF is validated instrument that uses 11-point numerical rating scale  Patients rate pain severity at its worst from no pain (0) to pain as bad as can be imagined (10)  Levels of pain severity are categorized by no/mild, moderate, and severe pain No painPain as bad as you can imagine No painMild painModerate painSevere pain “Please rate your pain by circling the one number that best describes your pain at its worst in the last week.” Cleeland CS. Clin Cancer Res. 2006:6236s. BPI-SF (worst pain)

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Denosumab Delayed Time to Moderate/ Severe Pain in Pts With No/Mild Pain at BL Moderate/severe pain corresponds to BPI worst pain score > 4. No/mild pain corresponds to BPI worst pain score ≤ 4. Risk reduction Fallowfield L, et al. ESMO Abstract Median Time Without Moderate/Severe Pain, Mos Denosumab Zoledronic acid BL Proportion of Patients Without a Moderate/Severe Worst Pain Score HR: 0.81 (95% CI: ; P =.0499) Study Mo Patients at Risk, n Denosumab Zoledronic acid %

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Proportion With No/Mild Pain at Baseline Reporting Moderate/Severe Pain by Visit *P < % Average relative difference No/mild pain corresponds to BPI worst pain score ≤ 4; moderate/severe pain corresponds to BPI worst pain score > 4. * * * Fallowfield L, et al. ESMO Abstract Denosumab (n = 323) Patients (%) Study Mo Zoledronic acid (n = 273)

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Denosumab vs Zoledronic Acid: Who Shifted to Strong Opioid Use? 22% Average relative difference * * * *P <.05 No/low analgesic use is an AQA score ≤ 2; strong opioids is an AQA score ≥ 3. Fallowfield L, et al. ESMO Abstract Denosumab (n = 502) Patients (%) Study Mo Zoledronic acid (n = 497)

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Denosumab and Pain: Summary  Denosumab delayed the time to moderate/severe pain compared with zoledronic acid in patients with no/mild pain at baseline  Consistently fewer denosumab-treated patients with no/mild pain at baseline reported moderate/severe pain  Denosumab was associated with a delay in time to clinically meaningful pain worsening compared with zoledronic acid  There was no difference in the time to clinically meaningful pain improvement between groups  Overall, fewer patients receiving denosumab required increased analgesic use over time Fallowfield L, et al. ESMO Abstract 7004.

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Phase III Study Denosumab vs Zoledronic Acid: Analysis of the Lung Cancer Subgroup *IV product dose adjusted for baseline creatinine clearance and subsequent dose intervals determined by serum creatinine (per zoledronic acid label) Lung Cancer Type, n (%)Zoledronic AcidDenosumab NSCLC352 (88)350 (85)  Adenocarcinoma211 (60)189 (54)  Squamous cell75 (21)88 (25)  Other66 (19)73 (21) SCLC48 (12)61 (15) Scagliotti G, et al World Conference on Lung Cancer. Abstract O Zoledronic Acid 4 mg IV* and Placebo SC q4w (n = 400) Denosumab 120 mg SC and Placebo IV* q4w (n = 411) Patients with advanced lung cancer and confirmed bone metastases, with no previous bisphosphonate exposure Supplemental calcium (500 mg) and vitamin D (400 IU) recommended

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Denosumab vs Zoledronic Acid: OS in Lung Cancer Scagliotti G, et al World Congress on Lung Cancer. Abstract O KM Estimate of Median OS, Mos Denosumab Zoledronic acid Proportion of Patients Remaining Alive HR: 0.80 (95% CI: ; P =.01) Study Mo Patients at Risk, n Zoledronic acid Denosumab

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Denosumab vs Zoledronic Acid: OS in Small-Cell Lung Cancer Scagliotti G, et al World Congress on Lung Cancer. Abstract O KM Estimate of Median OS, Mos Denosumab Zoledronic acid Proportion of Patients Remaining Alive HR: 0.81 (95% CI: ; P =.3580) Patients at Risk, n Zoledronic acid Denosumab Study Mo

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Denosumab vs Zoledronic Acid: OS in NSCLC Scagliotti G, et al World Congress on Lung Cancer. Abstract O KM Estimate of Median OS, Mos Denosumab Zoledronic acid Proportion of Patients Remaining Alive HR: 0.78 (95% CI: ; P =.0104) Patients at Risk, n Zoledronic acid Denosumab Study Mo

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Denosumab vs Zoledronic Acid: OS in NSCLC by Histologic Type Adenocarcinoma Squamous Cell Carcinoma Scagliotti G, et al World Congress on Lung Cancer. Abstract O KM Estimate of Median OS, Mos Denosumab Zoledronic acid Proportion of Patients Remaining Alive HR: 0.80 (95% CI: ; P =.0751) Study Mo Patients at Risk, n Zoledronic acid Denosumab KM Estimate of Median OS, Mos Denosumab Zoledronic acid Proportion of Patients Remaining Alive HR: 0.68 (95% CI: ; P =.0350) Study Mo Patients at Risk, n Zoledronic acid Denosumab

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Denosumab vs Zoledronic Acid in Lung Cancer: Adverse Events Event, n (%)Denosumab (n = 406) Zoledronic Acid (n = 395) All adverse events 393 (96.8)377 (95.4) Serious adverse events 268 (66.0)288 (72.9) Fatal adverse events 183 (45.1)189 (47.8) Adverse events of interest  Hypocalcemia 35 (8.6)15 (3.8)  ONJ3 (0.7)3 (0.8) Scagliotti G, et al World Congress on Lung Cancer. Abstract O01.01.

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Denosumab vs Zoledronic Acid in Lung Cancer: Conclusions  In this exploratory analysis of a large subgroup of patients with lung cancer and bone metastases, denosumab was associated with significantly improved OS vs zoledronic acid –OS not significantly improved vs zoledronic acid among subset of patients with SCLC  Preclinical investigation is under way to evaluate if RANKL inhibition has direct antitumor effects on lung cancer cells (eg, apoptosis, inhibition of cancer migration/ invasion)  These findings warrant further clinical investigation

clinicaloptions.com/oncology Optimizing Therapeutic Strategies Targeting Bone: Lung Cancer Denosumab vs Zoledronic Acid in Solid Tumors: Results  Results from a phase III trial in patients with solid tumors (excluding breast and prostate cancer) or multiple myeloma and bone metastases showed denosumab was superior to zoledronic acid [1] –Delayed time to first on-study SRE –Delayed time to first and subsequent SREs  Subgroup analyses demonstrated –Superior survival for denosumab vs zoledronic acid [2] –Better pain control [3] 1. Henry D, et al. ASCO Abstract Scagliotti G, et al World Congress on Lung Cancer. Abstract O Fallowfield L, et al. ESMO Abstract 7004.

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