DENOSUMAB. . Peter Harper Guy s, King s & St Thomas & Leaders in Oncology Care (LOC) DENOSUMAB. RANK-L/Bisphosphonates; Bone secondaries & Lung Cancer

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1 DENOSUMAB. Peter Harper Guy s, King s & St Thomas & Leaders in Oncology Care (LOC) DENOSUMAB RANK-L/Bisphosphonates; Bone secondaries & Lung Cancer. Peter Harper Guy s, King s & St Thomas & Leaders in Oncology Care (LOC)

DENOSUMAB RANK-L/Bisphosphonates; Bone secondaries & Lung Cancer Prevalence & Relevance, Evidence, Usefulness Breast cancer is one of the tumours

metastases, months 2 4 Breast 4408 65 75 20 24 Prostate 2369 65 75 12 53 Lung 1362 30 40 3 6 Bladder 1110 40 7 1. Parkin DM et al.

2 DENOSUMAB RANK-L/Bisphosphonates; Bone secondaries & Lung Cancer Prevalence & Relevance, Evidence, Usefulness Breast cancer is one of the tumours most likely to metastasise to bone Cancer Prevalence,* Incidence of bone Median survival after developing bone thousands 1 metastases, % 2 metastases, months 2 4 Breast Prostate Lung Bladder Parkin DM et al. CA Cancer J Clin 2005;55:74 108; 2. Coleman RE. Cancer Treat Rev 2001;27:165 76; 3. Coleman RE. Cancer 1997;80: ; 4. Otto T et al. Urology 2001;57:55 9. *World 5-year survival

3 Bone Metastases Have Debilitating Consequences Disease Skeletal-related events Consequences Bone metastases Fracture Radiation to bone Spinal cord compression Hypercalcemia Loss of autonomy Significant morbidity Bone pain Surgery to bone Increased healthcare costs and resources Kinnane N. Eur J Oncol Nurs. 2007;11(suppl):S28-S31. Bone Metastases Have Debilitating Consequences Disease Skeletal-related events Consequences Ultimate consequence Bone metastases Fracture Radiation to bone Spinal cord compression Hypercalcemia Loss of autonomy Significant morbidity Bone pain Decreased survival Surgery to bone Increased healthcare costs and resources Kinnane N. Eur J Oncol Nurs. 2007;11(suppl):S28-S31.

R lt f th t l f Z l d i A id Results from the control arm of Zoledronic

4 NSCLC Are Bone Metastases Important? What number of bone events might we see in Clinical Practice? NSCLC Are Bone Metastases Important? What number of bone events might we see in Clinical Practice? R lt f th t l f Z l d i A id Results from the control arm of Zoledronic Acid and Pamidronate trials

5 Skeletal-Related Events in the CONTROL ARM of the Zoledronic Acid and Pamidronate Studies 70 Patients with an SRE E, % % 49% 51% 46% 0 Breast Cancer 1 Hormone Refract. Prostate Ca 2 Multiple Myeloma 3 NSCLC and Other Solid Tumors 4 *ALL PATIENTS RECEIVED STANDARD ANTICANCER THERAPIES. 1. Kohno N, et al. J Clin Oncol. 2005;23: Saad F, et al. J Natl Cancer Inst. 2004;96: Berenson JR, et al. J Clin Oncol. 1998;16: Rosen LS, et al. Cancer. 2004;100: Skeletal-Related Events in the CONTROL ARM of the Zoledronic Acid and Pamidronate Studies Patients with an SRE E, % Guidelines recommend bisphosphonates for bone lesions 50% 49% 51% 46% 0 Breast Cancer 1 Hormone Refract. Prostate Ca 2 Multiple Myeloma 3 NSCLC and Other Solid Tumors 4 *ALL PATIENTS RECEIVED STANDARD ANTICANCER THERAPIES. 1. Kohno N, et al. J Clin Oncol. 2005;23: Saad F, et al. J Natl Cancer Inst. 2004;96: Berenson JR, et al. J Clin Oncol. 1998;16: Rosen LS, et al. Cancer. 2004;100:

6 Skeletal Related Events Are a Serious Threat to Patients With NSCLC / OST if Bone Metastases Are Untreated 21-month data from PLACEBO arm of randomised study Patients, % 50 46% Total SREs (except HCM) Pathologic fracture 40 34% Radiation to bone Surgical intervention Spinal cord compression 30 22% % 4% 0 n = 250 HCM, hypercalcaemia of malignancy; NSCLC, non-small cell lung cancer; OST, other solid tumours; SRE, skeletal-related event. Data from Rosen LS, et al. Cancer. 2004;100(12): DENOSUMAB Review of Bisphosphonates Evidence in Lung & Bone. Peter Harper Guy s, King s & St Thomas & Leaders in Oncology Care (LOC)

ZOL Risk of SREs in Multiple Cancer Types Breast 1 Prostate 2 Solid tumors 3 Lung cancer 3 RCC 4 Risk Reduction P Value 41%.019 36%.002 31%.003 32%.016 58%.010 Multiple myeloma 5 (vs CLO) 26%.

0 Relative Risk of SRE In favor of ZOL In favor of placebo Abbreviations: CLO, clodronate (1600 mg daily); RCC, renal cell carcinoma; SRE, skeletal-related event; ZOL, zoledronic acid (4 mg q3-4

7 ZOL Risk of SREs in Multiple Cancer Types Breast 1 Prostate 2 Solid tumors 3 Lung cancer 3 RCC 4 Risk Reduction P Value 41% % % % %.010 Multiple myeloma 5 (vs CLO) 26% Relative Risk of SRE In favor of ZOL In favor of placebo Abbreviations: CLO, clodronate (1600 mg daily); RCC, renal cell carcinoma; SRE, skeletal-related event; ZOL, zoledronic acid (4 mg q3-4 weeks) 1. Kohno N, et al. J CO. 2005;23(15): ; 2. Saad F, et al. JNCI. 2004;96(11): ; 3. Rosen LS, et al. Cancer. 2004;100(12): ; 4. Lipton A, et al. Cancer. 2003;98(5): ; 5. Morgan, G. et al. ESMO 2010, abstract 1123O. 1 3 NSCLC Patients With SREs Had ~ 50% Shorter Survival Than Patients Without SREs ANY SRE 187 days NO SREs 366 days Mean survival time, days Tsuya A, et al. Lung Cancer. 2007;57:

8 Median Survival of Patients Who Experience an SRE Is 4 Months Survival, % of patie nts Time after SRE, months n = SRE, skeletal-related event. Lung cancer patients with bone metastases, US database, Adapted from Delea T, et al. Oncology. 2004;67(5-6): Decreased Mortality With ZOL Treatment in Patients With Bone Metastases Survival Proportion, % ZOL vs PAM in Breast Cancer ZOL PAM Survival, years Survival Proportion, % ZOL vs no IV BP in Prostate Cancer ZOL No IV BP Survival, years 42% mortality; P < % mortality; P =.0073 Abbreviations: BP, bisphosphonate; IV, intravenous(ly); PAM, pamidronate; ZOL, zoledronic acid. Reprinted from 1. Henk H,et al. EBCC 2010, abstract 483; 2.Henk H, et al. EAU 2010, abstract

9 Zoledronic Acid Reduced the Risk of Developing an SRE Risk reduction P value NSCLC / OST %.003 NSCLC % Risk ratio (zoledronic acid 4 mg versus placebo) In favour of zoledronic acid In favour of placebo NSCLC, non-small cell lung cancer; OST, other solid tumours; SRE, skeletal-related event. 1. Rosen LS, et al. Cancer. 2004;100(12): ; 2. Belch A, et al. Proc Am Soc Clin Oncol. 2003;22:761. Abstract ZOL Significantly Reduced the Risk of further 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 prior SRE at study entry (P =.036) Risk reduction P value Prior SRE (n = 347) %.0009 No prior SRE (n = 156) % Risk ratio (zoledronic acid 4 mg versus placebo) In favour of zoledronic acid In favour of placebo SRE, skeletal-related event.; ZOL, zoledronic acid. Adapted from Hirsh V, et al. Clin Lung Cancer. 2004;6(3):

Denosumab Model of denosumab Fully human monoclonal antibody IgG2 isotype High affinity and specificity RANK ligand No

2004;19(7):1059-1066; Elliott R, et al. Osteoporos Int. 2007;18(suppl 1):S54. Abstract P149; McClung MR, et al.

19 Phase III Trials of Dmab vs ZOL in Patients With Malignant Bone Disease Advanced cancer 18 years of age At least 1

(N = 2,046) Prostate cancer (N = 1,901) OST/MM (N = 1,776) Event-driven analysis for primary endpoint Primary

(superiority), time to first and subsequent on-study SREs (superiority), laboratory values, safety, incidence of

10 Denosumab Model of denosumab Fully human monoclonal antibody IgG2 isotype High affinity and specificity RANK ligand No neutralizing antibodies detected in clinical trials Administered SC Data from Bekker PJ, et al. J Bone Miner Res. 2004;19(7): ; Elliott R, et al. Osteoporos Int. 2007;18(suppl 1):S54. Abstract P149; McClung MR, et al. N Engl J Med. 2006;354(8): Phase III Trials of Dmab vs ZOL in Patients With Malignant Bone Disease Advanced cancer 18 years of age At least 1 bone metastasis ECOG 0, 1, or 2 Adequate organ function 3 Multicenter, randomized, double blind trials Breast cancer (N = 2,046) Prostate cancer (N = 1,901) OST/MM (N = 1,776) Event-driven analysis for primary endpoint Primary endpoint: Time to first on-study SRE (non-inferiority trial) Secondary endpoints: Time to first on study SRE (superiority), time to first and subsequent on-study SREs (superiority), laboratory values, safety, incidence of anti-denosumab antibodies Abbreviations: Dmab, denosumab; ECOG, Eastern Cooperative Oncology Group; IV, intravenous; MM, multiple myeloma; OST, other solid tumors; q, every; R, randomization; SC, subcutaneous; SRE, skeletal related event. 20

Phase III Trials of Dmab vs ZOL in Patients With Malignant Bone Disease Advanced cancer 18 years of age At least 1 bone metastasis ECOG 0, 1, or 2 Adequate organ function 3 Multicenter, randomized,

1,026) Event-driven analysis for primary endpoint Primary endpoint: Time to first on-study SRE (non-inferiority trial) Secondary endpoints: Time to first on study SRE (superiority), time to first and

11 Phase III Trials of Dmab vs ZOL in Patients With Malignant Bone Disease Advanced cancer 18 years of age At least 1 bone metastasis ECOG 0, 1, or 2 Adequate organ function 3 Multicenter, randomized, double blind trials Breast cancer (N = 2,046) Prostate cancer (N = 1,901) OST/MM (N = 1,776) Dmab 120 mg SC* + placebo IV infusion q 4 wk (n = 1,020) ZOL 4 mg IV + placebo SC injection q 4 wk (n = 1,026) Event-driven analysis for primary endpoint Primary endpoint: Time to first on-study SRE (non-inferiority trial) Secondary endpoints: Time to first on study SRE (superiority), time to first and subsequent on-study SREs (superiority), laboratory values, safety, incidence of anti-denosumab antibodies Abbreviations: Dmab, denosumab; ECOG, Eastern Cooperative Oncology Group; IV, intravenous; MM, multiple myeloma; OST, other solid tumors; q, every; R, randomization; SC, subcutaneous; SRE, skeletal related event. 21 Denosumab vs ZOL in Solid Tumors and Multiple Myeloma Solid tumor (other than breast or prostate cancer) or multiple myeloma D b120 SC M/F, 18 years of age R At least 1 bone metastasis or osteolytic lesion ECOG 0, 1, or 2 Adequate organ function N = 1,776 Primary endpoint: Time to first SRE on study (non-inferiority) Denosumab 120 mg SC + placebo IV infusion q 4 wk (n = 886) Zoledronic acid 4 mg IV + placebo SC injection q 4 wk (n = 890) Event driven study: time to first and subsequent SREs Secondary endpoints: Time to first SRE on study (superiority), time to first and subsequent SREs on study (superiority), changes in laboratory values, safety, incidence of formation of antidenosumab antibodies Data from Henry D, et al. Presented at: 15th ECCO-34th ESMO Congress, Abstract 20LBA. 22

12 Denosumab vs ZOL in Solid Tumors and Multiple Myeloma Endpoint: Time to First On-Study SRE ent Proportion of patients without skeletal-related eve Patients at risk Zoledronic acid Denosumab KM estimate of median months Denosumab 20.6 Zoledronic acid Study month Primary: HR = 0.84 (95% CI = 0.71, 0.98) P =.0007 (non-inferiority) Secondary: Unadjusted P =.03 (superiority) a Adjusted P = a Due to multiplicity adjustment. Adapted from Henry D, et al. Presented at: 15th ECCO-34th ESMO Congress, Abstract 20LBA. 23 Summary of Efficacy Outcomes: Denosumab vs ZOL in Patients With Bone Metastases From Solid Tumours & MM P value Non-inferiority in time to 1 st SRE.0007 Time to 1 st and subsequent SREs.14 Overall survival Relative risk of SRE In favor of Dmab In favor of ZOL Data from Data from Henry D, et al. Presented at: 15th ECCO-34th ESMO Congress, Abstract 20LBA. 24

13 Dmab vs ZOL: Efficacy Overview Breast cancer 1,2 OST and MM 2,3 Prostate cancer 2,4 Dmab ZOL Dmab ZOL Dmab ZOL N 1,026 1, Pts with on-study SRE, % SRE breakdown, % RT Path Fx Surgery SCC Median time to SRE, mo NR HR P (non-inf.) P (superior.) 0.82 < < < Abbreviations: Dmab, denosumab; HR, hazard ratio; Path Fx, pathologic fracture; RT, radiotherapy; SCC, spinal cord compression; SRE, skeletal-related event; ZOL, zoledronic acid. 1. Stopeck AT, et al. JCO. 2010;28(35): ; 2. Xgeva (denosumab) injection, for subcutaneous use [package insert]. Thousand Oaks, CA. Amgen Inc. 2010; 3. Henry D, et al. ECCO-ESMO 2009, abstract 20LBA; 4. Fizazi K, et al. ASCO 2010, abstract LBA Overall survival improvement in patients with lung cancer treated with denosumab versus zoledronic acid: results from a randomised Phase 3 study 1 University of Turino, Orbassano, Italy; 2 McGill University Health Centre, Montreal, Canada; 3 Ospedale Niguarda Ca Granda, Milan, Italy; 4 Joan Karnell Cancer Center, Philadelphia, PA, USA; 5 Weston Park Hospital, University of Sheffield, Sheffield, UK; 6 Klinikum Mannheim, Mannheim, Germany; 7 Clinique Victor Hugo, Le Mans, France; 8 South Texas Oncology and Hematology, San Antonio, TX, USA; 9 The Maria Sklodowska-Curie Institute G Scagliotti of Oncology, 1, Warsaw, V HirshPoland; 2, S Siena 10 Oncology 3, D Henry Hematology 4, P Woll Associates 5, C Manegold of Northern Illinois, 6, Gurnee, IL, USA; 11 Western Hospital, Footscray, P Solal-Celigny Vic, Australia; 712, Hospital G Rodriguez Clínico San 8, M Carlos, Krzakowski Madrid, Spain; 9, ND 13 Instituto Mehtado 10, Cancer Arnaldo Vieira de Carvalho, Sao Paolo, Brazil; 14 Tata L Lipton Memorial 11 Hospital,, JA García-Sáenz Mumbai, India; 12 15, Institutul J Pereira Oncologic 13, K Prabhash I. Chiricuta, 14 Cluj-Naooca,, Romania; 16 Regional Oncology Dispensary with Inpatient Sector, Plovdiv, Bulgaria; 17 Amgen Inc., Thousand Oaks, CA, USA C Tudor-Eliade 15, V Kanarev 16, A Feng 17, I Jacobs 17

Introduction These are the results from a post hoc analysis on survival among patients with lung cancer, including non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) 1.

14 Introduction These are the results from a post hoc analysis on survival among patients with lung cancer, including non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) 1. Henry D, et al J Clin Oncol 2011;29: ; 2. Henry D, et al. J Clin Oncol 2010; 28:15s(suppl) :abstr Study design: lung cancer subgroup of international, randomised, double-blind, active-controlled, Phase 3 trial, (n=811) Key inclusion Adults with lung cancer and bone metastases Key exclusion Current or prior intravenous bisphosphonate administration 1.1 Denosumab 120 mg SC + Placebo IV* Q4W (n = 411) Calcium (500 mg) and Vitamin D (400 IU) strongly recommended Zoledronic acid 4 mg IV* + Placebo SC Q4W (n = 400) Lung cancer type, n (%) Zoledronic acid Denosumab Total NSCLC 352 (88) 350 (85) 702 (100) Adenocarcinoma 211 (60) 189 (54) 400 (57) Squamous Cell 75 (21) 88 (25) 163 (23) Other 66 (19) 73 (21) 139 (20) SCLC 48 (12) 61 (15) 109 (100) *IV product dose adjusted for baseline creatinine clearance and subsequent dose intervals determined by serum creatinine (per zoledronic acid label)

15 Overall survival: patients with lung cancer(nsclc & SCLC) Propo ortion of patients survived Patients at risk: Zoledronic acid Denosumab HR, 0.80 (95% CI, ) P = 0.01 KM estimate of median, months Denosumab 8.9 Zoledronic acid Study month Overall survival: patients with Non Small Cell Lung Cancer Propo ortion of patients survived Patients at risk: Zoledronic acid Denosumab HR, 0.78 (95% CI, ) P = KM estimate of median, months Denosumab 9.5 Zoledronic acid Study month

16 Overall survival: NSCLC by histological types Adenocarcinoma Squamous cell carcinoma Proportion of patients survived Patients at risk: Zoledronic acid Denosumab HR, 0.80 (95% CI, ) P = KM estimate of median, months Denosumab 9.6 Zoledronic acid Study month Proportion of patients survived Patients at risk: Zoledronic acid Denosumab HR, 0.68 (95% CI, ) P = KM estimate of median, months Denosumab 8.6 Zoledronic acid Study month Overall survival: patients with SCLC Propo ortion of patients survived Patients at risk: Zoledronic acid Denosumab HR, 0.81 (95% CI, ) P = KM estimate of median, months Denosumab 7.6 Zoledronic acid Study month

17 Adverse events among patients with lung cancer Event, n (%) Zoledronic acid Denosumab (n = 395) (n = 406) All AEs 377 (95.4) 393 (96.8) Serious AEs 288 (72.9) 268 (66.0) Fatal AEs 189 (47.8) 183 (45.1) AEs of interest Hypocalcaemia 15 (3.8) 35 (8.6) ONJ 3 (0.8) 3 (0.7) Hypotheses for longer survival observed with denosumab treatment in patients with lung cancer Indirect effect on tumour cells: Reduction in NSCLC tumour growth in skeleton through modulation of bone microenvironment is observed in a mouse model with RANK Ligand inhibition 1 Direct effect on tumour cells: RANK and RANK Ligand are expressed in the tumour epithelium of primary human NSCLC samples Among 16 samples with adenocarcinoma histotype: 56% expressed RANK, 75% expressed RANK Ligand, and 37% both Among 26 samples with squamous cell carcinoma histotype: 34% expressed RANK, 19% expressed RANK Ligand, and 8% both Adenocarcinoma Squamous cell carcinoma RANK RANK Ligand RANK RANK Ligand 1. Miller R, et al Poster presented at 14th World Conference on Lung Cancer; July 3 7, Amsterdam.

Uncommon AEs: ONJ Uncommon condition in cancer patients receiving complex treatment regimens

Abbreviation: AE, adverse event; BC, breast cancer; BP, bisphosphonate; CRPC, castrate

jaw; OST, other solid tumors (not breast or prostate cancer); ZOL, zoledronic acid. 1.

Stopeck A, et al. JCO. 2010;28(35):5132 5139; 4. Henry D, et al.

Lipton A, et al. ESMO 2010, abstract 1249.

BPs (N = 966) 1 A retrospective study in cancer patients receiving BPs (N = 128) 2 90% P =.

048 n = 38 n = 90 Abbreviations: BP, bisphosphonate; ONJ, osteonecrosis of the jaw; PAM,

18 Uncommon AEs: ONJ Uncommon condition in cancer patients receiving complex treatment regimens such as BPs, Dmab, sunitinib, and bevacizumab 1 5 Similar ONJ rates with Dmab vs ZOL Abbreviation: AE, adverse event; BC, breast cancer; BP, bisphosphonate; CRPC, castrate resistant prostate cancer; Dmab, denosumab; MM, multiple myeloma; ONJ, osteonecrosis of the jaw; OST, other solid tumors (not breast or prostate cancer); ZOL, zoledronic acid. 1. Hoff AO, et al. JBMR 2008;23(6): ; 2. McArthur HL, et al. ASCO 2008, abstract 9588; 3. Stopeck A, et al. JCO. 2010;28(35): ; 4. Henry D, et al. ECCO ESMO 2009, abstract 20LBA; 5. Fizazi K, et al. ASCO 2010, abstract LBA4507; 6. Lipton A, et al. ESMO 2010, abstract Preventive Measures Can ONJ Incidence A retrospective study in cancer patients receiving BPs (N = 966) 1 A retrospective study in cancer patients receiving BPs (N = 128) 2 90% P = % P =.025 P =.03 80% P =.048 n = 38 n = 90 Abbreviations: BP, bisphosphonate; ONJ, osteonecrosis of the jaw; PAM, pamidronate; PRE, pre implementation of preventive measures; POST, post implementation of preventive measures; ZOL, zoledronic acid. 1. Ripamonti CI, et al. Ann Oncol. 2009;20(1): ; 2. Data from Dimopoulos MA, et al. Ann Oncol. 2009;20(1):

19 Summary In this exploratory analysis of a large subgroup of patients with NSCLC or SCLC and bone metastases, denosumab treatment is associated with significantly improved overall survival versus zoledronic acid Preclinical investigation underway to evaluate if RANK Ligand inhibition has indirect (via osteoclast inhibition) and/or direct anti-tumour effects on lung cancer cells (eg apoptosis, inhibition of cancer migration/invasion) These findings warrant further clinical investigation Denosumab provides meaningful additional benefit over current standard of care SREs pe er patient per ye ear Incidence of SREs 1 Incidence of SREs Placebo 43% 0.63 Zoledronic acid Zoledronic acid 22% 0.45 Denosumab 1. Kohno N et al. J Clin Oncol 2005;23: Stopeck AT et al. J Clin Oncol 2010;28:

Lung cancer, characterized as non small-cell lung cancer

Lung cancer, characterized as non small-cell lung cancer ORIGINAL ARTICLE Overall Survival Improvement in Patients with Lung Cancer and Bone Metastases Treated with Denosumab Versus Zoledronic Acid Subgroup Analysis from a Randomized Phase 3 Study Giorgio Vittorio