Norton L et al. Nature Med 2006

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1 New Bone Targeting Agents Ana Maria Gonzalez-Angulo, M.D. Associate Professor Section Chief, Clinical Research and Drug Development Breast Medical Oncology Systems Biology Padua, Italy 11/2012

2 Outline Bone physiology and bone metastatsis t t The bisphosphonate story Denosumab New agents: Everolimus Cabozantinib Dasatinib Ra-223 Anti-sclerostin mab

3 Self-Seeding Seeding Theory of Metastasis In breast cancer bone is typically the First site of metastases Most common site of metastases Norton L et al. Nature Med 2006

4 What Might Bisphosphonates Do? Directly alter tumor cell behavior Alter the micro-environment by inducing changes Vasculature Immune modulating cells Bone cells/bone matrix Hematopoietic cells

5 Vicious Cycle PTHrP IL-6 IL-8 PGE 2 TNF- CSF-1 BMP PDGF FGFs IGFs TGFβ Roodman et al. N Engl J Med 2004

6 Breaking the Vicious Cycle X Anti-cancer therapy X Adjunctive Bone directed therapy Modified from Roodman. N Engl J Med 2004

7 Bone Metastases & SREs Skeletal Related Events (SREs) Fracture Need for radiation to bone Need for surgery to bone Spinal cord compression Hypercalcemia of malignancy Oncologic Emergency

8 Bone Modifying Agents in Clinical Practice Pivotal Trials in MBC: Endpoint SREs Hortobagyi NEJM 1996 Pamidronate vs Placebo (both + Chemo) Theriault JCO 1999 Pamidronate vs Placebo (both + Endocrine) Rosen Cancer J 2001 Pamidronate vs. Zoledronic acid Kohno JCO 2005 Zoledronic acid vs Placebo Stopeck JCO 2010 Denosumab vs Zoledronic Acid ASCO: Update on the Role of Bone Modifying Agents in Metastatic Breast Cancer Van Poznak, J Clin Oncol 2011

9 Neo-Adjuvant Zoledronic Acid & Disseminated Tumor Cells Baseline At surgery Zoledronic Acid Treated Control Aft et al. Lancet Onc 2010 Solomayer et al. Ann Onc 2012

10 Adjuvant Bisphosphonate p Clinical Trials: Primary Endpoints Bone metastases free survival Diel NEJM 1998: clodronate (+) Sarto JCO 2001: clodronate (-) Powles JCO 2002: clodronate (+) Disease free survival Gnant NEJM 2009: Coleman NEJM 2011: Mobus SABCS 2011: zoledronic acid (+) zoledronic acid (-) ibandronate (-) Paterson Lancet Oncol 2012: clodronate (-) Ongoing adjuvant studies are investigating Bisphosphonates Denosumab

11 ABCSG-12: Disease Free Survival Primary Endpoint Gnant et al. N Engl J Med 2009

12 ABCSG-12: DFS and OS by Age Gnant et al. SABCS 2011

13 Adjuvant Bisphosphonate p Seven studies & 3 bisphosphonates AZURE, ABCSG-12, Z/E-Zo/Z0-FAST, NSABP B-34 34, GAIN Postmenopausal Meta-Analysis Authors acknowledge approximations made due to limited details available Gregory et al. ASCO 2012 Abstract #513

14 BISMARK: Dosing of IV Bisphosphonate by Markers of Bone Turnover Met Breast Cancer to bone R A N D O M I Z E Zoledronic Acid Every 4 weeks Zoledronic Acid Dosed by Markers of Bone Resorption Follow For SREs Planned N= 1500 Study closed early due to poor accrual with N <300 Coleman et al. ASCO 2012

15 BISMARK: untx Directed Therapy Time to First SRE Larger number of SREs in M-Zol 150 vs 109 in S-Zol More patients on M-Zol experienced multiple SREs NTX levels were higher in M-Zol group at all time points Coleman et al. ASCO 2012

16 Study of Dosing Intervals in Prolonged Zoledronic Acid Use: ZOOM Metastatic Breast Cancer to bone 9-12 prior doses of zoledronic acid R A N D O M I Z E Zoledronic Acid Every 4 weeks Zoledronic Acid Every 12 weeks No Statistical tistic Difference in Skeletal Morbidity Rate OPEN LABEL Approx 300 patients Variable Intervals for: Clinical Assessments Imaging Assessments CALGB NCT Optimize-2 NCT Ripamonti et al. ASCO 2012

17 Balancing Bone Mass Osteoclast Bone Resorption Osteoblast Bone Formation RANKL Osteoprotegerin (OPG) Courtesy of Van Poznak 2012

18 Modulation of Osteoclast Differentiation RANKL is important to osteoclast differentiation Suda et al. Endocrine Rev 2003

19 Phase III Denosumab vs Zoledronic Acid Time to 1 st SRE ( 18%) Time to 1 st & Subsequent SREs ( 23%) Overall Survival: No Change Time to Progression: No Change Renal Toxicity: 4.9% (Dmab Dmab) vs 8.5% (ZA) ONJ: 2.0% (Dmab Dmab) vs 1.4% (ZA) Denosumab mean skeletal morbidity rate by 22% compared with ZA (0.45 vs events respectively) Stopeck et al. J Clin Oncol 2010

20 Uniformity Across 3 Parallel Phase III Studies Time to First SRE: Denosumab vs. Zoledronic acid Courtesy of Van Poznak 2012

21 Uniformity Across 3 Parallel Phase III Studies Time to First & Subsequent SREs: Denosumab vs. Zoledronic acid Courtesy of Van Poznak 2012

22 Skeletal Complication Risk: Incremental nt Benefits in Breast Cancer No bisphosphonate 64% 2 yrs Pamidronate ~ 20% risk reduction Zoledronic acid ~ 20% risk reduction Denosumab 18% risk reduction 64% 51% 34% 27% Lipton et al. Cancer 2000 Rosen et al. Cancer J 2003 Stopeck et al. J Clin Oncol 2010

23 Bone Modifying Agents (Osteoclast Inhibitors) in MBD Approved throughout the world for reduction in SREs in patients with Metastatic Bone Disease Denosumab Pamidronate (IV) Zoledronic acid (IV) Clodronate (IV, oral) Ibandronate (IV, oral) Approved in USA & outside of USA for MBD Approved for MBD Outside USA Osteoclast inhibition the risk of SREs ~ 30% Denosumab > zoledronic acid for SRE Zoledronic acid > pamidronate for Hypercalcemia of Malignancy Stopeck et al. J Clin Oncol 2010 and Major et al. J Clin Oncol 2001

24 Uncommon Adverse Events Associated with ih Bisphosphonates: h Etiology Eil Unknown Uk Atypical Fractures Osteonecrosis of the Jaw (ONJ) ONJ has also been seen with Denosumab

25 Bone Metastases Systemic Treatment Considerations Osteoclast inhibitors Other targets Bisphosphonates CXCR4 antagonists Denosumab Anti-CCR2 antibodies Gallium nitrate HDAC inhibitors Calcitonin Α v β 3 integrin inhibitors Src inhibitors TGF-β inhibitors cmet inhibitors Established practice of IVBP: Endothelin A antagonists t When to initiate therapy? mtor inhibitors Optimal dose? SOST/SclerostinSclerostin Optimal schedule? PDGFR inhibitors Duration of therapy? and more.

SRC signaling has a central role in tumor cell and osteoclast function Dasatinib inhibitory SRC

26 Role of SRC Inhibition in Bone Metastases During bone metastasis, systemic factors in the bone environment and bone-derived growth factors activate the release of stimulants of osteoclast activity SRC signaling has a central role in tumor cell and osteoclast function Dasatinib inhibitory SRC activity has a potential role in the prevention/treatment of osteolytic metastases Araujo et al. Cancer Treat Rev 2010

27 Phase II : Randomized Between Dasatinib Dosing MBC to bone R A N D O M I Z E Dasatinib ib 70mg Twice Daily Follow For PFS & Dasatinib correlatives 100mg Daily No concurrent bisphosphate use Accrual met, analysis ongoing

28 TBCRC 010: Dasatinib & Zolendronate in MBC with Predominant Bone disease

29 Role of PI3K Signaling in Osteoclast Survival PI3K inh MEK inh Rapalogs Adapted from Glantschnig et al. Cell Death Differ 2003

30 mtor Inhibition Decreases Bone Resorption and Osteoclast Maturation and Increases Osteoclast Apoptosis in Mice Adapted from Glantschnig et al. Cell Death Differ 2003

$BOLERO-2 Study: Exemestane ± Everolimus in Patients with ABC Progressing After NSAIs N = 724 PMW with HR+ HER2- ABC refractory to LET or ANA, defined as Recurrence during or within 12 months after$

31 BOLERO-2 Study: Exemestane ± Everolimus in Patients with ABC Progressing After NSAIs N = 724 PMW with HR+ HER2- ABC refractory to LET or ANA, defined as Recurrence during or within 12 months after end of adjuvant treatment, or Progression during or within 1 month after end of treatment for advanced disease EVE 10 mg/day + EXE 25 mg/day (n = 485) Placebo + EXE 25 mg/day h h (n = 239) Primary endpoint: PFS Secondary endpoints: OS, ORR, CBR, safety, QoL, bone markers Stratification Sensitivity to prior hormonal therapy Presence of visceral disease No crossover Baselga et al. N Engl J Med. 2012

eline, % from Base Change f 50 40 30 20 10

32 eline, % from Base Change f BOLERO-2: Bone Markers BSAP (18 18-Month Follow-Up Up) 6 weeks 12 weeks Bone Formation 20.9 P1NP Bone Resorption CTX 29.5 Bone Formation BSAP 18.1 Bone Resorption P1NP CTX % 56% 36% 20% 66% 40% EVE + EXE PBO + EXE -40 Gnant M,et al. ASCO 2012

33 BOLERO-2: Disease Progression in Bone (18-Month Follow-Up) 0.5 Overall Population 0.5 Patients with Bone Metastases at Baseline se es e of Diseas e Metastase e Incidence n from Bone Cumulative Progression EVE + EXE (n = 485) 0.4 PBO + EXE (n = 239) P =.0363 (Gray s test) e es of Disease e Metastase e Incidence n from Bone Cumulative Progression EVE + EXE (n = 371) PBO + EXE (n = 185) P =.0165 (Gray s test) Time, weeks Time, weeks Gnant M,et al. ASCO 2012

34 Everolimus Therapy Decreases Bone Loss Associated with Estrogen Deprivation in Models Kneissel et al. Bone 2004

35 Role for MET and VGEF Inhibition in Bone Metastases MET is highly expressed in bone metastases t OB & OC express MET & VEGFR2 and respond to the ligands of HGF & VEGF HGF & VEGF appear to direct cross-talk between tumor cells, OB & OC Courtesy of Schimmoller 2011

36 Phase II Study of Cabozantinib (XL184) in Metastatic Prostate Cancer All patients had a PR and pain control Hussain et al. ASCO 2011

Phase I Cabozantinib (XL-184) Breast Cohort Objective tumor shrinkage in heavily pre- treated patients 2/3 of patients with bone metastasis experieced partial

37 Phase I Cabozantinib (XL-184) Breast Cohort Objective tumor shrinkage in heavily pre- treated patients 2/3 of patients with bone metastasis experieced partial resolution by bone scan Symptomatic pain relief associated with bone scan improvement Phase II in ER+ breast cancer with dominant bone disease Gordon et al. ASCO 2011

38 Radium-223 Alpharadin Radiopharmaceutical Acts as a Calcium mimetic Alpha particles induced DNA double strain breaks in tumor cells Bowel clearance Phase III in prostate cancer (+) overall survival advantage reported but not published Phase II in breast cancer NCT accrued not reported

39 Anti-CCR2 Antibody MLN1202 SWOG 0916 Cifuentes et al. Clin Chimica Acta

40 Anti-Sclerostin mab and TKI Sclerostin has an inhibitory effect on bone formation It prevents the activation of lining cells as well as the inactivation of active osteoblasts Anti-sclerostin antibody for osteoporosis is in Phase III Small molecule l inhibitors hb in development Sclerostin has anabolic effects and is not favored for trials in breast cancer at this time Kamilla et al. Development 2008

41 Conclusions Bisphosphanates still the SOC for patients with bone metastasis Denusumab is an excellent option for the same patient population and preferred for patients with renal disfunction Multiple drugs being developed to target the fisiology of bone disease Exciting data with mtor inhibition and cmet/vegf inhibition Need to do a better work on techniques to measure disease and biomarker development for patient selection and follow up of disease

42 Thank you!!!! Cathy Van Poznak, MD Gabriel N. Hortobagyi, MD Michael Gnant, MD org

Managing Skeletal Metastases

School of Breast Oncology 2012 Managing Skeletal Metastases Cathy Van Poznak, MD Assistant Professor University of Michigan Comprehensive Cancer Center Saturday, November 3, 2012 Learning Objectives: Define