1 / 58

Bone and Lung Cancer

Bone and Lung Cancer. Dr Peter Harper Leaders in Oncology Care London. WHAT UNITES TORINO AND LIVERPOOL?. WHAT UNITES TORINO AND LIVERPOOL?. Prof Giorgio Vittorio Scagliotti & Prof Pieter Edsge Postmus. WHAT UNITES TORINO AND MANCHESTER?. TORINO

helenee
Download Presentation

Bone and Lung Cancer

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Bone and Lung Cancer Dr Peter Harper Leaders in Oncology Care London

  2. WHAT UNITES TORINO AND LIVERPOOL?

  3. WHAT UNITES TORINO AND LIVERPOOL? Prof Giorgio Vittorio Scagliotti & Prof Pieter Edsge Postmus

  4. WHAT UNITES TORINO AND MANCHESTER?

  5. TORINO 4th MAY 1949 The Superga air disaster occurred on 4 May 1949 when the Fiat G.212 of Avio Linee Italiane (Italian Airlines),carrying the Entire Torino football team crashed into the retaining wall at the back of the Basilica of Superga, which stands on the hill of Turin. 31 people died in the crash.

  6. After refuelling at Barcelona, the plane carrying the team flew into a thunderstorm on the approach to Turin and encountered conditions of low cloud and poor visibility. They were forced to descend to be able to fly visually.. The emotional impact of the crash on Italian sports fans was profound, as it claimed the lives of the players of a team which had won five successive Serie A titles, tying the all-time record, and seriously weakened the Italian national team, which had included up to 10 Torino players. Torino itself would not claim another title until 1976.

  7. Manchester United February 6th 1958 On that day in 1958, the darkest day in United's history, 23 people - including eight players and three members of the club's staff - suffered fatal injuries in the Munich air crash. Flying back from a European Cup tie against Red Star Belgrade, the team plane stopped in Germany to refuel. The first two attempts to take off from Munich airport were aborted; following a third attempt, the plane crashed. Twenty-one of the people on board died instantly. Aeroplane captain Kenneth Rayment died a few weeks later from the injuries he sustained while Duncan Edwards - one of the eight victims from the team - passed away 15 days after the crash. The tragedy is an indelible part of United's history, as is Sir Matt Busby overcoming his injuries to build another great team which won the European Cup 10 years later.

  8. Bone Metastases Have Debilitating Consequences‘Skeletal Related Events’ (SREs) Consequences Skeletal-related events Disease Loss of autonomy Fracture Radiation to bone Significant morbidity Bone mets Spinal cord compression Bone pain Hypercalcemia Increased healthcare costs and resources Surgery to bone Kinnane N. Eur J Oncol Nurs. 2007;11(suppl):S28-S31.

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

  10. Bone Remodeling Osteoclast Osteoblasts

  11. Phases of Bone “Metastasis” B) Tumour cell proliferation and bone metastasis progression A) Tumour cell colonisation of bone Tumour cells home to the HSC niche Environmental signals maintain tumour cell quiescence Re-circulation to other metastatic sites Escape from quiescence Tumour cell proliferation HSC Stimulation of bone resorption HSC niche Tumour cell Osteoblast Hematopoietic stem cell (HSC) Osteoclast Development of bone lesions

  12. Phases of Bone “Metastasis” B) Tumour cell proliferation and bone metastasis progression A) Tumour cell colonisation of bone Tumour cells home to the HSC niche Environmental signals maintain tumour cell quiescence Onward Dissemination Escape from quiescence Tumour cell proliferation HSC Stimulation of bone resorption HSC niche Tumour cell Osteoblast Hematopoietic stem cell (HSC) Osteoclast Development of bone lesions

  13. LPA Molecular Mechanisms Associated With the Formation of OSTEOLYTIC Lesions Bone marrow Tumor cell SMAD COX2 Ca2+ DKK-1 Noggin IGF PTHrP, IL-6, IL-8, IL-11, PGE2, CTGF, MG-CSF TGF RANK RANKL Osteoclast Osteolytic lesion Osteoblast Bone Clézardin P. Rev Rhum. 2008;75(4):327-331.

  14. Bone `marrow Tumor Cell Ca2+ IGF PTHrP ET-1 ET-1, VEGF, BMP-6, Wnt, … BMP PSA PTHrP(1-23) OPG OPG RANKL RANKL Osteoclast Osteoblast Bone Molecular Mechanisms Associated With the Formation of OSTEOBLASTIC Lesions Osteoblastic lesion LPA Clézardin P. Rev Rhum. 2008;75(4):327-331.

  15. Clinical Priorities Across the Spectrum of Bone Disease Prevention of Treatment Induced Bone Loss MetastasisPrevention Prevention of Skeletal Morbidity

  16. Clinical Priorities Across the Spectrum of Bone Disease Prevention of Treatment Induced Bone Loss MetastasisPrevention (ie ‘do something’) Prevention of Skeletal Morbidity (ie ‘do something’)

  17. Approved bone-targeted agents in the oncology setting Bisphosphonates14 Zoledronic acid Clodronate PamidronateIbandronate Radiopharmaceuticals69 Radium-223† Strontium-89‡ Samarium-153 RANK Ligandinhibitor5 Denosumab 1. Zometa SmPC, Novartis; 2. Bonefos SmPC, Bayer; 3. Aredia SmPC, Novartis;4. Bondronat SmPC, Roche; 5. XGEVA SmPC, Amgen; 6. Xofigo PI, Bayer and Algeta;7. Metastron PI, GE Healthcare; 8. Quadramet SmPC, CIS Bio International;9. Quadramet PI, EUSA Pharma. †Positive CHMP opinion for CRPC with symptomatic bone metastases;‡Not approved in EU.

  18. Bisphosphonates • High affinity for bone1 • Rapidly absorbed ontobone surface1 • Induce apoptosis of activated osteoclasts1 • Long half-life in bone(110 years)2 • Excreted unchanged bythe kidneys2 1. Green JR. Oncologist 2004;9(Suppl 4):3–13; 2. Lin JH. Bone 1996;18:7585.

  19. RANK Ligand • Member of the tumour necrosis factor (TNF) cytokine family1 • Binds to receptor RANK1 • Key factor forosteoclast differentiation and activation1 • Physiological rolesalso observed beyondthe bone211 1. Lacey DL, et al. Nat Rev Drug Discov 2012;11:40119; 2. Kong YY, et al. Nature 1999;397:31523;3. Dougall WC, et al. Genes Dev 1999;13:241224; 4. Rossi SW, et al. J Exp Med 2007;204:126772;5. Hanada R, et al. Nature 2009;462:5059; 6. Fata JE, et al. Nature 2000;103:4150;7. Ock S, et al. Cardiovasc Res 2012;94:10514; 8. Schramek D, et al. Nature 2010;468:98102;9. Gonzáles-Suárez E, et al. Nature 2010;468:1037; 10. Chen G, et al. Cancer 2006;107:28998;11. Brown JM, et al. Urology 2001;57:611–6. RANK, receptor activator of nuclear factor kappa-B.

  20. Metastatic Bone Disease Is Common Incidence of bone metastases in advanced cancers2 Proportion developing metastases 5-year world prevalence,thousands1 Median survival, months2-3 Renal 586 20 - 25 12 60% 20% 14 - 45 Melanoma 643 6 40% 1,100 Bladder 15 40 10% Thyroid 475 48 60 90% 6 - 7 Lung 1,362 30 - 40 Breast 65 - 75 19 - 25 4,406 40% 65 - 75 35% Prostate 2,369 12 - 53 1. Ferlay J et al. GLOBOCAN 2002: 2. Coleman RE. Cancer Treat Rev. 2001;27:165-176 3. Coleman RE. Cancer. 1997;80:1588-1594

  21. Frequency of Skeletal Morbidity (SREs) in Advanced Cancer with Bone metastases Data are from the placebo arms of 3 major trialsof placebovs. IV bisphosphonate in different tumour types Mean number of SREsper patient per year Percentage of patients developing SREs Percentage of patients Mean number of SREs/patient/year Breast1 Prostate2 Lung and other solid tumours3 Breast1(24 months fup) Prostate2(24 months fup) Lung and other solid tumours3(21 months fup) 1. Lipton A, et al. Cancer 2000;88:108290;2. Saad F, et al. J Natl Cancer Inst 2004;96:87982;3. Rosen LS, et al. Cancer 2004;100:261321.

  22. ZOL in Patients With Bone Metastases From NSCLC and Other Solid Tumors R A N DO M I Z E D n = 257 Zoledronic acid 4 mg q 3 weeks + Daily oral vitamin D 400 IU and calcium 500 mg n = 266 8-mg dose reduced to 4 mg for renal safety n = 250 Placebo q 3 weeks + Daily oral vitamin D 400 IU and calcium 500 mg 0 9 monthsCore analysis 21 months Final analysis • Stratification based on non-small cell lung cancer (NSCLC) versus other solid tumors Rosen LS, et al. Cancer. 2004;100(12):2613-2621.

  23. Tumour Types Enrolled: Randomized, Placebo-Controlled Trial of ZOL in Patients With Solid Tumours Rosen LS, et al. Cancer. 2004;100(12):2613-2621.

  24. Disease Progression and Survival in the Overall Trial Population Rosen LS, et al. Cancer. 2004;100(12):2613-2621.

  25. Bone Metastases are all bone metastases the same????

  26. Bone Resorption Rates Prior to Bisphosphonate Treatment as reflected in NTX excretion (nmol/mmol creatinine) % 40% 30% 30% NTX excretion (nmol/mmol creatinine) Coleman et al – J Clin Oncol 2005

  27. Elevated NTX Levels (high levels of bone turnover)Are Associated With an Increased Risk of ‘BAD’ Clinical Outcomes [from the control arm of the trial] NSCLC/OST(NTX ≥ 100 versus NTX < 100 nmol/mmol creatinine) P value 1.79 .010 SREs 1.91 .011 Diseaseprogression 2.67 <.001 Death 4 0 1 2 3 NTX < 100 NTX ≥ 100 Relative risk NTX= n-telopeptide

  28. Zoledronic Acid Normalized NTX Levels in a Majority of Patients With Elevated Baseline NTX 90 Normalized 3-month NTX (E-N) 80 Remain Elevated 3-month NTX (E-E) 70 60 50 Patients, % 40 30 20 10 (n =) 70 11 38 8 0 NSCLC/OST NSCLC Abbreviations: NSCLC, non-small cell lung cancer; NTX, N-telopeptide of type l collagen; OST, other solid tumors. Hirsh V. Presented at: 12th World Conference on Lung Cancer; September 2-6, 2007; Seoul, Korea. Abstract D5-07.

  29. Risk reduction, % P value Relative risk Reduced risk for E to N Reduced risk for E to E Normalization of NTX Levels With ZOL Improved Survival NSCLC/OST (n = 87) 0.39 Bone progression-freesurvival 61 .023 0.43 57 .012 Death NSCLC (n = 49) 0.48 Bone progression-freesurvival 52 .174 0.54 46 .142 Death 0 0.5 1.0 1.5 2.0 Abbreviations: NSCLC, non-small cell lung cancer; NTX, N-telopeptide of type I collagen; OST, other solid tumors; ZOL, zoledronic acid. Comparison is throughout the study for patients with elevated baseline NTX that normalized within 3 months of zoledronic acid (E-N group) versus patients whose NTX levels remained elevated at 3 months (E-E group). Hirsh V. Presented at: 12th World Conference on Lung Cancer; September 2-6, 2007; Seoul, Korea. Abstract D5-07.

  30. Survival in Patients With NSCLC and Normal Baseline NTX Normal NTX 100 Zoledronic acid (81 at risk, 68 died) Placebo (37 at risk, 26 died) 80 RR = 1.33 CI = (0.84, 2.09) P = 0.223 60 Proportion alive, % 40 20 0 0 3 6 9 12 15 18 21 Time since randomization, months Abbreviations: CI, confidence interval; NSCLC, non-small cell lung cancer; NTX = N-telopeptide of type I collagen; RR = Relative risk. Adapted from Hirsh V, et al. J Thorac Oncol. 2008;3(3):228-236.

  31. Survival in Patients With NSCLC and High Baseline NTX (> 64 nmol/mmol Cr) Who Received ZOL or Placebo Elevated NTX (> 64 nmol/mmol Cr) 100 Zoledronic acid (102 at risk, 91 died) Placebo (42 at risk, 41 died) 80 RR = 0.65 CI = 0.45 - 0.95 60 P = .025 Proportion alive, % 40 20 0 0 3 6 9 12 15 18 21 Time since randomization, months Abbreviations: CI, confidence interval; Cr, creatinine; NSCLC, non-small cell lung cancer; NTX, N-telopeptide of type I collagen; RR, relative risk. Adapted from Hirsh V, et al. J Thorac Oncol. 2008;3(3):228-236.

  32. Kaplan-Meier Estimates of Survival by 3-Month NTX Status NSCLC and OST 100 80 E-E E-N 60 Proportion deceased, % patients 40 P = .0116 20 0 3 6 9 12 15 18 21 Time on study, months (starting at month 3) Abbreviations: E-E = Patients whose NTX levels remained elevated at 3 months; E-N = Patients whose NTX levels normalized at 3 months from elevated baseline levels; NSCLC = Non-small cell lung cancer; NTX = N-telopeptide of type I collagen; OST = Other solid tumors. Hirsh V. Presented at: 12th World Conference on Lung Cancer; September 2-6, 2007; Seoul, Korea. Abstract D5-07.

  33. ZOL Significantly  Survival in NSCLC Patients With High Baseline NTX in a Multivariate Analysis P value 0.565 ZOL vs placebo .0047 43%  risk of death Other significant variables 0.569 No narcotics use .016 0.515 . 019 Excellent/good ECOG 0.977 .011 Lymphocytes (per % ) 0.2 0.4 0.6 0.8 1.0 1.2 Risk ratio Increased risk of death Reduced risk of death for variable Abbreviations: ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small cell lung cancer; ZOL, zoledronic acid. Hirsh V, et al. J Thoracic Oncol. 2008:3(3):228-236.

  34. Potential Survival Benefits With Zoledronic Acid in Metastatic Bone Disease; META-ANALYSIS Coleman et al. J Bone Oncology 2013 : 2, 70-76. QUESTION was; ‘Is survival improved by bisphosphonates in patients with a high rate of bone turnover?’

  35. Potential Survival Benefits With Zoledronic Acid in Metastatic Bone Disease; META-ANALYSIS Coleman et al. J Bone Oncology 2013 : 2, 70-76. QUESTION was; ‘Is survival improved by bisphosphonates in patients with a high rate of bone turnover?’ Independent individual patient level meta-analysis of placebo controlled trials of zoledronic acid 1642 patients • Prostate cancer – 643 patients • Breast cancer – 227 patients • Lung and other solid tumours – 772 patients • Overall survival RR, 0.939; 95% CI, 0.828 to 1.064,

  36. Survival Benefits With Zoledronic Acid Seen in Patients With Increased Bone Resorption (n = 703 - 62%) (n = 423 - 38%) Coleman et al. J Bone Oncology 2013:2, 70-76.

  37. RANK Ligand • Member of the tumour necrosis factor (TNF) cytokine family1 • Binds to receptor RANK1 • Key factor forosteoclast differentiation and activation1 • Physiological rolesalso observed beyondthe bone211 1. Lacey DL, et al. Nat Rev Drug Discov 2012;11:40119; 2. Kong YY, et al. Nature 1999;397:31523;3. Dougall WC, et al. Genes Dev 1999;13:241224; 4. Rossi SW, et al. J Exp Med 2007;204:126772;5. Hanada R, et al. Nature 2009;462:5059; 6. Fata JE, et al. Nature 2000;103:4150;7. Ock S, et al. Cardiovasc Res 2012;94:10514; 8. Schramek D, et al. Nature 2010;468:98102;9. Gonzáles-Suárez E, et al. Nature 2010;468:1037; 10. Chen G, et al. Cancer 2006;107:28998;11. Brown JM, et al. Urology 2001;57:611–6. RANK, receptor activator of nuclear factor kappa-B.

  38. Three Identical Randomized Trials ;Zoledronic Acid vs Denosumab ; (each ‘arm’Placebo Controlled) • Adults with breast, prostate, or other solid tumors and bone metastases, or multiple myeloma • No current or previous IV bisphosphonate administration for treatment of bone metastases • (N = 5723) Denosumab 120 mg SC + Placebo IV* q4w (n = 2862) Supplemental calcium and vitamin D recommended Zoledronic Acid4 mg IV* + PlaceboSCq4w (n = 2861) *Per protocol and zoledronic acid label, IV product dose adjusted for baseline creatinine. Lipton A, et al. ESMO 2010. Abstract 1249P.

  39. Primary Endpoint: Time to First On-Study SRE n=5,723pts 17% 1.0 0.8 0.6 0.4 0.2 0 HR 0.83 (95% CI: 0.76, 0.90)P<0.001 (Superiority) Risk Reduction Proportionwithout SRE • 0 6 12 18 24 30 Month Patients at Risk: Denosumab 2862 1666 1077 570 197 22 Zoledronic Acid 2861 1596 991 522 178 26 Lipton A, Fizazi K, Stopeck A, et al. Eur J Cancer 2012; http://dx.doi.org/10.1016/j.ejca.2012.08.002.

  40. Risk of First On-study SRE by Solid Tumor Type Risk Reduction, % P Value(Superiority) HR (95% CI) Integrated Analysis 0.82 (0.75-0.89) 18 < .0001 Tumor Type Breast 0.82 (0.71-0.95) 18 .0101 Prostate 0.82 (0.71-0.95) 18 .0085 Lung and other Solid tumors 0.81 (0.68-0.96) 19% .0168 0 0.6 1.0 1.4 2.0 HR FavorsDenosumab FavorsZoledronic Acid Richardson G, et al. Clinical Oncological Society of Australia Annual Meeting 2011. Abstract 296.

  41. Denosumab Trial Results: Effects on First and Subsequent SREs Time to first and subsequent SREs (n = 5723) 1.6 RR = 0.82 (95% CI, 0.75–0.89) P < 0.001 (superiority) 1.4 18% Risk Reduction 1.2 1.0 Cumulative mean numberof SREs per patient 0.8 0.6 0.4 Total SREs: Denosumab: 1360 0.2 Zoledronic acid: 1628 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 Study month Lipton A et al. Poster presented at ESMO 35; Milan, Italy; 8–12 October, 2010 [Abstract 1249P]. Events occurring at least 21 days apart (multiple event analysis) RR, rate ratio

  42. QoL: FACT-G Mean Change From Baseline 1 0 From Baseline Mean Change in FACT-G Score -1 -2 Denosumab Zoledronic acid -3 1 3 6 9 12 15 18 Mos Pts at risk, n Denosumab 913 878 787 709 640 575 460 Zoledronic acid 890 845 768 700 640 592 467 Health-related QoL higher with denosumab than zoledronic acid throughout study Fallowfield L, et al. ASCO 2010. Abstract 1025.

  43. Denosumab Trials: Safety Results 572 (20.2%) 246 (8.7%) 141 (5.0) 273 (9.6) Lipton A et al. Poster presented at ESMO 35; Milan, Italy; 8–12 October, 2010 [Abstract 1249P].

  44. Denosumab Phase III Bone Metastasis Programme - ONJ Summary 6 Zoledronic acid (n = 2836) Denosumab (n = 2814) 4 P = 0.13* Proportion of patients (%) 1.8 1.8 2 1.3 1.0 0.8 0.5 0 Year 1 Year 2 Year 3* Prostate Breast Other solid tumours & MM Brown J et al. Presented at CIBD, 2010 [Abstract OC-15]. Proportions are % of all patients treated with zoledronic acid or denosumab

  45. Phase III Denosumab SRE Prevention Trial in Solid Tumours/MM: Exploratory Endpoint Overall Survival 1.00 HR = 0.95 (95% CI, 0.83–1.08) P= 0.43 0.75 0.50 Overall survival (proportion) 0.25 Denosumab Zoledronic acid 0.00 27 0 3 6 9 12 15 18 21 24 Study month Subjects at risk: Zoledronic acid 890 727 540 410 343 232 176 118 64 26 Denosumab 886 726 557 420 340 247 181 127 66 15 Henry DH, et al. J Clin Oncol 2011;29:1125−32.

  46. Post-hoc Analysis in Lung Cancer Subgroup of Study 244 Scagliotti GV, et al. J Thorac Oncol 2012;7:18239. Denosumab 120 mg SC Q4W +Placebo IV* Q4W Key inclusion Adults with lung cancer and bone metastases Key exclusion Current or prior IV bisphosphonate administration 1:1 Calcium and Vitamin D Supplementation Zoledronic acid 4 mg IV* Q4W + Placebo SC Q4W

  47. Post-hocAnalysis  Overall Survival:Denosumab vs Zoledronic Acid in NSCLC 1.0 KM estimate of median, months Denosumab 9.5 Zoledronic acid 8.0 0.8 0.6 Proportion of patients surviving 0.4 0.2 HR = 0.78 (95% CI, 0.65–0.94) P= 0.0104 0.0 0 3 6 9 12 15 18 21 Study month Patients at risk: Zoledronic acid Denosumab 352 350 275 278 185 203 123 148 91 110 40 66 23 39 12 24 Scagliotti GV, et al. J Thorac Oncol 2012;7:18239.

  48. What is the Mechanism of the Observed Survival Benefit in the Denosumab Lung Cancer Subgroup? Mechanism currently unknown Possible explanations: Direct or indirect anticancer effect of denosumab NFkB modulation through RANK in cancer cells Impact on micro-environment? Secondary consequence of SRE reduction Spurious result

  49. A Randomised Phase III Trial Evaluating the Addition of Denosumab to Standard First-line Anticancer Treatment in Advanced NSCLC SPLENDOUR • Sponsor: European Thoracic Oncology Platform (ETOP) • Trial Coordinators: • European Organization for Research and Treatment of Cancer (EORTC) • Central European CooperativeOncology Group (CECOG) • Pharma Partner: Amgen • PI: Solange Peters Survival imProvement in Lung cancEr iNduced by DenOsUmab theRapy (SPLENDOUR)

  50. SPLENDOUR Study Design Screening, Eligibility and Enrollment Trial Treatment RANDOMI SE 46 Cycles Chemotherapy q. 3 Weeks + BSC A Stratify: - Bone Mets - Region - ECOG PS - Histology First-line Stage IV NSCLC 46 Cycles Chemotherapy q. 3 Weeks + Denosumab 120 mg q. 3 (4) Weeks s.c. B Sample size: 1000

More Related