Bisphosphonates in Oncology Michael Naughton, M'D'

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Bisphosphonates in OncologyMichael Naughton,
M.D.
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Incidence of Bone Metastases in Selected Cancers
Bone Metastases ()

• Myeloma 95-100
• Breast 65-75
• Lung 30-40
• Prostate 65-90
• Thyroid 60
• Bladder 40
• Renal 20-25
• Melanoma 14-45

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Complications of Skeletal Metastases

• Pain
• Analgesics,
• constipation, confusion
• Radiation
• Pathologic fracture
• Pain, immobility
• Surgery, radiation, analgesics
• Spinal cord compression
• Hypercalcemia
• Anorexia, confusion, constipation,azotemia

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Pathophysiology of Skeletal Metastases
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Tumor Mediated Bone Invasion
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BisphosphonatesCellular Effects

• Osteoclast inhibition and apoptosis
• Tumor cell apoptosis
• Prevention of breast and prostate cancer cell
  adhesion to bone
• Synergistic effects with anticancer treatments
• Steroids (myeloma)
• Chemotherapy (breast)
• Hormonal therapy (breast)
• Anti-angiogenic activity

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Bisphosphonates

• Inhibit bone resorption
• Major effects on osteoclasts
• Reduction in bone resorbing cytokine production
• Limited bioavailability
• Poor oral tolerance
• Renal clearance
• Concentrated in bone

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Skeletal Metastases

• Observation
• Osteoclast activation is central event in bone
  metastases
• Hypothesis
• Therapies targeted to block osteoclast
  development and function may interfere with
  progression of bone metastases

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Pamidronate and Bone Metastases
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Effect on Survival

• Survival of patients with multiple myeloma
  receiving salvage chemotherapy
• 66 pts. Pamidronate 21 months
• 65 pts. Placebo 14 months (plt.05)

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ASCO Guidelines on Bisphosphonates in Breast
Cancer

• Intravenous Pamidronate every 3-4 weeks for All
  Patients with bone metastases until significant
  decline in Performance Status
• No Treatment for High Risk Patients
• Oral treatment to preserve bone density in women
  with treatment induced menopause

J Clin Oncology 2000 18(6) 1378-1391
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Relative Potency of Bisphosphonates

• Etidronate 1.0
• Clodronate 10
• Pamidronate 100
• Alendronate 1000
• Ibandronate 10,000
• Zoledronate 100,000

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Zoledronate Clinical Development Objectives

• Breast Cancer and Myeloma (007,010)
• Equal or greater efficacy than pamidronate
• Prostate Cancer (039)
• Superiority to placebo
• All other cancers (011)
• Superiority to placebo
• Primary Efficacy Variable
• Proportion of patients experiencing at least
  one SRE other than HCM
• Secondary Efficacy Variables
• Time to first SRE, Time to first pathological
  fracture, Pain, Analgesic use, Safety

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Protocol 007

• Multicenter study 280 patients
• multiple myeloma 108
• breast cancer 172
• Randomized, double blind, dose finding
• Zometa 0.4 mg.
• Zometa 2 mg.
• Zometa 4 mg.
• Pamidronate 90 mg.
• Repeated every 4 weeks for up to 10 months
• Berenson JR,et al. Cancer.911191,April 2001

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Protocol 007

• Patient characteristics
• mean age 56.5 to 59.9
• ECOG PS 2 125 (45)
• previous SRE 81-84
• systemic therapy 42-54
• Berenson JR,et al. Cancer.911191,2001

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007 Proportion of Patients with SREs
During the Trial
30
zoledronic acid 0.4mg
28
zoledronic acid 2 mg
25
24
zoledronic acid 4 mg
22
21
21
21
pamidronate 90mg
20
19
18
15
10
7
7
5
4
3
3
3
3
0
0
Fractures
HCM
Bone surgery
Radiation
Berenson et al, Cancer Vol 91/No.7 April 1, 2001
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Protocol 007

• Parameter Z-0.4mg Z-2mg Z-4mg P-90mg
• pain score -0.3 -0.6 - 0.7
  - 0.1
• analgesics -19 -11 -27 -21
• BMD 6.2 9.0 9.6 9.2
• Berenson JR,et al. Cancer.911191,2001

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Protocol 007

• Toxicity
• Parameter Z-0.4mg Z-2mg Z-4mg P-90mg
• pain 45 55 46 60
• nausea 44 44 39 51
• vomiting 24 26 36 34
• inc.creat(gt0.5) 16 10
• Berenson JR,et al. Cancer.911191,2001

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Protocol 007

• Conclusions
• 0.4 mg dose on Zoledronate was inferior to the 2
  and 4 mg doses and to 90 mg Pamidronate in
  preventing SREs
• 2 and 4 mg doses of Zoledronate as effective as
  90 mg Pamidronate with greater convenience and
  similar toxicity profile
• pain score and analgesic use favor the 4mg dose
• Berenson JR,et al. Cancer.911191,2001

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Protocol 010

• A randomized, double-blind, multicenter trial of
  Zometa 4 mg or 8 mg vs. pamidronate 90 mg in
  myeloma and breast cancer

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Protocol 010

• Patient characteristics
• multicenter 1648 patients enrolled
• multiple myeloma 513
• breast cancer 1130
• Chemotherapy 867
• Hormonal therapy 263
• mean age 58.5 to 60
• ECOG PS gt2 296 (18)
• previous SRE 67
• Rosen LS, et al. Cancer Journal. 7377-387,2001

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Protocol 010

• Randomized, double blind, dose finding
• Zometa 4 mg.
• Zometa 8 mg.
• Pamidronate 90 mg.
• Repeated every 3-4 weeks for 12 months ( 60-63
  completed 12 months)
• closed June 2000
• Rosen LS, et al. Cancer Journal.
  7377-387,2001

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Clinical Trial HistoryBreast Cancer and
Multiple Myeloma (010)
Renal amendment 2 (8-mg ? 4-mg dose)
Renal amendment 1 (5-min ? 15-min infusion)
N1648
815
6/98
12/98
6/99
6/00
12/00
12/99
1/01
Accrual
Treatment and follow-up
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Proportion of Patients with SRE (-HCM) at Month
13 by Stratum and Treatment
p values n.s.
47
49
47
46
44
44
43
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Proportion with SRE
MM Multiple myeloma BCC Breast cancer,
chemotherapy BCH Breast cancer, hormonal therapy
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Time to First Skeletal-related Event (SRE) in
Breast Cancer with Lytic Metastases
Significant delay in time to the first event in
patients with lytic lesions
110
Median Time ZOMETA 4 mg 310 days Pamidronate
90 mg 174 days
100
90
80
70
60
without event
50
40
30
20
P0.013
10
0
0
60
120
180
240
300
360
420
480
540
Time after start of study drug (d)
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Response and Survival (010)

• Zoledronate Pamidronate
• PR 17 18
• Stable 30 28
• Dis. Prog. 136 days 113 days
• Survival not reached 802 days
• pNS

Rosen LS, et al. Cancer Journal. 7377-387,2001
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Renal Function Data

• Patients with renal function deterioration
• Zometa 4mg Aredia 90mg
• 5 infusion 10.2 6.7
• 15 infusion 8.8 8.2
• Rosen LS, et al. Cancer Journal. 7377-387,2001

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Protocol 010 Toxicity

• Parameter Zol-4mg Zol 4/8mg
  Pam-90mg
• pain 55 53 55
• nausea 44 46 44
• vomiting 30 30 30
• fever 36 34 29
• inc.creat (gt.5 or gt2 x baseline)
• nl. (lt1.4) 9 18 8
• abnl. 4 29 9
• Rosen LS, et al. Cancer Journal. 7377-387,2001

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Protocol 010 Conclusions

• Efficacy
• Zometa (4 mg/15 minutes) is clinically effective
• Results meet criteria for statistical
  non-inferiority to pamidronate
• Zometa reduces the complications of bone
  involvement in patients with breast cancer and
  multiple myeloma
• Safety
• Zometa 4 mg (15 minutes) is safe and well
  tolerated with a safety profile comparable to
  pamidronate in this population
• Rosen LS, et al. Cancer Journal. 7377-387,2001

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Protocol 011
A Randomized, Double-blind, Placebo-controlled,
Multicenter Trial to Evaluate the Safety and
Efficacy of Zoledronate (4 and 8 mg) in Patients
with Lytic Bone Metastases from Solid Tumors
Other than Breast or Prostate Cancer
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Protocol 011

• Patient Population
• 507 cancer patients with
• Objective evidence of metastatic disease to bone
  (? 1 lytic skeletal lesion)
• Bone metastases not due to breast cancer or
  prostate cancer
• Rosen L, et al. IASLC. 2001
  (abstract)

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Protocol 011
Tumor type Zometa 4 mg Placebo

• NSCLC 134 (52.1) 130 (52.0)
• Other tumors 123 (47.9) 120 (48.0)
• Total 257 250
• Rosen L, et al. IASLC. 2001 (abstract)

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Protocol 011

• Primary Objective
• To assess the efficacy of zoledronate treatments
  antineoplastic therapy compared to
  antineoplastic therapy alone in preventing
  skeletal-related events.
• Primary Efficacy Variable
• Proportion of patients having at least one
  skeletal-related event.

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Protocol 011

• Secondary Objectives
• Time to first SRE, time to disease progression in
  bone and time to overall disease progression
• Skeletal Morbidity Rate
• Pain scores (BPI)
• Analgesic scores
• Performance status (ECOG)
• Quality of Life (FACT-G )

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Protocol 011

• Secondary Objectives (cont.)
• Objective bone lesion response from radiological
  studies.
• Biochemical variables
• urinary N-telopeptide/creatinine ratio
• urinary pyridinoline/creatinine ratio
• urinary deoxypyridinoline/creatinine ratio
• serum bone alkaline phosphatase

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Protocol 011

• Treatment Groups
• Zoledronate 4 mg in 50 ml normal saline iv every
  3 weeks plus calcium 500 mg and a multivitamin
  (400-500 IU of Vitamin D) tablet PO daily.
• Zoledronate 8 mg in 50 ml normal saline iv every
  3 weeks plus calcium 500 mg and a multivitamin
  (400-500 IU of Vitamin D) tablet PO daily.
• Placebo 50 ml normal saline iv every 3 weeks plus
  calcium 500 mg and a multivitamin (400-500 IU of
  Vitamin D) tablet PO daily.

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Clinical Trial History Solid Tumors Metastatic
to Bone (-PC/BC) (011)
Renal amendment 2 (8 mg ? 4 mg dose)
Renal amendment 1 (5 ? 15 min infusion)
6/98
12/98
6/99
6/00
12/00
12/99
1/01
Accrual
Treatment and follow-up
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Protocol 011

• Zoled. Placebo p.___
• All Patients
• with SRE 38 47 .039
• Patients with OST
• with SRE 33 46 .047
• TT 1st SRE 314d 163d .023
• Rosen L, et al. IASLC. 2001 (abstract)

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Solid Tumors (study 011) Proportion () of
Patients With an SRETime to First SRE
P 0.039 when include hypercalcemia of
malignancy as an SRE
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Protocol 011 Conclusions

• Zometa 4 mg infused over 15 minutes
• Significantly delayed the time to first
• SRE
• Significantly reduced proportion of
  patients with SRE (HCM)
• Significantly delayed the time to first fracture
• Rosen L, et al. IASLC. 2001 (abstract)

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Protocol 011 Conclusions

• Zometa has a similar overall safety profile to
  that of IV pamidronate
• The results support the use of Zometa in the
  treatment of bone metastases in this patient
  population
• Rosen L, et al. IASLC. 2001 (abstract)

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What About Prostate Cancer?
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Pathogenesis of Skeletal Metastases

• Resorption Formation
• Lytic
• Blastic

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Osteoblastic Metastases

• Bone biopsies reveal increased bone resorption
  at
• Tumor infiltrated bone
• Bone adjacent to metastases
• Bone at distant sites

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Skeletal Complications of Metastatic Prostate
Cancer

• Prospective study of 112 men with HRP and
  skeletal metastases
• Annual incidence of skeletal complications was
  12
• Cumulative incidence of skeletal complications
  was 30
• Berutti, J.Urol. 1641248,2000

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Skeletal Complications of Metastatic Prostate
Cancer

• Most common skeletal complications were
• Vertebral body collapse 51
• Pathologic fracture 26
• Spinal cord compression 18
• Berutti, J.Urol. 1641248,2000

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Rationale for Bisphosphonates in CaP

• Bone resorption is increased in osteoblastic
  metastases
• Bone resorption contributes to skeletal morbidity
• Androgen deprivation further increases bone
  resorption

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Bisphosphanates in Metastatic Prostate Cancer

• Etidronate
• No effect on pain
• Clodranate
• Minimal effect on pain
• No effect on skeletal progression
• Pamidronate
• Minimal effect on pain
• No effect on SREs
• Prevents osteopenia secondary to androgen
  deprivation

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Trial Design International, Multicenter,
Randomized, Double-blind,Parallel, ?18
years/Ambulatory

• Eligibility Criteria
• Prostate carcinoma with documented history of
  bone metastases
• 15-month observation period
• Appropriate antineoplastic therapy at entry into
  trial
• Serum creatinine ?3.0 mg/dL (265 ?mol/L)
• ECOG performance 0,1,2
• Serum testosterone at baseline below the castrate
  range(50 ng/dL)

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• Primary Efficacy Variables
• Skeletal-Related Events
• Secondary Efficacy Variables
• Pain relief
• Time to first SRE
• Time to first pathological fracture
• Primary Safety Variables
• Safety profile
• Survival

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Protocol 039 SRE Prevention Study in Hormone
Refractory P.C.

• Bone metastases with progressive disease after
  ADT (n639)
• randomize
• std.care std.care
• Zometa (24 mo.) placebo

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Protocol 039 Study Design

• Original study design
• Zometa (8 and 4 mg) as 5-minute infusion
• Amendment 1 ( June 1999)
• Infusion time increased to 15 minutes
• Infusion volume increased to 100 ml.
• Amendment 2 (June 2000)
• Zometa dose reduced from 8 mg. to 4 mg.
• Serum creatinine monitoring implemented

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Protocol 039 Results

• 442 evaluable patients
• Zometa 4mg v. placebo (24mo)
• SRE _at_15 mo 33 v. 44 (p0.02)
• median time to SRE not reached v. 321d
• Consistent reduction in analgesic score compared
  to placebo

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Primary Endpoint Proportion of Patients with
SRE(-HCM)
p 0.069 p .152 p .021
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45
42
Proportion with SRE
35
34
33
No mets Mets Total
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Kaplan-Meier EstimatesTime to First SRE (-HCM)
by Treatment Total
110 100 90 80 70 60 50 40 30 20 10 0
Zometa 4 mg N.R. Placebo Median Time 321 days
without the event
p 0.011
0 50 100 150 200 250 300 350 400 450 500 550
Time after the Start of Study Drug (Days)
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ZOMETA analgesic scores
P .030
P .003
Higher score means more pain
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Protocol 039Conclusions

• Zometa 4 mg. via 15-minute infusion
• Decreases SREs in men with HRPC and osteoblastic
  bone metastases
• Delays time to first SREs
• No significant effects on bone lesion response or
  overall disease progression
• Safety profile is similar to other intravenous
  bisphosphanates

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Conclusions

• Zometa significantly delayed the first SRE
  (Proportions, SMR, and Time to first SRE)
• Significantly delayed the first fracture
  (Proportion,SMR and Time to first fracture)
• No significant effects were noted for bone
  lesions response, bone lesion progression and
  overall disease progression
• Similar overall safety profile to that of other
  intravenous bisphosphonates

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FDA Approval Feb. 25,2002

• for the treatment of patients with multiple
  myeloma and patients with documented bone
  metastases from solid tumors in conjunction with
  standard antineoplastic therapy. Prostate cancer
  should have progressed after treatment with at
  least one hormonal therapy.

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Adjuvant Bisphophonate Studies Prostate Cancer

• NCIC HRPC Randomized Phase III
• Novantrone/Pred /- IV clodronate
• NCI HRPC Phase II
• Ketoconazole /- alendronate
• Novartis Asymptomatic bone mets
• Zoledronate v placebo (accrual completed)
• Novartis Asymptomatic D0
• Zoledronate v placebo ( accrual on hold)

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ADT Decreases BMD
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ZOMETA 705Lumbar Spine BMD
Zoledronic acid
Placebo
9
6.68
5.27
6
3.65
3
LS Mean percent change from baseline
-2.03
-2.37
-1.93
0
-3
GnRH Antiandrogen
GnRH
All
-6
plt0.001 for difference from placebo
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Can Bisphosphonates Prevent Skeletal Metastases?
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Skeletal Metastases

• Observation
• Osteoclast activation is central event in bone
  metastases
• Hypothesis
• Therapies targeted to block osteoclast
  development and function may interfere with bone
  metastases

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Reduction in New Metastases in Breast Cancer with
Adjuvant Clodronate

• 302 primary Breast cancer patients with tumor
  cells detected in bone marrow
• Randomized 1600mg daily oral clodronate for 2
  years versus standard follow up
• Median observation time was 3 yrs

Diel et al. NEJM, 1998339(6)357-63
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Adjuvant Clodronate in Node Positive Breast Cancer

• 299 women studied 1990-1993, F/U gt5yrs
• Rx Clodronate 1600mg/d for 3 yrs v. plac.
• premen.--CMF postmen.--Tamoxifen
• Results Clodronate Placebo p
• bone mets 26 18 -
• visc. mets 45 27
• survival 68 81
• Saarto T, et al. ASCO, 1999 489

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Trials of Adjuvant Clodronate

• Author pts. Duration Placebo Skel.Mets.
  Non Skel. Mets. Surv.
• Diehl 327 2 yrs. -
  
• Powles 1079 2 yrs.
  
• Saarto 299 3 yrs. -
  
• during treatment only

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Adjuvant Clodronate Completed Studies

• Author pts. selection skel.mets visc.mets
  surv.
• Diel 327 BM
  
• Powles 1079 Node /-
  
• Saarto 299 Node
  
• 
  during treatment only

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Adjuvant Bisphophonate Studies Breast Cancer

• NSABP B-34
• 2,450 Stage I or II
• Clodronate or placebo for 3 years
• SWOG S9905
• 3,300 Stage I - IIIa
• Zoledronate every 4 weeks v. observation
• CALGB-79809
• 400 Stage I III
• Calcium,vitamin D daily for 36 months,
  Zoledronate every 3 months x 2 years beginning
  month 1 v. month 13.
• BMD measured at 12 and 36 months.

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Adjuvant Bisphophonate Studies Breast Cancer

• NSABP 34 ( 2,450 pts stages I-II)
• Adjuvant systemic Rx
• Clodronate or placebo x 3 yrs
• SWOG-9905 (3,300 pts stages I-IIIa)
• Adjuvant systemic Rx
• Zometa every 4 weeks x 2 yrs or observation
• CALGB 79809 (400 pts stages I-III)
• Adjuvant sytemic Rx
• Calcium vitamin D x 36 months
• Zoledronate every 3 months months 1-24 or 13-36
• BMD assessed at months 12 and 36

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Zometa Effects on BMD in Postmenopausal Women
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Zometa Bone Resorption in Postmenopausal Women

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Zometa Bone Formation in Postmenopausal Women

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ZoledronateCurrent Status

• Hypercalcemia of malignancy FDA approval
  granted August 2001
• 4mg as 15 minute infusion
• Skeletal Metastases FDA approval granted
  February 2002
• 4mg as 15 minute infusion
• Adjuvant therapy in breast cancer and prostate
  cancerin progress