Clinical Application of Evolving Treatment Paradigms in Advanced Breast Cancer

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Clinical Application of Evolving Treatment
Paradigms in Advanced Breast Cancer
Expert Review of Breast Cancer Treatment

• Clifford A. Hudis, MD
• Chief, Breast Cancer Medicine Service
• Memorial Sloan Kettering Cancer Center
• Professor of Medicine
• Weill Cornell Medical College
• New York, NY

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Case 1

• 47 year-old woman, BRCA1 () with h/o stage IIa
  breast cancer (3-years ago) at age 44
• ER weakly positive
• PR negative
• HER2 negative
• Treatment dose-dense AC?T and on tamoxifen for
  2 years
• Presents now with RUQ pain, 4kg weight loss, and
  fatigue
• LFTs normal
• CT with multiple hepatic metastases confirmed by
  biopsy c/w original tumor

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Case 1

• Which treatment option would you recommend
• Hormone therapy
• Chemotherapy
• Bevacizumab

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Case 1

• Which treatment option would you recommend
• Hormone therapy
• Chemotherapy
• Bevacizumab
• Recommended Approach
• Clinical considerations for selection of
  appropriate treatment will be discussed

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Management of Metastatic Breast Cancer
Diagnosis of Metastatic Breast Cancer
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Many Chemotherapy Options

• Spindle toxins
• paclitaxel (Pac)
• docetaxel (Doc)
• vinorelbine (Vin)
• nab-Pac (ABI-007)
• Ixabepilone (Ixa)
• Nucleoside analogues
• gemcitabine (Gem)
• capecitabine (Cap)
• 5-fluorouracil (5-FU_
• Topoisomerase inhibitors
• CPT-11 (Topo)
• doxorubicin (Dox)

• Platinums
• Antifolates
• methotrexate (MTX)
• pemetrexed (PTX)
• Unique delivery
• liposomal doxorubicin (LD)
• Targeted therapy
• HER2 trastuzumab (Trastuzumab) and lapatinib
  (Lap)
• VEGF BVM and small-molecule TKIs
  (investigational)
• farnesyltransferase inhibitors
• EGFR inhibitors (investigational)

Albumin-bound paclitaxel. CPT camptothecin
VEGF vascular endothelial growth factor BVM
bevacizumab mAb monoclonal antibody TKI
tyrosine kinase inhibitor EGFR epidermal
growth factor receptor.
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Approval is Different from Common Usage
Metastatic1
Adjuvant
3rd Line
2nd Line
1st Line
Anthracyclines (A)
Taxanes (after A) Taxanes (after A) Cap (after AT)
Cap (after A T) Cap (after A T) Ixa (after ATCap)
Ixa (after A T Cap) Cap (after A T)
Combination Captaxane (after A) Gem taxane (after A) Cap Ixa (after A T)
Taxanes (T)

• Despite treatment, most advanced tumors become
  resistant and progress2
• Chemoresistance is the major cause of treatment
  failure3

1. Adapted from National Comprehensive Cancer
Network. NCCN Clinical Practice Guidelines in
Oncology Breast Cancer V.2.2007.
http//www.nccn.org. Accessed April 30, 2007
2. Bernard-Marty C et al. Oncologist.
20049(6)617-632 3. Longley DB, Johnson PG. J
Pathol. 2005205(2)275-292.
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• Rationale for Combination Therapy
• in the Treatment of MBC

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Principles of Treatment With Multiple Agents

• MBC-inherent drug resistance barrier to
  response (cure)
• There are many subpopulations of cancer cells
  with different types of resistance
• Combination CT should reduce the different
  sensitive subpopulations of cancer cells, leading
  to an improved disease response
• Improved disease response will translate into an
  improvement in outcome
• Meta-analysis (2005) standard CT vs intensified
  CT (10 trials, 2126 patients)
• Intensified CT associated with OR0.60 for
  response
• Tumor response was predictive of survival
  (Plt0.001)
• Median OS CR29 mon PR21 mon NR15 mon

OR odds ratio OS overall survival CR
complete response PR partial response NR
no response.
Bruzzi P et al. J Clin Oncol. 200523(22)5117-512
5.
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Single-agent vs Combination Front-line CT in MBC

• Response rate ? favors combination
• TTP ? favors combination
• Survival ? ?
• Toxicity ? favors single agent
• Quality of life ? ?

Very few combination trials using investigational
drugs truly tested the hypothesis of combination
vs sequential single-agent therapy
TTP time to progression.
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Single-agent vs Combination Trials
Clinical Trial Median TTP (mon) Overall Survival (mon) Grade IV Neutropenia ()
Albain et al (N529) PacPac Gem 2.9 5.2 15.8 18.5 7 17
OShaughnessy et al (N511)Docetaxel (Doc) Doc Cap 4.26.1 11.514.5 1112
Albain KS et al. J Clin Oncol. 200422(14)
Abstract 810. O'Shaughnessy J et al. J Clin
Oncol. 200220(12)2812-2823.
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E1193 Phase III Trial Dox vs Pac vs Dox Pac
Combination in MBC
Results Efficacy and Tolerability
Outcome Dox Pac Dox Pac P Value
Response rate () 36 34 47 0.007 0.004
Median survival (mon) 18.9 22.2 22.0 NS
TTP (mo) 6.0 6.3 8.2 0.00220.0567
Gr III/IV leukopenia () 47 60 55
Gr III/IV infection () 4.1 8.3 12.7
Gr III/IV neurologic complications () 1.6 3.7 10.7
Dox vs Dox Pac Pac vs Dox Pac.
Sledge GW et al. J Clin Oncol.
200321(4)588-592.
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CALGB 9840 Design
Seidman AD et al. J Clin Oncol. 200422(14
suppl) Abstract 512.
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CALGB 9840Results (All Patients)
Seidman AD et al. J Clin Oncol. 200422(14
suppl) Abstract 512.
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CALGB 9840 Conclusions

• Pac once weekly is superior to Pac q 3 wks for
  the treatment of MBC (with respect to response
  rate and TTP)
• Pac once weekly is associated with slightly less
  frequent myelosuppression but more frequent
  neurotoxicity than Pac q 3 wks
• Trastuzumab does not improve outcome when added
  to Pac in HER2-neutral MBC

Seidman AD et al. J Clin Oncol. 200422(14
suppl) Abstract 512.
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TAX-31 Docetaxel vs Paclitaxel s/p
anthracycline / 0-1 prior chemo for MBC
Docetaxel 100q3w (N225) Paclitaxel 175q3w (N224)
ORR (ITT) TTP OS 32 5.7 15.4 25 3.6 12.7
Severe AE (gt5) Neutropenia Feb Neutropenia Infection Anemia Neurosensory Neuromotor Asthenia Peripheral oedema Stomatitis Diarrhea (3 deaths) 93 15 10 10 7 5 21 7 11 5 (0 deaths) 55 2 2 7 4 2 5 1 0 1

• P 0.05

Jones et al. JCO 2005.
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New Formulations
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Nab-Pac Transport Tumor Targeting Tapping Into
Biology of Albumin and Rapid Cell Growth
SPARC secreted protein and rich in cysteine.
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Phase III TrialAlbumin-Bound (Nab) Pac vs Pac in
MBC
Albumin-bound Pac 260 mg/m2 q3w Pac 175 mg/m2
q3w
Albumin-Bound (Nab) Pac (N229) Pac (N225) P Value
ORR () 33 19 0.001
TTP (wk) 23.0 16.9 0.006
Gr IV neutropenia () 9 22 lt0.001
Gr III sensory neuropathy () 10 2 lt0.001
Median time to improvement 22 days.
Gradishar WJ et al. J Clin Oncol.
200523(31)7794-7803.
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Phase II Study of Weekly or q3wk Nab-Pac vs q3wk
Doc as First-line Therapy in MBC
RANDOMIZE
Arm A nab-Pac 300 mg/m2 q3wk

• Eligibility criteria
• Stage IV adenocarcinoma
• No prior CT for metastatic disease

Arm B nab-Pac 100 mg/m2 weekly, 3 out of 4
Arm C nab-Pac 150 mg/m2 weekly, 3 out of 4
Arm D Doc 100 mg/m2 q3wk
Primary endpoint Antitumor response (q 8 wks) and toxicity
Comparisons nab-Pac vs Doc (A, B, C vs D) weekly vs q3wk nab-Pac (B, C vs A) low- vs high-dose weekly nab-Pac (B vs C)
Gradishar W et al. SABCS 2006. Abstract 46.
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Where Exactly Are We?
Hudis JCO 2005.
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Novel Microtubule Inhibitors
Need for change in Novel microtubule inhibitors
Toxicity profile Albumin-bound Pac (nab-Pac)
Therapeutic Efficacy Halicrobdrin analogue (E7389)
Improve effect at target site Epothilones (Ixa, patupilone)
Overcome resistance Polyglutamic acid conjugated Pac (CT 2103)
Cross blood-brain barrier Vinflunine (novel vinca alkaloid)
Lee JJ, Swain SM. Semin Oncol. 200523(2 suppl
7)S22-26. Cortes J, Baselga J. Oncologist.
200712(3)271-280.
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Epothilones in Clinical Developmentfor Breast
Cancer
Agent (Manufacturer) Epothilone Analog Phase inDevelopment Clinical Toxicities
EPO-906/patupilone Epothilone B (natural product) III Diarrhea
ZK-EPO Epothilone B (fully synthetic) II Neuropathy, nausea, ataxia
KOS-1584 Epothilone D (desoxyepothilone B) II Myelosuppression, neuropathy
BMS-310705 Epothilone B(semi-synthetic) I / II Hypersensitivity reactions, pancytopenia, neuropathy, arthralgia/myalgia
Goodin S et al. J Clin Oncol. 200422(10)2015-202
5. Kolman A. Curr Opin Investig Drugs.
20056(6)616-622. Schmid P et al. J Clin Oncol.
200523(16 suppl) Abstract 2051.
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Ixabepilone (Ixa) First in the New Class of
Epothilones

• Naturally occurring epothilone Bchemically
  modified to improvemetabolic activity,
  proteinbinding, and antitumor activity1
• Tubulin-binding mode distinctfrom other
  microtubule-stabilizing agents1
• Active against multiple tumor xeno grafts,
  including drug-resistant types that
  overexpressP-gP, MRP-1, and b-III
  tubulinisoforms1
• Active in taxane-resistant disease2,3

IxabepiloneSemi-synthetic analogof epothilone B
1. Ixempra (ixabepilone) prescribing
information. Princeton, NJ Bristol-Myers Squibb
Company 2007. 2. Perez E et al. J Clin Oncol.
200725(23)3407-3414. 3. Thomas E et al. J Clin
Oncol. 200725(23)3399 3406.
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Ixa Mechanism of Action

• Poor substrate for efflux pumps, eg, P-gP and
  MRP-11
• P-gP and MRP-1 are involved in drug resistance2
• Binds multiple ß-tubulin isoforms, including
  ßIII-tubulin to inhibit microtubule dynamics1
• Overexpression of ßIII is associated with in vivo
  and clinical resistance to taxanes3,4

1. Ixempra (ixabepilone) prescribing
information. Princeton, NJ Bristol-Myers Squibb
Company 2007. 2. Lee JJ, Swain SM. Semin Oncol.
200532(6 suppl 7)S22-S26. 3. Kamath K et al. J
Biol Chem. 2005280(13)12902-12907. 4. Mozzetti
S et al. Clin Cancer Res. 200511298-305.
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Phase II Trial Ixa in Anthracycline-, Taxane-,
and Capecitabine-Resistant MBCEfficacy
Efficacy (N113 Evaluable Patients) Efficacy (N113 Evaluable Patients)
ORR 11.5
SD 50.0
Median PFS 3.1 mo
Grade III/IV Toxicities
Neutropenia 54
Peripheral neuropathy 14
Fatigue 10
Myalgia 7
Stomatitis 7

• Single-agent Ixa 40 mg/m2 IV over 3 hrs q3w until
  disease progression

Perez E et al. J Clin Oncol. 200725(23)3407-341
4.
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Ixa Study 046Design
Ixa in Combination With Cap in Patients Resistant
to an Anthracycline and a Taxane

• Strict resistance criteria prospectively defined
  as
• Disease progression 3 mon of the last
  anthracycline dose in the metastaticsetting OR
  recurrence 6 mon in the adjuvant or neoadjuvant
  setting
• AND
• Disease progression 4 mon of the last taxane
  dose in the metastatic setting OR recurrence
  12 mon in the adjuvant or neoadjuvant setting

Pts who received a minimum cumulative dose of
240 mg/m2 of Dox or 360 mg/m2 of epirubicin were
also eligible. RR independent radiologic
review.
Imprexa (ixabepilone) prescribing information.
Princeton, NJ Bristol-Myers Squibb Company
2007. Thomas ES et al. J Clin Oncol. 2007
25(33)5210-5217.
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Ixabepilone Study 046Significant Improvement in
Median PFS
Median PFS
5.8 mosvs4.2 mos(95 CI, 3.84.5)
HR 0.75(95 CI, 0.640.88)
Based on IRR of ITT population Stratified by
visceral metastasis in liver/lung, prior CT in
metastatic setting, and anthracycline
resistance..
Thomas ES et al. J Clin Oncol. 2007 Early online
release 0 JCO.2007.12.6557v1.
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Grade 3/4 Non-hematologic Toxicities
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What About Anti-angiogenics?
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E2100 Study Design
DFI disease-free interval.
Miller KD et a. SABCS 2005. Abstract 3.
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First-line Therapy of Metastatic Breast Cancer
with Bevacizumab Added to Paclitaxel Improved PFS
484 events reported
Miller K, NEJM 2007.
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AVADODouble-blind, Placebo-controlled Trial
Docetaxel was administered for a maximum of 9
cycles, but earlier discontinuation was permitted

• Primary endpoint Progression-free survival
• Secondary endpoints Overall response rate,
  duration of response, time to treatment
  failure, overall survival, safety, quality of life

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Progression-free Survival (ITT population)
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Sorafenib Targets Both Tumor-cell Proliferation
and Angiogenesis
PDGF platelet-derived growth factor EGF
epidermal growth factorVEGF vascular
endothelial growth factor TGF-a transforming
growth factor-alpha Mcl-1 myeloid cell
leukemia-1
Wilhelm SM, et al. Cancer Res 2004647099109.
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Sorafenib in Breast CancerSix Randomized,
Double-blind, Placebo-controlled Phase 2b Trials
includes 2nd line patients
1. Letrozole, anastrozole, or exemestane 2.
Paclitaxel/bevacizumab /- sorafenib 3.
Bevacizumab-progressors
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Conclusions

• Newly approved and other novel agents for the
  treatment of patients with MBC continue to
  improve outcomes
• The addition of biologics may make a substantial
  impact
• There is a clear and immediate need for larger,
  better designed clinical trials to assess the
  role of these new agents
• As monotherapy
• As combination therapy
• As additions to therapies employing a growing
  number of biologics