Combination Anastrozole and Fulvestrant in Metastatic Breast Cancer: Resurrection of Survival Endpoint

1

• Combination Anastrozole and Fulvestrant in
  Metastatic Breast Cancer Resurrection of
  Survival Endpoint

Rita Mehta, MD Associate Clinical
Professor Division of Hematology/Oncology Departme
nt of Medicine
November 6th 2012
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San Antonio Breast Cancer Symposium - Cancer
Therapy and Research Center at UT Health Science
Center December 6-10, 2011

• A phase III randomized trial of anastrozole
  versus anastrozole and fulvestrant as first-line
  therapy for postmenopausal women with metastatic
  breast cancer SWOG S0226

Mehta RS, Barlow WE, Albain KS, Vandenberg TA,
Dakhil SR, Tirumali NR, Lew DL, Hayes DF, Gralow
JR, Livingston RB, and Hortobagyi GN
This presentation is the intellectual property of
the author/presenter. Contact them at
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3
Original Article Combination Anastrozole and
Fulvestrant in Metastatic Breast Cancer
Rita S. Mehta, M.D., William E. Barlow, Ph.D.,
Kathy S. Albain, M.D., Ted A. Vandenberg, M.D.,
Shaker R. Dakhil, M.D., Nagendra R.
Tirumali, M.D., Danika L. Lew, M.A., Daniel F.
Hayes, M.D., Julie R. Gralow, M.D., Robert B.
Livingston, M.D., and Gabriel N. Hortobagyi, M.D.
N Engl J Med Volume 367(5)435-444 August 2, 2012
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Epidemiology of breast cancer
San Antonio Breast Cancer Symposium - Cancer
Therapy and Research Center at UT Health Science
Center December 6-10, 2011

• Female/male ratio 1001
• More than 200,000 women will be Dxd in US
• gt40,000 will die of breast cancer
• 2nd leading cause of cancer deaths in women

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5
MajorDeterminants of treatment

• Staging
• ER status-Negative and positive
• HER2 status-Negative and positive

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6
Staging

• Stage 0 -- carcinoma in situ
• Stage I tumor lt 2 cm, no nodes
• Stage II tumor 2 to 5 cm, /- nodes
• Stage III locally advanced disease,
• fixed or matted lymph nodes and
• variable tumor size
• Stage IV distant metastases (bone,
• liver, lung, brain)

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Estrogen Receptor and Antiestrogen
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HER2 Over-Expression and Trastuzumab in Breast
Cancer
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Background
San Antonio Breast Cancer Symposium - Cancer
Therapy and Research Center at UT Health Science
Center December 6-10, 2011

• Of all women with breast cancer, 60 have tumors
  that are positive for hormone receptors this
  figure rises to 75 for postmenopausal women with
  breast cancer
• Anastrozole lowers estrogen levels and
  fulvestrant down-regulates the estrogen receptor
• The combination of anastrozole and fulvestrant
  may be additive in postmenopausal breast cancer

This presentation is the intellectual property of
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10
Preclinical Data

Jelovac et al. Can Research 2005
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Preclinical Data
Anastrozole fulvestrant down-regulate signaling
proteins Insulin-like growth factor type I
receptor ß, mitogen-activated protein kinase
(MAPK), p-MAPK, AKT, mammalian target of
rapamycin (mTOR), p-mTOR, and estrogen receptor
a.
Macedo et al. Can Research 2008
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S0226 Main Eligibility Criteria
San Antonio Breast Cancer Symposium - Cancer
Therapy and Research Center at UT Health Science
Center December 6-10, 2011

• Postmenopausal women with metastatic breast
  cancer (measurable or non-measurable)
• ER-positive or PgR-positive by local
  institutional standards
• No prior chemotherapy, hormonal therapy, or
  immunotherapy for metastatic disease
• Prior adjuvant tamoxifen allowed (stratification
  factor)
• Prior adjuvant AI allowed if completed 12 months
  earlier
• Neoadjuvant or adjuvant chemotherapy completed
  more than 12 months prior
• Patients were not allowed chemotherapy or other
  hormone therapy while on treatment
• Must have given informed consent

This presentation is the intellectual property of
the author/presenter. Contact them at
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distribute.
13
S0226 Schema
San Antonio Breast Cancer Symposium - Cancer
Therapy and Research Center at UT Health Science
Center December 6-10, 2011
R A N D O M I Z E
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14
S0226 Statistical Design
San Antonio Breast Cancer Symposium - Cancer
Therapy and Research Center at UT Health Science
Center December 6-10, 2011

• Accrual goal 690 eligible patients equally
  allocated and stratified by use of adjuvant
  tamoxifen
• Primary endpoint Progression-free survival
  (PFS)
• 90 power to detect an increase in median PFS
  from 10 months (monotherapy) to 13 months
  (combination) with 2-sided a 0.05 overall
• Planned analyses of the primary endpoint
• Two interim analyses at 50 and 75 of the events
• Final analysis at 2-sided a 0.04
• Subset analyses were not planned and are not
  adjusted for multiplicity
• Overall survival is a secondary endpoint

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Primary Comparisons
San Antonio Breast Cancer Symposium - Cancer
Therapy and Research Center at UT Health Science
Center December 6-10, 2011

• Intent-to-treat analysis of eligible patients
• Analysis stratified by prior adjuvant tamoxifen
• Results as of December 2011
• Population characteristics
• 707 patients randomized in the periodJune 2004
  to June 2009
• 694 analyzed excluding 12 ineligible patients and
  one who withdrew consent
• Progression-free survival
• Overall survival
• Toxicity

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distribute.
16
Crossover
San Antonio Breast Cancer Symposium - Cancer
Therapy and Research Center at UT Health Science
Center December 6-10, 2011

• Patients in the anastrozole arm were strongly
  encouraged to crossover to fulvestrant after
  progression
• After Feb 15, 2011 patients on either arm could
  crossover to 500 mg fulvestrant dosing after
  progression
• 143 of 345 patients (41) on anastrozole did
  crossover to fulvestrant after progression
  (including 5 who took the 500 mg dosing)
• 9 of 349 patients on the combination took500 mg
  dosing after progression

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the author/presenter. Contact them at
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17
Baseline Characteristics of the Patients and the
Disease, Accord
ing to Treatment Group.
Mehta RS et al. N Engl J Med 2012367435
-
444.
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San Antonio Breast Cancer Symposium - Cancer
Therapy and Research Center at UT Health Science
Center December 6-10, 2011
This presentation is the intellectual property of
the author/presenter. Contact them at
rsmehta_at_uci.edu for permission to reprint and/or
distribute.
21
San Antonio Breast Cancer Symposium - Cancer
Therapy and Research Center at UT Health Science
Center December 6-10, 2011
This presentation is the intellectual property of
the author/presenter. Contact them at
rsmehta_at_uci.edu for permission to reprint and/or
distribute.
22
San Antonio Breast Cancer Symposium - Cancer
Therapy and Research Center at UT Health Science
Center December 6-10, 2011
This presentation is the intellectual property of
the author/presenter. Contact them at
rsmehta_at_uci.edu for permission to reprint and/or
distribute.
23
San Antonio Breast Cancer Symposium - Cancer
Therapy and Research Center at UT Health Science
Center December 6-10, 2011
This presentation is the intellectual property of
the author/presenter. Contact them at
rsmehta_at_uci.edu for permission to reprint and/or
distribute.
24
Prior tamoxifen as a predictive factor?
San Antonio Breast Cancer Symposium - Cancer
Therapy and Research Center at UT Health Science
Center December 6-10, 2011

• Overall planned analysis is highly significant
• Unplanned analysis by prior tamoxifen may suggest
  benefit only in the tamoxifen naive group
• Prior tamoxifen use is confounded with time
  between adjuvant diagnosis and metastatic
  diagnosis
• Need to better understand other possible
  predictive factors since the prior tamoxifen
  factor could be a false lead from an unplanned
  analysis

This presentation is the intellectual property of
the author/presenter. Contact them at
rsmehta_at_uci.edu for permission to reprint and/or
distribute.
25
(No Transcript)
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S0226 Toxicity Grade 4 and 5
San Antonio Breast Cancer Symposium - Cancer
Therapy and Research Center at UT Health Science
Center December 6-10, 2011

• Three patients on the combination had grade 5
  toxicities
• two had pulmonary embolism
• one had cerebrovascular ischemia
• Two other patients on the combination had grade 4
  toxicities
• one had pulmonary embolism
• one had neutropenia and lymphopenia
• Four patients on anastrozole alone had Grade 4
  toxicities (thrombosis/embolism, arthralgia,
  thrombocytopenia, dyspnea)

This presentation is the intellectual property of
the author/presenter. Contact them at
rsmehta_at_uci.edu for permission to reprint and/or
distribute.
27
S0226 Toxicity
San Antonio Breast Cancer Symposium - Cancer
Therapy and Research Center at UT Health Science
Center December 6-10, 2011

• Grade 3 toxicities
• 46 (13) on the combination
• 38 (11) on anastrozole alone
• Includes musculo-skeletal pain, fatigue, hot
  flashes, mood alterations and gastrointestinal
  symptoms with frequency 1-4
• Adverse events did not differ significantly by
  treatment group
• Few patients went off treatment early due to
  adverse events or side effects (anastrozole
  alone 4 combination 11)

This presentation is the intellectual property of
the author/presenter. Contact them at
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distribute.
28
First-Line Hormonal Agent Phase-III Studies in
Breast Cancer Overall Survival
San Antonio Breast Cancer Symposium - Cancer
Therapy and Research Center at UT Health Science
Center December 6-10, 2011

Study N OS Control Arm (months) OS Experimental Arm (months) HR for OS P-value
S0226 NEJM 2012 707 Anastrozole (?fulvestrant (41.3) Anastrozole Fulvestrant (47.7) 0.81 0.049
Bergh SABCS JCO 2012 514 Anastrozole (38.2) Anastrozole Fulvestrant (37.8) 1.00 1.00
Nabholtz Eur J C 2003 1021 Tamoxifen (40.1) Anastrozole (39.2) 0.97 ?
Mouridsen JCO 2003 916 Tamoxifen (30) Letrozole (34) ? 0.53
Paridaens JCO 2008 371 Tamoxifen (43.3) Exemestane (37.2) 1.04 0.82
Goss JCO 2007 865 Letrozole (34) Toremifen Atamestane (36) 0.98 0.76
Howell JCO 2004 587 Tamoxifen (38.7) Fulvestrant (36.9) 1.29 0.04
This presentation is the intellectual property of
the author/presenter. Contact them at
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29
Table. Comparison of the S0226 and FACT trial.
Study S0226 (n707) FACT (514)
Eligibility HR metastatic breast cancer, first-line postmenopausal HR breast cancer after first relapse (local or metastatic) postmenopausal or premenopausal
Progression-free survival 15.0 months vs. 13.5 months favoring fulvestrant arm (HR, 0.80 P0.0070) 10.8 months vs. 10.2 months no difference (HR, 0.99 P0.91)
Overall survival 47.7 months vs. 41.3 months favoring fulvestrant (HR, 0.81 P0.049) 37.8 months vs. 37.2 months no difference (HR, 1.0 P1.00).
Prior adjuvant chemotherapy 33 (completion more than 12 months prior) 46 (timing not specified)
Cross-over to fulvestrant Strongly encouraged (41 crossed over) Not encouraged
Progression within 12 months of prior tamoxifen Low Approximately 30
Intent to Rx Analysis of eligible patients Patient characteristics balanced Patient characteristics balanced?
Prior treatment 40 de-novo All in first relapse
Prior tamoxifen 140/140 (280) 40 in combination arm. 175 combination/164 mono-therapy (339) 70 in combination arm.
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KaplanMeier Estimates of Progression-free
Survival, According to Whether Patients Were
Randomly Assigned to Receive Chemotherapy plus
Trastuzumab or Chemotherapy Alone (Panel A), and
Whether Chemotherapy Consisted of Either a
Combination of an Anthracycline and
Cyclophosphamide (Panel B) or Paclitaxel (Panel
C).
Slamon DJ et al. N Engl J Med 2001344783-792.
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KaplanMeier Estimates of Overall Survival,
According to Whether Patients Were Randomly
Assigned to Receive Chemotherapy plus Trastuzumab
or Chemotherapy Alone (Panel A) and Whether
Chemotherapy Consisted of Either a Combination of
an Anthracycline and Cyclophosphamide (Panel B)
or Paclitaxel (Panel C).
HR0.80
Slamon DJ et al. N Engl J Med 2001344783-792.
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ECOG Trial, E2100 The Study Overview

• This trial tested the effect of adding
  bevacizumab, a monoclonal antibody against
  vascular endothelial growth factor A, to the
  taxane paclitaxel for the initial treatment of
  metastatic breast cancer
• As compared with paclitaxel alone, the
  combination increased progression-free survival
  but not overall survival
• The results are a demonstration of the potential
  benefit of antiangiogenic treatment for breast
  cancer

33
Survival Analyses
HR 0.60
HR 0.88
Miller K et al. N Engl J Med 20073572666-2676
34
CLEOPATRA The Study Overview

• Pertuzumab, an anti-HER2 antibody, recognizes a
  different epitope of HER2 than does trastuzumab
  and behaves differently.
• In patients with metastatic breast cancer, the
  combination of the two antibodies plus docetaxel
  significantly increased progression-free survival.

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CLEOPATRA Progression-free Survival, as Assessed
at an Independent Review Facility.
Baselga J et al. N Engl J Med 2012366109-119
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Overall Survival.
Baselga J et al. N Engl J Med 2012366109-119
37
Which one of the following statements summarizes
the results of S0226?

1. Combination therapy was associated with increase
   in progression-free survival and the effect
   increased with time
2. Combination therapy was associated with increase
   in progression-free survival and the effect
   decreased with time
3. Combination therapy was associated with shorter
   progression-free survival
4. There was no difference between the groups with
   respect to progression-free survival

THE STUDY OBJECTIVE, SHOWING A SIGNIFICANT
IMPROVEMENT IN THE PRIMARY END POINT OF
PROGRESSION-FREE SURVIVAL WITH THE COMBINATION
THERAPY, WAS MET (P0.007 WITH THE USE OF A
TWO-SIDED STRATIFIED LOG-RANK TEST). GENERALLY,
THE SUPERIORITY OF THE COMBINATION THERAPY OVER
ANASTROZOLE ALONE WITH RESPECT TO
PROGRESSION-FREE SURVIVAL EMERGED OVER TIME AT 1
YEAR, THE RATE OF PROGRESSION-FREE SURVIVAL WAS
57 WITH COMBINATION THERAPY AND 56 WITH
ANASTROZOLE ALONE AT 2 YEARS, THE CORRESPONDING
RATES WERE 35 AND 28, AND AT 3 YEARS, THE RATES
WERE 25 AND 16
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Which one of the following conditions was the
most common grade 3 toxic effect observed in
S0226?

1. Gastrointestinal disturbances
2. Hematologic effects
3. Musculoskeletal pain
4. Thrombosis

THE MOST COMMON GRADE 3 TOXIC EFFECTS WERE
MUSCULOSKELETAL PAIN (2.8), INFLUENZA-LIKE
SYMPTOMS (2.4), GASTROINTESTINAL DISTURBANCES
(1.5), AND HEMATOLOGIC EFFECTS (1.5).
39
Which one of the following characteristics
applies to the mechanism of action of fulvestrant?

1. It is an aromatase inhibitor.
2. It is an estrogen Modulator (SERM).
3. It is an estrogen receptor down-regulator (SERD).
4. It is a gonadotropin-releasing hormone agonist.

FULVESTRANT (FASLODEX, ASTRAZENECA) IS AN
ANALOGUE OF ESTRADIOL THAT DOWN-REGULATES THE
ESTROGEN RECEPTOR BY DISRUPTING ESTROGEN-RECEPTOR
DIMERIZATION AND ACCELERATING DEGRADATION OF THE
UNSTABLE FULVESTRANTESTROGEN-RECEPTOR COMPLEX.2
THIS EFFECT LEADS TO REDUCED CROSS-TALK BETWEEN
THE ESTROGEN RECEPTOR AND ESTROGEN-INDEPENDENT
GROWTH FACTOR SIGNALING, THUS DELAYING RESISTANCE
TO HORMONE THERAPY.
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The overall survival for combination was
statistically superior than for anastrozole
alone, despite higher-than-projected survival for
anastrozole alone. The combination was not
statistically associated with higher toxicity,
despite longer time on the combination. Comparison
of S0226 (and its subsets) to FACT suggests that
benefit of combination decreases with increasing
endocrine resistance (acquired or inherent).
41
How to Rx this patient?

• Age 61 (A pt at Hoag)
• ER 95
• PR 95
• Tumor Type IDC
• Tumor Size 0.9 cm
• Tumor Grade 2
• HER-2 Neg (FISH)

www.adjuvantonline.com.
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How to Rx this patient?
Age 35 ( a frequent patient at UCI) ER
neg/PR neg Tumor Type IDC Tumor Size gt5
cm Tumor Grade 3 HER-2 pos (FISH) Chemo-sensi
tive vs chemo-resistant
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Neoadjuvant Chemotherapy Trastuzumab
Neoadjuvant vs Adjuvant Pathologic Complete
Response in Neoadjuvant (in vivo dynamic lab) vs
Survival Endpoint in Adjuvant settings
Pretest probability near 0 in AC resistant
tumors, after 5/5 pathologic response, post test
probability is not Zero. FDA will not allow
indication based on pathologic complete response
July 2004
A prem. female with HER2-positive relapsed IBC
(2003)
Young adult with HER2-pos. primary IBC (2003)
Pre Rx
Mid Rx
Post Rx
pCR
pCR
Annals of Oncology Trastuzumab in inflammatory
breast cancer Mehta et al. 2008 Patient is the
teacher of clinician
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Neoadjuvant options at UCI

• 2003-4Pilot Study AC followed by weekly
  paclitaxel, carboplatin trastuzumab (TCH)
• Sequential TCH reverses anthracycline resistance
  
• high pathologic complete response will translate
  into high overall survival ?
• short course of trastuzumab concurrent with
  optimized chemotherapy is adequate Rx
• minimum anthracycline may be important as it
  potentially targets cells with topoisomerase-II
  co-amplified cells in a heterogeneous HER2
  population (SWOG, SABCS 2004)
• 2004-5 UCI03-70 AC followed by weekly
  paclitaxel, carboplatin /- trastuzumab (n48)
• - Pathologic complete response following
  TCH does translate into superior overall survival
  (SABCS 2008)
• 2005-7UCI 05-38 AC followed by
  Albumin-paclitaxel, carboplatin /- trastuzumab
  or bevacizumab (n43)
• Pathologic complete response following dose-dense
  metronomic chemotherapy translates into high
  overall survival for triple negative breast
  cancer (JCO 2008)
• 2008-2013 UCI07-61 Albumin-paclitaxel,
  carboplatin /- trastuzumab or bevacizumab
  (n100/120) DD AC is optional

45
Trastuzumab-based combinations

• Studies 1 2 NSABP 31 (UCI) and NCCTG NEJM
  Oct 2005
• After completion of AC, Herceptin weekly taken
  with Taxol weeks 1-12 followed by Herceptin alone
  weekly
• 52 higher chance of remaining cancer free longer
  in the group of women who received AC?TH
  (n1872) compared with the group that received
  AC?T (n1880)
• Study 3 HERA NEJM Oct 2005
• After surgery and chemotherapy, Herceptin taken
  every 3 weeks
• 46 higher chance of remaining cancer free longer
  in the group of women who received Herceptin
  alone (n1693) compared with the group that did
  not receive Herceptin (n1693)
• Study 4 Slamon et al. NEJM 2012
• After completion of AC, Herceptin weekly taken
  with Taxotere weeks 1-12 followed by Herceptin
  alone every 3 weeks
• 40 higher chance of remaining cancer free longer
  in the group of women who received AC?TH
  (n1074) compared with the group that received
  AC?T (n1073)
• Study 4
• After surgery, Herceptin weekly taken with
  Taxotere and carboplatin weeks 1-18 followed by
  Herceptin alone every 3 weeks

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Trial Design Neoadjuvant vs Adjuvant in Triple
Negative Breast Cancer

• Each 10 increase in pathologic complete response
  will translate into an absolute 2.6 3-year
  survival-TN breast cancer specific calculation
• Combination cytotoxic chemotherapy administered
  in a dose-dense or metronomic schedule remains
  the standard therapy for early-stage TNBC.2011
  NCI PDQ
• Dose-dense and/or metronomic schedules of
  specific chemotherapies consolidate the
  chemosensitivity of triple-negative breast
  cancer a step toward reversing triple-negative
  paradox
• Mehta RS. J Clin Oncol 26 (19), 2008

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FDA will allow pathologic complete response rate
endpoint for accelerated approval of new drugs
2012. Immediate Goal is to find the driver
mutation and treat.
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Courtesy Albain
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Breast Center Team Collaborators

• Campus Drs. Tromberg, Su, Chen, Nelson (MRI and
  Laser Optics)
• Breast Center Drs. Butler, Lane and Hsiang
• Hematology/Oncology Drs. Sender, Nelson,
  Fruehauf, Zell, Nangia, Seery, Fellows
• Cancer Center
• Radiologists Drs. Feig and Campbell
• Members of IRB/CTPRMC/CRO/CRAC
• Nurses
• Patients

Thank You