Transcript the rash turner

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Disclosure of Conflicts of Interest
Edith A. Perez, MD
During the development of this activity,
Edith A. Perez, MD, the activity Chair,
disclosed no real or apparent conflicts of
interest.
Learning Objectives
Upon completion of this activity, participants
should be better able to:
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Analyze key pathologic and molecular findings in the identification
and diagnosis of early stage, locally advanced, and metastatic
breast cancer (MBC)
Determine optimal sequencing and duration for individualized
treatments for patients with HER2+ MBC
Evaluate the benefits of mTOR inhibitors, non-taxane microtubules,
epothilones, antibody-drug conjugates, and other agents for MBC
Assess the optimal use of hormonal therapy in patients with breast
cancer
Apply current and emerging evidence supporting VEGF and other
targeted therapy in breast cancer treatment
Assess the role of prognostic assays in determining treatments for
patients with breast cancer
Incorporate current treatment guidelines into decision making for
treating patients with breast cancer
Activity Agenda
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Program overview
What are some outstanding pathologic and
molecular concerns in the diagnosis and
treatment of breast cancer?
How do we treat early stage breast cancer?
What therapies and strategies are appropriate in
treating locally advanced and metastatic breast
cancer?
Question and answer session
Today’s Breast Cancer Biology
in the Clinic
Incidence
Therapy
70%
Endocrine
chemotherapy
HER2+
15%-30%
Anti-HER2
chemotherapy
Triple negative
10%-20%
chemotherapy
ER+ and/or PR+
ER+, estrogen receptor positive; HER2, human epidermal growth factor receptor 2; PR+, progesterone receptor positive.
HER2 Testing Guidelines
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HER2 testing should be requested for every primary invasive breast
cancer (and for metastatic sites for stage IV disease) to guide the
decision regarding HER2-targeted therapy. This includes patients
who previously tested HER2-negative in a primary tumor who
present with disease recurrence with clinical behavior suggestive of
HER2-positive or triple-negative disease.
HER2-targeted therapy should be recommended if the HER2 test
result is positive, if there is no apparent histopathologic discordance
with HER2 testing, and if clinically appropriate. In the case of any
outcomes of HER2 testing, additional testing should be discussed if
the pathologist or oncologist observes an apparent histopathologic
discordance after testing.
The decision regarding HER2-targeted therapy should be delayed if
the initial HER2 test is equivocal. Reflex testing should be
performed on the same specimen using the alternative test or on an
alternative specimen.
HER2, human epidermal growth factor receptor 2.
Wolff AC, et al. ASCO/CAP Clinical Practice Guideline Update. J Clin Oncol. 2013;31:3997-4013.
HER2 Testing Guidelines (cont.)
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HER2-targeted therapy must not be recommended if the HER2 test
result is negative and if there is no apparent histopathologic
discordance with HER2 testing.
The decision on HER2-targeted therapy should be delayed if HER2
status cannot be confirmed as positive or negative after separate
HER2 tests. The oncologist should confer with the pathologist
regarding the need for additional HER2 testing on the same or
another tumor specimen.
If HER2 testing is ultimately deemed to be equivocal, even after
reflex testing with an alternative assay, HER2-targeted therapy may
be considered. The feasibility of testing another tumor specimen to
definitively establish HER2 status should also be considered. The
clinical decision to consider HER2-targeted therapy should be
individualized based on patient status (comorbidities, prognosis, etc)
and patient preferences after discussing available clinical evidence.
HER2, human epidermal growth factor receptor 2.
Wolff AC, et al. ASCO/CAP Clinical Practice Guideline Update. J Clin Oncol. 2013;31:3997-4013.
ER/PR Testing Guidelines
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The ER and PR status should be tested on the primary tumor and/or
areas of spread (called metastases) for each patient with newly
diagnosed invasive breast cancer or a breast cancer recurrence.
A tumor is ER and/or PR positive if at least 1% of the cells examined
have estrogen and/or progesterone receptors, and for such a tumor,
patients should talk with their doctors about considering hormone
therapy.
Testing is best done on larger tissue samples. If the cancer has
spread, testing on those areas may be considered as well.
Laboratories testing for ER and PR should be accredited by the CAP
or meet the additional accreditation requirements in the guideline
and show agreement with other validated ER and PR tests for both
positive and negative results. The laboratory must also be inspected
every 2 years to be sure that the testing methods conform to the
guideline requirements.
CAP, College of American Pathologists; ER, estrogen receptor; PR, progesterone receptor.
Hammond MEH, et al. ASCO/CAP Guideline Recommendations. J Clin Oncol. 2010;28:2784-2795.
How Do We Treat
Early Stage Breast Cancer?
Clinicopathologic and Genomic
Factors in Breast Cancer

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Conglomerate of multiple,
molecularly defined syndromes with
different natural histories and
sensitivities to therapeutics
ER, PR, and HER2 represent critical
molecular markers that identify the
largest subsets
High-throughput diagnostic
techniques to identify novel
molecular markers might serve to
identify new subsets, new targets
ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; PR, progesterone receptor.
Adjuvant Treatment for ER+/PR+
Breast Cancer: Standard

Premenopausal
– >5 years of hormonal therapy
• MA.17; ATLAS, aTTom
– Consider AI or tamoxifen if OFS is performed

Postmenopausal
– Tamoxifen for 10 years
– AI for 5 years
• Studies testing longer duration pending
– AI for 2 years followed by tamoxifen for 3 years
AI, aromatase inhibitor; OFS, ovarian function suppression.
Burstein et al, 2014.
Davies et al, 2013.
Gray et al, 2013.
Adjuvant Endocrine Treatment for
ER+/PR+ Breast Cancer:
Questions


Exact role of ovarian function suppression
(premenopausal)
Addition of other agents
– mTOR inhibitors
– palbociclib

Molecular determinants for chemotherapy options
– Prospective data from TAILORx (NCT00310180) and
MINDACT (NCT00433589) trials expected in 20162018
ER+, estrogen receptor positive; mTOR, mechanistic target of rapamycin; PR+, progesterone receptor positive.
Management of the Premenopausal Woman
with HR+ Early Stage Breast Cancer: SOFT

Suppression of ovarian function trial (SOFT)
– Trial studying ovarian suppression with either tamoxifen or
exemestane to see how well they work compared to tamoxifen alone
in treating premenopausal women who have undergone surgery for
hormone-responsive breast cancer
– Adding ovarian suppression to tamoxifen did not show significant
benefit in the overall population in SOFT after 67 months median
follow-up
– For cohort receiving chemotherapy and who remained
premenopausal, the addition of ovarian suppression improved breast
cancer outcomes, and further improvement was seen with the use of
exemestane plus ovarian suppression
– Toxicity of OFS was notable
HR+, hormone receptor positive; OFS, ovarian function suppression.
Francis et al, 2014.
Neoadjuvant Therapy
How Valid Is the
Neoadjuvant Model?
Agent (s)
Neoadjuvant
Pertuzumab
+ neoSPHERE
Lapatinib
+ neoALTTO
+ CALGB 40601
+ CHER-LOB
+ US Oncology
Bevacizumab
+ NSABP B-40
+ GBG44 (TN)
+ CALGB 40603 (TN)
Platinum/TNBC
+ CALGB 40603
+ GeparSixto
Adjuvant
Practice change
?
Yes*
Negative ALTTO
No
Negative E5103
Negative BEATRICE (TN)
No
?
No
* Based on FDA accelerated approval as neoadjuvant. No adjuvant data yet.
WSG-ADAPT Phase 2 Trial: Neoadjuvant
TDM-1 in HER2+ HR+ EBC
EBC, early breast cancer; HER2+, human epidermal growth factor receptor 2; HR+, hormone receptor positive.
Harbeck et al, 2015.
WSG-ADAPT Trial: Efficacy and
Safety Results
Agent
pCR (%)
TDM-1
40.5
TDM-1 + ET
45.8
Trastuzumab + ET
6.7
Study medication administered for 4 cycles:
100.0%: TDM-1
95.8%: TDM-1 + ET
95.2%: Trastuzumab + ET
16 serious AEs in 13 patients (all CTCAE grades 1-3)
No reported CTCAE grade 4 events
14 termed serious due to unplanned hospitalization, 7 related to study medication,
all patients recovered completely.
AEs, adverse events; CTCAE, common terminology criteria for adverse events; pCR, pathologic complete response.
Harbeck et al, 2015.
WSG-ADAPT Trial: Conclusions
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More than 40% pCR (breast and nodes) in TDM-1
treated patients after 12 weeks without systemic
chemotherapy
Very low overall toxicity
Adding endocrine therapy to TDM-1 increases pCR in
pre, but not post-menopausal patients
Early response biomarkers:
– No trend for Ki-67 (3 week vs baseline) as predictor of
pCR
– Early therapy effect affected Ki-67 quantification in 3week biopsy (low cellularity in 43.1%) and was
associated with pCR
pCR, pathologic complete response.
Take-Home Messages on
Neoadjuvant Therapy
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Not shown to be superior to adjuvant therapy
Comparative changes in pathologic complete response
not yet shown to correlate with comparative changes in
event free or overall survival
More cumbersome and costly to the patient and the
healthcare system
Good strategy to try to decrease surgical extent in
patients with large tumors
Good to evaluate short-term biological changes,
although not clear whether early biological changes
predict patient outcome
What Is the Optimal Adjuvant
Regimen for HER2-Targeting?
N9831/B-31 Disease-Free Survival
81.4%
AC  T+H
% Event-Free
76.8%
AC  T
AC→T
AC→T+H
73.7%
11.5%
69.5%
64.9%
62.2%
N Events
2018 680
2028 473
HRadj 0.60 (95% CI 0.53-0.68)
P < .0001
Years from Randomization
Perez et al, 2014.
N9831/B-31 Overall Survival
93.2%
AC  T
AC  T+H
89.8%
87.0%
90.3%
84.0%
8.8%
84.3%
79.4%
% Survival
75.2%
∆=2.9%
AC→T
AC→T+H
N Events
2018 418
2028 286
∆=5.5%
∆=7.6%
HRadj 0.63 (95% CI 0.54-0.73)
P < .0001
Years from Randomization
Perez et al, 2014.
∆=8.8%
Phase 2 Study (APT Trial) for
Patients With Small HER2+ Tumors
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406 women with HER2+, node-negative tumors ≤3 cm received only
paclitaxel at 80 mg/m2 weekly plus trastuzumab weekly at 2 mg/kg for 12
weeks, followed by 9 months of trastuzumab every 3 weeks at 6 mg/kg
alone.
After a median follow-up of 3.6 years, only 10 of 406 patients died or had
disease recurrence. There were only 4 local recurrences (0.9%).
Three new contralateral primary breast cancers (0.7%) developed in study
patients; all were HER2−, and 2 were distant recurrences (0.5%).
DFS at 3 years was 98.7% (P < .0001).
– By hormone receptor status, DFS rates were 98.5% in receptor-positive
patients and 99.2% in receptor-negative patients.
The recurrence-free survival rate (invasive locoregional recurrence, distant
recurrence, death from breast cancer) was 99.2%.
Few adverse events were noted.
DFS, disease-free survival; HER2, human epidermal growth factor receptor 2.
Tolaney et al, 2013.
ALTTO Adjuvant HER2+ Trial
8,381 women with early stage HER2+ breast cancer
Anthracycline/taxane
Non-anthracycline/taxane
Anthracycline/taxane
Design 1
=
sequential
administration
Trastuzumab
CHEMOTHERAPY
Lapatinib*
Trastuzumab
↓
then Lapatinib
Translational research effort
(tumor/blood collection→ back to the lab)
*Closed in 2011 as per IDMC recommendation; not reported at 2014 ASCO Annual Meeting.
HER2+, human epidermal growth factor receptor 2 positive.
Piccart-Gebhart et al. 2014.
Design 2
=
concomitant
administration
Trastuzumab
combined with
Lapatinib
1 yr
ALTTO: Study Objectives
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Primary endpoint: DFS
– Invasive breast cancer recurrence at any site
– Second primary cancer (invasive contralateral breast
cancer or non-breast malignancy)
– Death from any cause as first event
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Statistics
– Plan for 850 DFS events in L+T versus T comparison;
or 4.5 years median follow-up, whichever occurred
first
– Actually observed: 555 such DFS events
– P ≤ .025 required for statistical significance to test
both L+T versus T, and T→ L versus T
DFS, disease-free survival.
Piccart-Gebhart et al, 2014.
ALTTO: Disease-Free Survival
*
**
Median f/u 4.5 yrs
*97.5% CI.
**P ≤ .025 required for statistical significance.
Piccart-Gebhart et al. 2014.
ALTTO: Overall Survival
*
Median follow-up 4.5 yrs
*95% CI.
Piccart-Gebhart M, et al. 2014.
Main Differences in AEs by
Treatment Arm
Hepatobiliary
% AEs by Treatment Arm
Diarrhea
Rash or Erythema
Defined
primary
cardiac
events per
protocol in
<1% in all
arms
All Grades
L+T
T L
T
AEs, adverse events.
Piccart-Gebhart M, et al. 2014.
P < .001 for incidence for all arms
when compared to T
ALTTO Conclusions
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Event rate was lower than anticipated: 555 DFS events
at 4.5 years median follow-up instead of 850 target
The ALTTO trial did not meet its primary endpoint (DFS)
– Neither the L+T vs T nor the T→ L vs T comparisons
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Doubling in pCR observed with L+T in NeoALTTO did
not translate into improved survival outcomes in ALTTO
Lapatinib is associated with increase in diarrhea,
hepatobiliary, and rash/erythema compared with
trastuzumab
Cardiac toxicity remained low in all treatment arms
Follow-up of study participants is continuing
DFS, disease-free survival; L, lapatinib; pCR, pathologic complete response; T, trastuzumab.
APHINITY Adjuvant HER2+ Trial
Pertuzumab
AC-T or TCarbo
S
U
R
G
E
R
Y
Central
confirmation
of HER2
status
Trastuzumab + Pertuzumab*
×1 year
R
N = 3,806
AC-T or TCarbo
Trastuzumab + Placebo*
×1 year
*Antibody therapy starts with taxane
Accrual completed 2013
AC, doxorubicin and cyclophosphamide; Carbo, carboplatin; HER2+, human epidermal growth factor receptor 2
positive; R, randomized; T, paclitaxel.
Hoffmann-La Roche, NCT01358877.
Phase 3 ExteNET Trial:
Neratinib in HER2+ EBC
DFS, disease-free survival; EBC, early breast cancer; ER, estrogen receptor; HER2+, human epidermal growth factor
receptor 2 positive; PR, progesterone receptor.
Chan et al, 2015.
Primary Endpoint: Invasive DFS
(ITT)
DFS, disease-free survival; ITT, intention to treat.
Chan et al, 2015.
Efficacy Subgroups
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DCIS: 2-year DFS rate
– 93.9% with neratinib vs 91.0% with placebo (HR 0.63;
95% CI 0.46-0.84)
HR-positive breast cancer (n = 1,631): 2-year invasive DFS rate
– 95.4% with neratinib vs 91.2% with placebo (HR 0.51; P = .001)
HR-negative breast cancer (n = 1,209): 2-year invasive DFS rate
– 92% with neratinib vs 92.2% with placebo (HR 0.93; P = .735)
High-risk patients: 2-year DFS rate
– 92.9% with neratinib vs 89.8% with placebo (HR 0.66; P = .01)
Centrally confirmed HER2+ disease: 2-year DFS rate
– 94.7% with neratinib vs 90.6% with placebo (HR 0.51; P = .002)
DCIS, ductal carcinoma in situ; DFS, disease-free survival; HER2+, human epidermal growth factor receptor 2 positive;
HR, hormone receptor.
Chan et al, 2015.
Adverse Events
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Diarrhea
– 95.4% of patients treated with neratinib experienced all-grade diarrhea
(39.9% grade 3/4)
• Most occurred <30 days
• Dose reduction 26.4%
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– Placebo arm, 35.4% of patients had all-grade diarrhea with grade 3/4
incidence of 1.6%
Gastrointestinal-related side effects
– Nausea (43%)
– Fatigue (27%)
– Vomiting (26.2%)
– Abdominal pain (24.1%)
Cardiac toxicity
– QT prolongation (N 3.5% vs PI 6.6%)
– LVEF decline ≥grade 2 (N 1.3% vs PI 1.1%)
Interstitial lung disease
– 0.1% in both groups
LVEF, left ventricular ejection fraction; N, neratinib; Pl, placebo.
Chan et al, 2015.
Conclusions
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Primary analysis demonstrates significant iDFS benefit
with 2.3% absolute difference at 2 years with neratinib
for 12 months
– 2.9% absolute difference in DFS-DCIS at 2 years
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Possible greater benefit in HR+ disease—requires
further evaluation
Diarrhea was predictably most common adverse event
– Intensive prophylaxis with loperamide recommended
DCIS, ductal carcinoma in situ; iDFS, invasive disease-free survival; HR+, hormone receptor positive.
Chan et al, 2015.
What Is the Optimal Treatment
Strategy for Early Stage
Triple-Negative Breast
Cancer?
Triple-Negative Breast Cancer
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15%-20% of all breast cancers
worldwide
Up to 20% of women with triplenegative breast cancer may have a
BRCA or PALB2 germline mutation
Molecularly heterogeneous
Local-regional and distant relapse
(CNS) peaks at 1-3 years after
treatment
Antoniou et al, 2014.
Couch et al, 2015.
Domcheck, 2015.
Evans and Longo, 2014.
New Data in Triple-Negative
Adjuvant Approaches
Bevacizumab improves neoadjuvant pCR,
but does not improve event-free or overall
survival in the adjuvant setting
 Role of homologous recombination tests to
determine whether they help predict
benefit of platinums or PARP inhibitors
have not panned out so far

pCR, pathologic complete response.
Tutt, 2014.
Von Minckwitz et al, 2015.
GeparSixto Trial:
Prediction of pCR by Homologous
Recombination Deficiency in TNBC
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Investigators previously showed that adding carboplatin
to paclitaxel/liposomal doxorubicin (PM) can improve
pCR rates in patients with TNBC at the cost of added
toxicity.
This study examined whether HRD with BRCA mutation
in the primary tumor (tmBRCA) can predict pCR.
Patients were randomized to receive PM or PM plus
carboplatin stratified by subtype (TNBC, HER2+/HR−,
HER2+/HR+) and Ki67 level.
HER2+, human epidermal growth factor receptor 2 positive; HR−, hormone receptor negative; HRD, homologous recombination
deficiency; pCR, pathologic complete response; TNBC, triple-negative breast cancer.
Von Minckwitz et al, 2014, 2015.
pCR Rates by HR Deficiency
(treatment arms combined)
HR, hormone receptor; pCR, pathologic complete response.
Von Minckwitz et al, 2015.
Conclusions
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HR deficiency in TNBC as well as HRD score in nontmBRCA TNBC are predictors of response to
neoadjuvant anthracycline and taxane containing
chemotherapy irrespective of the use of carboplatin with
the highest response rate being in the HR-deficient
group treated with carboplatin (pCR rate of 64.9%).
HR deficiency may be used to identify patients likely to
have a high response to DNA-damaging agents.
Results have to be confirmed with other studies.
HR, hormone receptor; HRD, homologous recombination deficiency; pCR, pathologic complete response;
TNBC, triple-negative breast cancer.
Management of Patients With Early
Stage TNBC
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Optimal chemotherapy reduces annual odds of
recurrence by ~50%-60%
Anthracyclines and taxanes standard of care
pCR is prognostic, but not predictive
Also important to realize that not all patients who achieve
a pCR are cured; and that most patients without pCR do
not experience disease recurrence at 5 years
Role of platinum agents appealing based on biology and
neoadjuvant therapy, but effect on disease-free survival
or overall survival yet to be evaluated
pCR, pathologic complete response; TNBC, triple-negative breast cancer.
Isakoff et al, 2011.
New Data of Therapies for
Patients With Locally Advanced
and Metastatic Breast Cancer
Entinostat: Differentiated HDAC Inhibitor
Targets Resistance Pathways in Cancer Cells



Oral, class 1 isoform-selective, non-hydroxamic acid
HDAC inhibitor
Differentiated pharmacological properties – long half-life
allows long exposure with infrequent dosing
Combination activity in solid tumors
– Breast cancer with aromatase inhibitors
Inhibition of HDAC causes death of cancer cells.
HDAC, histone deacetylase.
4
CDK Inhibitors: PD 0332991
(Palbociclib)


Highly selective inhibition
of CDK4/6 kinase activity
prohibits progression from
G1 to S phase and thus
prevents cellular DNA
synthesis
Preclinical models
revealed particular
sensitivity in estrogen
receptor–positive breast
cancer
Rocca et al, 2014.
Palbociclib (PD-0332991)



Palbociclib is an oral, highly selective inhibitor of CDK4/6 kinase activity
On February 3, 2015, the FDA granted accelerated approval to palbociclib for use in
combination with letrozole for the treatment of postmenopausal women with ER+,
HER2− advanced breast cancer as initial endocrine-based therapy based on
PALOMA-1/TRIO-18 phase 2 study.
– The PALOMA-1 trial randomized 165 postmenopausal patients with ER+, HER2−
advanced breast cancer
– In the open-label phase 2 study, treatment with palbociclib plus letrozole (n = 84)
reduced the risk for disease progression by 51% compared with letrozole alone
(n = 81).
– Final analysis for PFS (median follow-up 29.6 mo; 95% CI 27.9-36.0) for the
palbociclib plus letrozole group and 27.9 mo (95% CI 25.5-31.1) for the letrozole
group); 41 PFS events had occurred in the palbociclib plus letrozole group and
59 in the letrozole group.
– Median PFS with palbociclib was 20.2 versus 10.2 months for letrozole alone
(HR 0.488; P = .0004).
PALOMA-2 is an ongoing clinical trial of palbociclib + letrozole vs letrozole for first-line
treatment of post-menopausal women with ER+/HER2− advanced breast cancer
(NCT01740427).
ER+, estrogen receptor positive; FDA, US Food and Drug Administration; HER2−, human epidermal growth factor receptor 2
negative; PFS, progression-free survival.
Food and Drug Administration, 2015; Pfizer, NCT01740427, 2015; Finn et al, 2015.
PALOMA-3 Study





The PALOMA-3 study assessed the efficacy of palbociclib and
fulvestrant in endocrine-resistant advanced breast cancer.
Women with HR+/HER2− advanced MBC in whom cancer had
relapsed or progressed on prior endocrine therapy were randomized
2:1 to:
– Palbociclib (125 mg/day orally for 3 wk followed by 1 wk off) and
fulvestrant (500 mg per standard of care) (n = 347)
OR
– Placebo and fulvestrant (n = 174)
Pre- and peri-menopausal women also received goserelin. One
previous line of chemotherapy for metastatic disease was permitted.
Primary endpoint: investigator assessed progression-free survival.
Secondary endpoints: overall survival, response assessment,
patient-reported outcomes, and safety and tolerability.
HER2−, human epidermal growth factor receptor 2 negative; HR+, hormone receptor positive; MBC, metastatic breast cancer.
Turner et al, 2015.
Primary Endpoint:
PFS (ITT Population)
Consistent benefit was seen in both pre- and post-menopausal women.
ITT, intention to treat; PFS, progression-free survival.
Turner et al, 2015.
PALOMA-3 Study: Secondary Endpoints
Palbociclib + Fulvestrant
(n = 347)
% of patients
Placebo + Fulvestrant
(n = 174)
% of patients
P
ORR
10.4
6.3
.1582
CBR*
34.0
19.0
.0004
*CBR is underestimated
At time of interim analysis, overall survival data were immature with 28 deaths.
Summary of Adverse Events
In patients receiving palbociclib + fulvestrant vs placebo + fulvestrant
• Overall incidence of SAEs was similar (9.6% vs 14.0%)
• Incidence of febrile neutropenia was the same (0.6% vs 0.6%)
• Infections were more common (34.2% vs 24.4.%)
No deaths occurred due to AEs/toxicity
AEs, adverse events; CBR, clinical benefit rate; ORR, overall response rate; SAEs, serious adverse events.
Turner et al, 2015.
Conclusions

Palbociclib combined with fulvestrant improved PFS
compared to placebo and fulvestrant in women with
HR+/HER2− advanced breast cancer in whom disease
has progressed on prior endocrine therapy
– HR 0.422 (95% CI 0.318-0.560; P < .000001)



Benefit from palbociclib was also demonstrated across
prespecified groups
Palbociclib was well tolerated
Palbociclib + fulvestrant is an effective treatment option
for women whose cancer progressed on prior endocrine
therapy
HER2−, human epidermal growth factor receptor 2 negative; HR+, hormone receptor positive;
PFS, progression-free survival.
Single Agent Chemotherapy
Outcomes in Refractory MBC
RR
Prior Therapy
Author
PFS
(mo)
Agent
A
T
C
Perez et al,
2007
Ixabepilone
x
x
x
11%
3.1
Cortes et al,
2010
Eribulin
x
x
x
9%
2.6
Cortes et al,
2011
Eribulin
x
x
x/‒
13%
3.7
Etirinotecan pegol
(q 14 days + q 21
days)
x
x
x/‒
29%
4.7
Etirinotecan pegol
(q 21 days only)
x
x
x/‒
29%
5.6
Awada et al,
2013
A, doxorubicin, C, cyclophosphamide; MBC, metastatic breast cancer; PFS, progression-free survival; q, every;
RR, relative rate; T, trastuzumab.
53
BEACON Phase 3 Study Design
CBR, clinical benefit rate; CTC, circulating tumor cell; DoR, duration of response; ECOG PS, Eastern Cooperative Oncology
Group performance status; HRQoL, health-related quality of life; ORR, overall response rate; PD, phamacodynamic;
PFS, progression-free survival; R, randomized
Perez et al, 2015.
Primary Efficacy Endpoint:
Overall Survival
OS, overall survival; TPC, single-agent treatment of physician’s choice.
Perez et al, 2015.
Pre-Planned OS Subgroup
Analyses
EP, endpoint; HER2+, human epidermal growth factor receptor 2 positive; HR+ hormone receptor positive; TNBC, triplenegative breast cancer; TPC, single-agent treatment of physician’s choice.
Perez et al, 2015.
Adverse Events: All Grades
TPC, single-agent treatment of physician’s choice.
Perez et al, 2015.
Conclusions







Etirinotecan pegol has clinical activity and good tolerability in patients
with heavily pretreated advanced breast cancer
The 2.1 month improvement in median survival favoring etirinotecan
pegol did not reach statistical significance
Important survival results in predefined subgroups of patients warrant
further study
History of brain metastases: 10.0 vs 4.8 mo (HR 0.51, P < .01)
History of liver metastases: 10.9 vs 8.3 mo (HR 0.73, P = .002)
Etirinotecan pegol has fewer grade ≥ 3 toxicities and improved quality
of life compared to physician’s choice
Exploration of potential predicative biomarkers is ongoing
Evolving HER2 Landscape

Initial agents
– Trastuzumab (1998)
– Lapatinib (2007)

Recently approved therapies
– Pertuzumab (2012)
– T-DM1 (2013)

Agents in development
– Second-generation HER family TKIs
– Other targets
HER2, human epidermal growth factor receptor 2; TKIs, tyrosine kinase inhibitors.
CLEOPATRA Study
n = 406
Patients with
HER2+ MBC
centrally confirmed
(N = 808)
Placebo + trastuzumab
Docetaxel
1:1
n = 402
≥6 cycles recommended
Pertuzumab + trastuzumab
Docetaxel
≥6 cycles recommended




Median OS: 56.5 mo (95% CI 49.3 to not reached) in the group receiving the
pertuzumab combination vs 40.8 mo (95% CI 35.8-48.3) in the group receiving the
placebo combination (HR favoring the pertuzumab group, 0.68; 95% CI 0.56-0.84; P
< .001)
Median PFS as assessed by investigator: 6.3 mo improvement in the pertuzumab
group (HR 0.68; 95% CI 0.58-0.80)
Pertuzumab extended the median DOR by 7.7 mo, as independently assessed
Most adverse events occurred during the administration of docetaxel in the 2 groups,
with long-term cardiac safety maintained
DOR, duration of response; HER2+, human epidermal growth factor receptor 2 positive; MBC, metastatic breast cancer;
OS, overall survival; PFS, progression-free survival.
Swain et al, 2015.
VELVET: Study Design

A 2-cohort, open-label, multicenter phase 2 trial assessing the efficacy and safety of
pertuzumab in combination with trastuzumab and vinorelbine as first-line treatment
for HER2+ MBC
Male or female patients
with HER2+ MBC not
previously treated with
systemic non-hormonal
anticancer therapy in
the metastatic setting
(n~210)



Cohort 1
Sequential administration of
pertuzumab and trastuzumab
followed by vinorelbine
Cohort 2
Pertuzumab and trastuzumab
administered in a single infusion bag
followed by vinorelbine
As of Jan 22, 2015, the median number of cycles received was 15 for P + T and 9 for
V (range, 2-28).
Grade ≥3 AEs were reported in 78% of patients. Grade ≥3 AEs in ≥5 patients were
neutropenia (30.8%), hypertension (13.1%), diarrhea (5.6%), leukopenia (4.7%),
increased gamma-glutamyl transferase (4.7%), and fatigue (4.7%).
Interim efficacy analyses (ORR and PFS) for C2 are ongoing and will be presented.
AEs, adverse events; HER2+, human epidermal growth factor receptor 2 positive; MBC, metastatic breast cancer; ORR, overall
response rate; P, pertuzumab; PFS, progression-free survival; T, trastuzumab; V, vinorelbine.
Andersson et al, 2015.
Investigating T-DM1 (EMILIA)
Study Design
Women with
HER2+
unresectable
LABC or MBC
(N = 991)

T-DM1
3.6 mg/kg every 3 wk IV
1:1
Primary endpoints
– OS
– PFS by independent review
– Safety
(n = 495)
Capecitabine
1,000 mg/m2 orally twice daily
days 1-14, every 3 wk
+
Lapatinib
1,250 mg/day orally every day
(n = 496)
HER2+, human epidermal growth factor receptor 2 positive; LABC, locally advanced breast cancer; MBC,
metastatic breast cancer; T-DM1, trastuzumab emtansine.
Verma et al, 2012.
EMILIA: PFS and Overall Survival
Lapatinib/Cape vs T-DM1
PFS
T-DM1: 9.6 months
OS
T-DM1: 30.9 months
OS, overall survival; PFS, progression-free survival; T-DM1, trastuzumab emtansine.
Verma et al, 2012. From The New England Journal of Medicine, Verma et al, Trastuzumab emtansine for HER2-positive
advanced breast cancer, 367, 1784. Copyright © 2012 Massachusetts Medical Society. Reprinted with permission from
Massachusetts Medical Society.
MARIANNE Study Design
HER2+, human epidermal growth factor receptor 2 positive; LABC, locally advanced breast cancer; LD, loading dose; MBC,
metastatic breast cancer; OS, overall survival; PFS, progression-free survival; q, every; T-DM1, trastuzumab emtansine; w, week.
Ellis et al, 2015.
Progression-Free Survival by IRF
HT, hormone therapy; IRF, independent review facility; P, pertuzumab; PFS, progression-free survival;
T-DM1, trastuzumab emtansine.
Ellis et al, 2015.
Overview of Adverse Events
AE, adverse event; HT, hormone therapy; LVEF, left ventricular ejection fraction; P, pertuzumab; T-DM1, trastuzumab
emtansine.
Ellis et al, 2015.
Conclusions



T-DM1 and T-DM1+P demonstrated non-inferior PFS
compared with HT, but were not superior to HT
The addition of P to T-DM1 did not improve PFS
T-DM1 was better tolerated than HT
– Fewer grad ≥3 Aes and less treatment discontinuations due to Aes
observed with T-DM1 vs HT
– No febrile neutropenia; less neuropathy, diarrhea and alopecia seen with
T-DM1
– More transaminase elevation and thrombocytopenia observed with T-DM1


Health-related quality of life maintained for a longer
duration with T-DM1
T-DM1 is an alternative treatment option to HT in
previously untreated HER2-positive MBC
AEs, adverse events; HER2, human epidermal growth factor receptor 2; HT, hormone therapy; MBC, metastatic breast
cancer; PFS, progression-free survival; P, pertuzumab; T-DM1, trastuzumab emtansine.
What Is the Optimal Duration
of Therapeutic Options for
Triple-Negative Breast Cancer?
Enzalutamide in TNBC: Results of
Phase 2 Study (MDV3100-11)





An open-label, Simon 2-stage study evaluating single agent
enzalutamide (160 mg/day orally) in advanced AR+ TNBC (AR >0%
by IHC).
Eligibility: Patients could be prescreened for AR; have nonmeasurable bone disease and unlimited prior regimens; CNS
metastases or seizure history were exclusionary.
Primary endpoint: clinical benefit (CR, PR, or SD) at 16 wk (CBR16)
in evaluable patients defined as having both AR IHC ≥10% and a
response assessment.
Other endpoints: CBR24, PFS, response rate, and safety.
An androgen-driven gene signature (Dx) was created from gene
profiling and outcomes were assessed accordingly.
AR, androgen receptor; CR, complete response; IHC, immunohistochemistry; PFS, progression-free survival; PR, partial
response; SD, stable disease; TNBC, triple-negative breast cancer;
Traina et al, 2015.
Clinical Benefit in Evaluable
and ITT Populations
AR, androgen receptor; CBR, clinical best response; CR, complete response; IHC, immunohistochemistry; ITT,
intention to treat; PR, partial response.
Traina et al, 2015.
Conclusions



Enzalutamide has clinical activity in patients with “AR
positive” TNBC
Safety data are consistent with the known profile of
enzalutamide
A novel genomic diagnostic assay, PREDICT AR, may
identify patients with TNBC who benefit from
enzalutamide treatment
– Clinical outcomes with enzalutamide treatment, including overall
survival, were superior in patients with PREDICT AR+ vs PREDICT AR–
TNBC in exploratory analyses

Results from this phase 2 study support continued
development of enzalutamide in patients with PREDICT
AR+ TNBC
AR, androgen receptor; TNBC, triple-negative breast cancer.
Immunotherapy in
Triple-Negative Breast Cancer
Rationale


Patients with triple-negative breast cancer have
a worse prognosis than patients with other
breast cancer subtypes, and in the United
States, there is currently no targeted treatment
available; therefore, immunotherapy is an area
of research that bears merit for pursuing
Anti–PD-1/PD-L1 agents are approved in
melanoma and are showing promise in other
tumor types, such as breast cancer
PD-1, programmed cell death protein 1; PD-L1, programmed cell death protein ligand 1.
Pembrolizumab: KEYNOTE-012
Trial


Phase 1b trial of pembrolizumab (MK-3475) in heavily pretreated
patients with TNBC who had either experienced disease relapse
after treatment of early stage disease or disease progression while
on therapy for advanced disease
Results
– 27 evaluable patients
• 5 patients (18.5%) had overall response including 1 CR (3.7%) and 4 PRs
(14.8%)
• 7 patients (25.9%) had stable disease
• 12 patients (44.4%) had progressive disease
• 3 patients (11.1%) were not assessed
–
–
–
–
Median time to response: 18 weeks
Median PFS: 1.9 months
Durable responses ranging from 15 to 40 weeks
These promising results warrant further research and clinical trials
CR, complete response; PFS, progression-free survival; PR, partial response; TNBC, triple-negative breast cancer.
Nanda et al, 2014.
MPDL3280A Phase 1 Study


Phase 1 study of MPDL3280A in heavily pretreated
patients with TNBC (N = 54); 59% had visceral
metastases and 11% had bone metastases
Results
–
–
–
–
–
24-week PFS rate = 27%; ORR = 19%
2 PRs; 2 CRs
DOR = 0.1 to >41.5 weeks
Median response time = not reached
Common adverse effects included loss of appetite, nausea,
fatigue, and fever
CR, complete response; DOR, duration of response; ORR, overall response rate; PR, partial response;
TNBC, triple-negative breast cancer.
Emens et al, 2014.
Overall Summary

Medical practice is based on standards of care
– Best approach for the average populations, not for
specific individuals

Application of systems biology to personalized
breast cancer therapy
– Molecular profiling technologies to tailor medical care

Challenges
– Identifying and validating molecular markers
– Molecular crosstalk and bypass mechanisms
– Early predictors of outcome