Transcript Building on the Success of Targeted Therapies in

Building on the Success of Targeted
Therapies in Metastatic Disease
Harold J. Burstein, MD, PhD
Assistant Professor of Medicine
Department of Oncology
Dana-Farber Cancer Institute
Boston, Massachusetts
1
Trastuzumab




Monoclonal antibody binding to HER2/neu (erbB2)
receptor
Standard treatment (in combination with
chemotherapy) for HER2-positive metastatic breast
cancer for past 7 years
Reduces the risk of recurrent HER2-positive disease
by ~50%
Cardiotoxicity the most important adverse event
– Trastuzumab + paclitaxel: 13%
– Trastuzumab + anthracycline: 27%
Piccart-Gebhart MJ. 42nd ASCO; June 2-6, 2006. Education Session.
2
Bevacizumab
Targets tumor angiogenesis—the formation of
new blood vessels necessary to support tumor
growth and metastasis—by inhibiting vascular
endothelial growth factor, an important signaling
molecule in regulating this process1,2
1. Cross MJ, Claesson-Welsh L. Trends Pharmacol Sci. 2001;22:201.
2. Brown JM, Giaccia AJ. Cancer Res. 1998;58:1408.
3
Bevacizumab + Paclitaxel
Phase III Trial
The addition of bevacizumab (BEV) to paclitaxel (PAC) doubled
the response rate and extended progression-free survival by
almost 5 months, compared with paclitaxel alone
PAC Alone PAC/BEV
(n = 316) (n = 330)
Response rate (%)
14.2
28.2
Progression-free survival (mo) 6.1
10.97
Miller KD, et al. 41st ASCO; May 13-17, 2005.
4
Bevacizumab + Paclitaxel
Toxicities




13% of patients receiving bevacizumab developed
hypertension requiring treatment
Serious bleeding events were rare and not
substantially increased with addition of bevacizumab
There was a significant increase in grade 3 neuropathy
from 13.6% with paclitaxel alone to 19.9% in the
combination arm
Chemotherapy-related toxicities were mild and did not
interfere with therapy
Miller KD et al. 41st ASCO; May 13-17, 2005. Abstract.
5
ASCO 2006—New Trastuzumab Combination
Regimens in Metastatic/Recurrent Disease




Trastuzumab + vinorelbine
Trastuzumab + bevacizumab
Trastuzumab + docetaxel +/- carboplatin
Trastuzumab + heat shock protein inhibitor
6
Trastuzumab + Vinorelbine vs Trastuzumab + Taxane
HER2+ Metastatic Breast Cancer
Trastuzumab/
Vinorelbine
n = 41
Trastuzumab/
Taxane*
n = 40
P-Value
Response rate
(strict criteria)
51%
40%
.37
Response rate
(unconfirmed)
66%
58%
.50
8.5
6.0
.09
Median time to
Progression (mo)
Weekly trastuzumab + vinorelbine is at least as effective as weekly
trastuzumab/taxane
* Paclitaxel (n=14), docetaxel (n=24), or paclitaxel/carboplatin (n=2) at discretion of treating oncologist.
Burstein HJ, et al. 42nd ASCO; June 2-6, 2006. Abstract 650.
7
Trastuzumab + Vinorelbine vs
Trastuzumab + Taxane
Time to Tumor Progression (TTP)
1.0 Median TTP:
Probability
0.8 -
A (Trast + Vln)
B (Trast + Tax)
0.6 0.4 0.2 Log-rank P = .20
0.0 0
2
4
6
8
10
Months
12
14
16
18
Courtesy of Burstein HJ, et al. 42nd ASCO; June 2-6, 2006. Abstract 650. Poster Session.
8
Trastuzumab + Vinorelbine vs Trastuzumab + Taxane
Toxicities




Generally similar
Trastuzumab + vinorelbine
– Greater myelosuppression
Trastuzumab + taxane
– Greater hair loss, nail changes, rash,
and fluid retention
Cardiotoxicity <5% in all groups
Burstein HJ, et al. 42nd ASCO; June 2-6, 2006. Abstract 650. Poster Session.
9
Trastuzumab + Bevacizumab
Relapsed/Metastatic HER2+ Disease


First report of 2 humanized monoclonal antibodies in
humans
Phase 1 (9 patients)
– 2 complete responses; 3 partial responses;
2 stable disease (>6 mo)

Phase II ongoing (16 patients with response)
– 8 partial responses; 6 stable disease
Rugo HS. 42nd ASCO; June 2-6, 2006. Education Session.
10
Trastuzumab (T) + Docetaxel (D) +/- Carboplatin (C)
Phase III Trial in HER2+ Metastatic Breast Cancer
TD
n = 131
TDC
n = 131
P-Value
Median time to
tumor progression (mo)*
11.1
10.4
.57
Objective response rate
73%
73%
Duration of response (mo)
10.7
9.4
Not reached
41.7
67%
67%
Median overall survival (mo)
Clinical benefit
* Primary end point
No increase in benefit with the addition of carboplatin to trastuzumab + docetaxel
Forbes JF, et al. 42nd ASCO; June 2-6, 2006. Abstract LBA516.
11
Trastuzumab + Heat Shock Protein (HSP)
Inhibitor




Chaperone protein is required for maturation and stabilization of
certain client proteins, including HER2
Inhibition of HSP90 chaperone function induces degradation of
client protein
Phase I trial of KOS-953, an HSP90 inhibitor, plus trastuzumab:
17 HER2+ patients with trastuzumab-resistant metastatic breast
cancer
– 1 partial response, 3 minimal response, 5 prolonged (>4 mo)
stable disease
Phase II trial under way
Modi S, et al. 42nd ASCO; June 2-6, 2006. Abstract 501.
12
Trastuzumab Resistance


Virtually all HER2+ metastatic breast cancers
develop resistance
Adjuvant trastuzumab reduces the annual
hazard rate by 1/2, ie, 1/2 of recurrences are
not prevented
Sledge GW. 42nd ASCO; June 2-6, 2006. Education Session.
13
Possible Causes of Trastuzumab
Resistance





Suboptimal drug delivery
Altered target expression
Altered target
Modified target-regulating proteins
Alternative pathway signaling
Sledge GW. 42nd ASCO; June 2-6, 2006. Education Session.
14
Overcoming Trastuzumab Resistance



Block the HER pathway(s) at other points
Block other growth factor receptor pathways
(HER1, IGF-1R)
Block angiogenesis
Sledge GW. 42nd ASCO; June 2-6, 2006. Education Session.
15
Lapatinib
Dual inhibitor targeting both erbB1 (or epidermal
growth factor) and erbB2 (or HER2/neu) receptors
16
Lapatinib
Mechanism of Action
Lapatinib and Trastuzumab:
Potential for Synergy
Phase I trial:
Storniolo, SABC 2005
Trastuzumab
Lapatinib
Maximum inactivation of
ErbB2 Pathway
• ErbB2 receptor
• Truncated Erb2 receptor
• ErbB1/ErbB2 heterodimes
Downstream signaling cascade
Cell Division/Tumor Growth
Rugo HS. 42nd ASCO; June 2-6, 2006. Education Session.
17
Lapatinib+Capecitabine vs Capacitabine in
Trastuzumab-Resistant Disease
Time to Tumor Progression
Lapatinib/
Capecitabine
n = 160
Capecitabine
n = 161
Progressed or died
45 (28%)
69 (43%)
Median TTP (wk)
36.9
19.7
Hazard ratio (95% CI)
P-value (log rank, 1-sided)
0.51 (0.35, 0.74)
.00016
Geyer CE, et al. Presented at 42nd ASCO; June 2-6, 2006. Special Session.
18
Lapatinib + Capecitabine vs Capecitabine
in Trastuzumab-Resistant Disease
Brain Metastases as Site of Progression
Lapatinib/
Capecitabine
n = 160
Capecitabine
n = 161
Patients with CNS
metastases at baseline
2
2
Patients with CNS relapse*
4
11
Patients with CNS as
only site of relapse
3
10
*P-value (Fisher’s exact, 2-sided) = .110
Geyer CE, et al. 42nd ASCO; June 2-6, 2006. Special Session.
19
Lapatinib + Capecitabine vs Capacitabine
in Trastuzumab-Resistant Disease
Adverse Events (AEs)





Similar rates for all AEs and serious AEs
Most common AEs: diarrhea, PPE, rash, and/or skin reactions
AEs leading to discontinuation of study medication
– Lapatinib + capecitabine: 22 (14%)
– Capecitabine: 16 (11%)
Cardiac events
– 4 lapatinib + capecitabine; 1 capecitabine
– All asymptomatic (grade 2)
– No withdrawals due to decreased LVEF
1 treatment-related death in capecitabine arm
PPE = palmar-plantar erythrodysesthesia; LVEF = left ventricular ejection fraction.
Geyer CE, et al. 42nd ASCO; June 2-6, 2006. Special Session.
20
Lapatinib + Capecitabine vs Capecitabine
in Trastuzumab-Resistant Disease
Summary
Compared with capecitabine alone, lapatinib +
capecitabine results in
– Significantly longer time to tumor progression
– Fewer CNS metastases
– Comparable safety
21
Lapatinib in Brain Metastases



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Approximately 1/3 of women with HER2+ metastatic breast
cancer develop CNS metastases
Apparently higher incidence of CNS metastases in women
treated with trastuzumab
Trastuzumab is not thought to cross the blood-brain barrier
Phase II trial of lapatinib monotherapy in CNS metastases
– 39 patients with CNS metastases that developed on
trastuzumab (38 of whom progressed after prior radiation)
 2 partial responses by RECIST
 8 progression-free in CNS at 16 weeks
 Volumetric declines >30% in 4 patients; declines of
10% to 30% in an additional 6 patients
RECIST = Response Evaluation Criteria in Solid Tumors.
Lin NU, et al. 42nd ASCO; June 2-6, 2006. Abstract 503.
22
Lapatinib Monotherapy
in Inflammatory Breast Cancer
Partial response
Cohort A:
erbB2+
(n = 24)
Cohort B:
erbB1+/erbB2(n = 12)
62%
8.3%
erbB2 overexpression, but not erbB1 expression alone,
predicts for sensitivity to lapatinib in inflammatory breast cancer
Spector NL, et al. 42nd ASCO; June 2-6, 2006. Abstract 502
23
Conclusions
Targeted therapy has assumed a prominent role in the
treatment of breast cancer



Three targeted agents—trastuzumab, bevacizumab,
and lapatinib—have demonstrated impressive activity
in metastatic breast cancer
Trastuzumab + vinorelbine has proven at least as
efficacious as trastuzumab + taxane-based treatment
The combination of 2 targeted agents—trastuzumab
and bevacizumab—shows promising early results
24
Conclusions
(cont’d)
New agents and approaches continue to expand the
benefit of targeted therapy
• Inhibition of heat shock protein (HSP) chaperone
function by a HSP90 inhibitor induces degradation of
HER2 and may increase efficacy of trastuzumab when
used in a combination regimen
• Lapatinib is effective in treating trastuzumab-resistant
tumors; early results indicate that it may be beneficial
in treating CNS metastases and inflammatory breast
cancer, as well
25
Getting the Most Out
of Targeted Therapy
Francisco J. Esteva, MD, PhD
Associate Professor of Medicine
Breast Medical Oncology
The University of Texas
M.D. Anderson Cancer Center
Houston, Texas
26
Trastuzumab in Early-Stage Disease
27
HERA Trial
2-Year Follow-Up
HERA Trial Design
Women with locally determined HER2 +
invasive early breast cancer
Surgery + (neo)adjuvant CT ± RT
Centrally confirmed IHC 3+
or FISH+ and LVEF ≥ 55%
Randomization
Observation
1 year trastuzumab
8 mg/kg
6 mg/kg
3 weekly schedule
2 year trastuzumab
8 mg/kg
6 mg/kg
3 weekly schedule
X
After ASCO 2005,
option of switch
to trastuzumab
CT = chemotherapy; RT = radiotherapy; IHC = immunohisochemistry; FISH = fluorescence
in situ hybridization; LVEF = left ventricular ejection fraction.
Smith IE. Presented at 42nd ASCO; June 2-6, 2006.
28
HERA Trial
Disease-Free Survival (ITT)
Median Follow-Up 2 years
100
1 year trastuzumab
Patients (%)
80
6.3%
Observation
60
3-year
Events DFS
40
218
321
20
80.6
74.3
HR
95% Cl
P-Value
0.64 0.54, 0.76 <.0001
0
No.
at risk
0
6
1703
1698
1591
1535
24
12
18
30
Months from Randomization
1434
1330
1127
984
742
639
383
334
36
140
127
ITT = intent to treat; DFS = disease-free survival; HR = hazard ratio; CI = confidence interval.
Smith IE. 42nd ASCO; June 2-6, 2006.
29
HERA Trial
Overall Survival (ITT)
Median Follow-Up 2 Years
1 year trastuzumab
100
2.7%
Patients (%)
80
Observation
60
3-year
Events OS
40
59
90
20
92.4
89.7
HR
95% Cl
P-Value
0.66 0.47, 0.91 .0115
0
No.
at risk
0
6
1703
1698
1627
1608
24
12
18
30
Months from Randomization
1498
1453
1190
1097
794
711
407
366
36
146
139
ITT = intent to treat; OS = overall survival; HR = hazard ratio; CI = confidence interval.
Smith IE. 42nd ASCO; June 2-6, 2006.
30
HERA Trial
Cardiac Safety
Number Patients (%)
Observation
n = 1708
Trastuzumab: 1 y
n = 1678
Cardiac death
Severe CHF
(NYHA III and IV)
1 (0.1)
0 (0.0)
0 (0.0)
10 (0.6)
Symptomatic CHF
3 (0.2)
36 (2.1)
Confirmed significant
LVEF drop
9 (0.5)
51 (3.0)
CHF = congestive heart failure; NYHA = New York Heart Association; LVEF = left
ventricular ejection fraction.
Smith IE. 42nd ASCO; June 2-6, 2006.
31
HERA Trial
Summary



Trastuzumab following adjuvant chemotherapy
significantly improves overall survival (HR 0.66)
in women with early-stage HER2+ breast cancer
Gain in disease-free survival after 1 year median
follow-up is maintained after 2 years median
follow-up
Risk of cardiac toxicity remains low
HR=hazard ratio
Smith IE. 42nd ASCO; June 2-6, 2006.
32
Identification of Patients Likely to Benefit


Balancing risk and benefit
Using biomarkers to predict response
– Trastuzumab
– Anti epidermal growth factor receptor therapy
33
Trastuzumab for All HER2+ Patients?



Adjuvant trastuzumab results in significant reduction of
recurrence in high-risk HER2+ breast cancer patients
However, trastuzumab is associated with significant cardiac
toxicity
What is the risk of adverse effects vs survival benefit of
trastuzumab in patients with low risk of recurrence and/or high
risk of cardiac toxicity?
Gupta AK, et al. 42nd ASCO; June 2-6, 2006. Abstract 6022.
34
Low Risk of Recurrence and/or High Risk of Toxicity
Patient
Treatment
Cumulative
Cardiac
Toxicity (%)
50 y
2 cm
node+
ER/PREF 60%
CT
0.8
20.61
CT+T
6
25.34
81.9
0.68
CT
0.8
13.58
62.1
0.06
CT+T
20
14.18
66.8
2.03
70 y
2 cm
nodeER/PREF 50%
QALYs
10-y
DFS (%)
70.2
10-y
Cardiac Deaths (%)
0.06
QALYs = quality adjusted life years; DFS = disease-free survival; CT = chemotherapy;
T= trastuzumab; ER = estrogen receptor; PR = progesterone receptor; EF = ejection fraction.
Gupta AK, et al. 42nd ASCO Abstracts. J Clin Oncol. 2006;24:Abstract 6022. Reprinted with
permission from the American Society of Clinical Oncology.
35
Conclusions


The addition of trastuzumab to standard
chemotherapy is more beneficial than standard
chemotherapy alone in most cases, including
elderly patients with node-negative disease and
those at increased risk of cardiac toxicity
However, incremental benefit decreases with
increasing age, higher risk of cardiac toxicity,
and lower risk of recurrence
Gupta AK, et al. 42nd ASCO Abstracts. J Clin Oncol. 2006;24:Abstract 6022. Reprinted with
permission from the American Society of Clinical Oncology.
36
Change in Serum HER2 and Outcome
Change in HER2
Serum Levels
from Baseline
ORR
DR
(median/d)
<20% decrease
28.4%
230
182
593
>20% decrease
56.5%
369
320
898
P value
<.001
.008
<.001
.018
TTP
(median/d)
OS
(median/d)
Patients with <20% decrease in serum HER2 have decreased benefit from
trastuzumab and should be considered for additional HER2-targeted therapies
ORR = objective response rate; DR = duration of response; TTP = time to tumor progression;
OS = overall survival.
Ali SM, et al. 42nd ASCO Abstracts. J Clin Oncol. 2006;24:Abstract 500. Reprinted with
permission from the American Society of Clinical Oncology.
37
ER+/PR- Status

Compared with ER+/PR+ disease, ER+/PRbreast cancer has
– Lower response rate to estrogen deprivation
– Worse prognosis
– May be dependent on other signaling
pathways
ER = estrogen receptor; PR = progesterone receptor.
Finn RS, et al. 42nd ASCO; June 2-6, 2006. Abstract 514.
38
ER+/PR- Breast Cancer and EGFR Inhibition



Presurgical exposure to short-term gefitinib, an EGFR inhibitor, in 43
patients with operable breast cancer
Tissue obtained at surgery
– ER+/PR- tumors more likely to show molecular growth inhibition
– ER+/PR+ tumors more likely to show molecular growth
proliferation
Conclusions
– ER+/PR- breast cancer is growth factor dependent
– ER+/PR- patients may be more likely to benefit from EGFR
inhibition
ER = estrogen receptor; PR = progesterone receptor; EGFR = epidermal growth factor receptor.
Finn RS, et al. 42nd ASCO; June 2-6, 2006. Abstract 514.
39
EGFR Expression and Tumor Characteristics




Comparision of EGFR+ and EGFR- tumors in 2567 patients
EGFR+ tumors were more common in patients who were
– Younger (<50 y)1
– Premenopausal1
– Black2
EGFR expression was associated with
– Larger tumors1
– Aneuploidy1
– High S-phase fraction1
– Nodal involvement3
EGFR+ tumors were more likely to be HER2+1, but less likely to be ER+1 and
PR+1
P <.0001
2 P = .005
3 P = .009
EGFR = epidermal growth factor receptor; ER = estrogen receptor; PR = progesterone receptor.
Rimawi MF, et al. 42nd ASCO; June 2-6, 2006. Abstract 513.
40
1
EGFR Expression and Prognosis


1256 treated patients;1 1068 untreated patients2
In treated patients, EGFR expression was negatively correlated
with
– DFS (P = .001)
– 0S (P = .001)

No relationship was found between EGFR status and DFS or
OS in untreated patients
EFGR expression is associated with significant resistance to adjuvant
hormonal therapy and chemotherapy. Blocking EFGR activity may help to
overcome this resistance in selected patients
1 Systemic
chemotherapy and/or hormonal therapy
2 No systemic therapy
EGFR = epidermal growth factor receptor; DFS = disease-free survival; OS = overall survival.
Rimawi MF, et al. 42nd ASCO; June 2-6, 2006. Abstract 513.
41
Cost-Effectiveness of Trastuzumab—Model 1



Cost-effectiveness of adding trastuzumab to standard adjuvant therapy
(doxorubicin, cyclophosphamide, and paclitaxel)
Based on Markov model with 3 disease states
– Disease-free survival
– Recurrence
– Death
Costs included
– Testing for HER2 status
– Drug and administration costs for trastuzumab
– Cardiac monitoring
– Treatment of cardiac toxicity
– Treatment following recurrence
– End-of-life costs for dying patients
Garrison LP Jr, et al. 42nd ASCO; June 2-6, 2006. Abstract 6023.
42
Cost-Effectiveness of Trastuzumab—Model 1
(cont’d)



Patient: 50 year-old woman
Efficacy based on NCCTG N9831 and NSABP B-31 trials; projections to
recurrence and death based on literature (Lancet, 2005)
With trastuzumab
– Lifetime cost per QALY gained: $27,800 (range: $17,900 to $39,100)
– Projected life expectancy 3 years longer (trastuzumab: 19.4 years;
without trastuzumab: 16.4 years)
– Additional cost of adding trastuzumab: $46,300
– Expected gain of 1.28 QALY
– Cost/QALY = $36,100
Utility/cost ratio of adding trastuzumab is below that of many
treatments used for oncology patients.
Garrison LP Jr, et al. 42nd ASCO; June 2-6, 2006. Abstract 6023.
43
Cost-Effectiveness of Trastuzumab in EarlyStage and Metastatic Breast Cancer—Model 2
Comparison of
 Cost per relapse prevented by adjuvant
chemotherapy (docetaxel, paclitaxel, filgrastim)
vs
 Cost per relapse prevented by adjuvant
trastuzumab
Wilson E, et al. 42nd ASCO; June 2-6, 2006. Abstract 6081.
44
Cost-Effectiveness of Trastuzumab in EarlyStage and Metastatic Breast Cancer—Model 2
(cont’d)
Trastuzumab Docetaxel Paclitaxel
Reduction
in relapse
Cost per relapse
prevented
50%
€ 147,000
Filgrastim
7%1
5%2
4%3
€ 126,000
€ 148,000
€ 231,000
Adjuvant trastuzumab is more cost-effective than adjuvant paclitaxel
or filgrastim
BCIRG 001
2 CALGB 9344
3 CALGB 9741
Wilson E, et al. 42nd ASCO; June 2-6, 2006. Abstract 6081.
1
45
Cost-Effectiveness of Trastuzumab in EarlyStage and Metastatic Breast Cancer—Model 2
(cont’d)
Conclusions
 Assuming no retreatment with trastuzumab,
adjuvant trastuzumab appears to be a relatively
cost-effective means of reducing relapses
 Possibility of a shorter treatment regimen
(FinnHER study) should result in even greater
cost-effectiveness
Wilson E, et al. 42nd ASCO; June 2-6, 2006. Abstract 6081.
46
Conclusions



Initial gains in disease-free survival and overall survival
observed with trastuzumab in early-stage breast
cancer continue to be sustained after median follow-up
of 2 years
Trastuzumab is cost-effective in reducing relapse and
compares favorably with many treatments used for
oncology patients
Clinical benefit and cost-effectiveness can be
increased with the use of biomarkers to identify
patients most likely to benefit from targeted therapies
47
Adverse Events and
Targeted Therapy
Maureen Major, RN, MS
Clinical Nurse Specialist
Department of Nursing
Memorial Sloan-Kettering Cancer Center
New York, New York
48
Adverse Events


Cardiac toxicity
Osteoporosis
49
NCCTG N9831 Trial Designs
NCCTG N9831
Arm A
Arm B
Arm C
= Doxorubicin/cyclophosphamide 60/600 mg/m2 q3wk x 4
= Paclitaxel 175 mg/m2 q3wk x 4
= Paclitaxel 80 mg/m2 qwk x 12
= Trastuzumab 4 mg/kg loading  2 mg/kg qwk x 51
NCCTG = North Central Cancer Treatment Group.
N9831 PI. EA Perez.
With permission from Romond E. ASCO 2005; May 13–17, 2005. Oral Presentation.
50
Incidence of Trastuzumab-Related Cardiac Toxicity
in NSABP B31
Percent
6
4
Arm 2: AC P+T (N = 850)
31 CHFs
No cardiac deaths
HR = 5.9
Arm 1: AC P (N = 814)
4 CHFs
0.8%
1 cardiac death
2
0
4.1%
0.0
0.5
Cohort
1.0
1.5
2.0
2.5
Years Post Day 1 Cyc 5
3.0
Arm 1 Evaluable Cohort
Arm 2 Evaluable Cohort
NSABP = National Surgical Breast and Bowel Project; AC = doxorubicin/cyclophosphamide; P = paclitaxel;
T = trastuzumab; CHF = congestive heart failure; HR = hazard ratio.
Tan-Chiu E, et al. J Clin Oncol. 2005;23:7811-7819.
51
Assessing Cardiotoxicity
with Trastuzumab Therapy





Goal—to discover dysfunction early
Diastolic dysfunction may be better predictor
Diagnostic testing
– Echocardiography and doppler flow study
– Multiple gated acquisition Scan (MUGA)
Blood testing
– Troponin = measurement of heart injury
– Brain natriuretic peptide (BNP) = strain
Monitor every 3 months
Swain SM. 42nd ASCO; June 2-6, 2006.
52
Radiotherapy + Trastuzumab
Does Concomitant Administration
Increase Risk?



Preclinical studies suggest that
trastuzumab may enhance radiotherapy
Trastuzumab, doxorubicin, and
ARM
radiotherapy are potentially cardiotoxic
A
The NCCTG N9831 study examined
adverse effects of concomitant
radiotherapy + trastuzumab following
chemotherapy in patients with stage I–IIA B
breast cancer:
NCCTG N9831
C
NCCTG = North Central Cancer Treatment Group.
Halyard MY, et al. 42nd ASCO; June 2-6, 2006. Abstract 523.
N9831 PI. EA Perez.
With permission from Romond E. ASCO 2005; May 13–17, 2005. Oral Presentation.
53
Radiotherapy + Trastuzumab
Does Concomitant Administration
Increase Risk?



Timing: radiotherapy (RT) given concurrently with trastuzumab
and within 5 weeks of completing paclitaxel
Patient characteristic
– Lumpectomy: whole breast RT with optional tumor bed
boost
– Mastectomy: ≥ 4+ nodes received nodal and chest wall RT
Internal mammary nodal (IMN) RT not permitted
– However, 41/1433 (3%) of patients received IMN
– Dosimetry review showed that all 41 had cardiac sparing
Halyard MY, et al. 42nd ASCO; June 2-6, 2006. Abstract 523.
54
Radiotherapy + Trastuzumab
Cardiac Events
Cardiac Events (% Pts)*
NCCTG 9831
B
C
+RT
2.2
–RT
2.9
1.5
6.3
*Median follow-up of 1.5 years
NCCTG = North Central Cancer Treatment Group; RT = radiotherapy.
Halyard MY, et al. 42nd ASCO; June 2-6, 2006. Abstract 523.
With permission from Romond E. ASCO 2005; May 13–17, 2005. Oral Presentation.
55
Lapatinib
Dual Tyrosine Kinase Inhibitor





Lapatinib is an epidermal growth factor receptor and
ErbB2 (Her2/neu) inhibitor
Studies under way in treatment of solid tumors, such as
breast and lung cancer
ErbB2 signaling is important for cardiac function
Trastuzumab is known to be associated with cardiac
toxicity
Is lapatinib associated with cardiac toxicity?
56
Prospective Evaluation of Lapatinib
Cardiac Safety





1674 breast cancer patients treated with lapatinib
Decreased LVEF: 22 (1.3%)
– Symptomatic:
2 (0.1%)
– Asymptomatic: 20 (1.2%)
Average LVEF decrease relative to baseline: 29%
(range 22%–42.3%)
Average duration: 40 days (9–113)
41% (9/22) recovered while continuing to receive
lapatinib
Perez EA, Byrne JA. 42nd ASCO: June 2-6, 2006. Updated abstract 583.
57
22 Patients
with Decreased LVEF
Characteristics of 22 Patients with Breast Cancer and Decreased LVEF
45
13
Symptomatic Patients
11
35
10
30
9
8
7
Patient
% LVEF Decrease Relative to Baseline
40
25
20
6
15
5
4
10
3
2
1
5
0
Symptomatic Patients
12
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 22
0
Patient
20
40
60
80
100
120
LVEF Event Duration (D)
Perez EA, Byrne JA. 42nd ASCO: June 2-6, 2006. Updated abstract 583.
58
Osteoporosis



Breast cancer patients with bone metastases are at an increased risk
for skeletal-related events
– Fractures
– Hypercalcemia of malignancy
– Spinal cord compression
– Pain
Goals of treatment
– Treat underlying disease
– Stabilize the bone
– Prevent further bone breakdown
– Relieve pain
– Improve quality of life
Measurement of bone loss
– Urinary N-telopeptide levels (uNTx): biomarker for bone turnover
Peterson MC, et al. 42nd ASCO; June 2-6, 2006. Abstract 3086.
59
Bone Turnover
Bone remodeling is characterized by 2 activities
 Resorption of old bone by osteoclasts
 Formation of new bone by osteoblasts
60
Osteoporosis
Current and Emerging Treatment Options
Bisphosphonate therapy
– Oral
– Intravenous
 Zoledronic acid
 Pamidronate disodium
 Emerging therapies
– Denosumab

Peterson MC, et al. 42nd ASCO; June 2-6, 2006. Abstract 3086.
61
Denosumab—Mechanism of Action


RANKL
– A key mediator of osteoclast formation, function,
and survival, thus, a pivotal factor in much of the
pathologic bone destruction associated with bone
metastases
Denosumab
– Binds to and inhibits RANKL, potentially reducing
bone destruction in patients with breast cancer
RANKL = receptor activator of NFKappa B ligand.
Lipton A. 42nd ASCO; June 2-6, 2006. Abstract 512.
62
Effects of Denosumab on Bone Resorption in
Breast Cancer Patients
with Bone Metastases



5 cohorts of ~40 patients each
Dosages
– Denosumab 30 mg Q4W
– Denosumab 120 mg Q4W
– Denosumab 180 mg Q4W
– Denosumab 60 mg Q12W
– Denosumab 180 mg Q12W
Rapid and sustained suppression of uNTx from
baseline in all 5 cohorts
Peterson MC, et al. 42nd ASCO; June 2-6, 2006. Abstract 3086.
63
Effect of Denosumab on Bone Resorption
and Skeletal-Related Events
% Change in uNTx
from baseline to week 13
IV bisphosphonates
Denosumab
30 mg Q4wk SC
120 mg Q4wk SC
180 mg Q4wk SC
60 mg Q12wk SC
180 mg Q12wk SC
Lipton A. 42nd ASCO; June 2-6, 2006. Abstract 512.
No. (%) of pts with
>1 SRE on study
-79
7 (16)
-71
-82
-71
-63
-71
4 (10)
5 (12)
5 (12)
3 (5)
3 (7)
64
Denosumab Adverse Events

Commonly reported adverse events
– Nausea
– Vomiting
– Asthenia
– Diarrhea
– Bone pain
Lipton A. 42nd ASCO; June 2-6, 2006. Abstract 512.
65
Denosumab
Summary




Resulted in a rapid suppression of bone turnover among
advanced cancer patients with bone metastases; these results
were also sustained at all time points measured in the study
Appears to be at least as effective as intravenous
bisphosphonates in preventing skeletal-related events
No dose-dependent increase in adverse events
No serious or fatal adverse events
Lipton A. 42nd ASCO; June 2-6, 2006. Abstract 512.
66
Cancer …………
Touches One and All