Current status of adjuvant HER2 targeting therapy
Valentina Guarneri, MD, PhDIstituto Oncologico Veneto IRCCS
University of Padova
• Trastuzumab plus chemotherapy: the gold standard for
HER2 positive early breast cancer
• Improving on cardiac toxicity: different regimens and
different treatment durations
• Improving on treatment efficacy: dual blockade and new
anti-HER2 agents
• Toward personalized cancer medicine: challenging the
gold standard for specific patient subgroups
Outline
• Trastuzumab plus chemotherapy: the gold standard for
HER2 positive early breast cancer
• Improving on cardiac toxicity: different regimens and
different treatment durations
• Improving on treatment efficacy: dual blockade and new
anti-HER2 agents
• Toward personalized cancer medicine: challenging the
gold standard for specific patient subgroups
Outline
Meta-analysis of adjuvant trastuzumab trials: Disease-free Survival
Moja L, et al. The Cochrane Library 2012, Issue 4
Meta-analysis of adjuvant trastuzumab trials: Overall Survival
Moja L, et al. The Cochrane Library 2012, Issue 4
OS : ∆ 5.5% at 6y ∆ 8.8% at 10y
DFS : ∆ 11.9% at 6y ∆ 11.5% at 10y
Are all trastuzumab adjuvant trials the same?
BCIRG 006 DC x 6+ H
AC x 4 D x 4+ H
Trastuzumab up to 1 yr
FIN-HER D/N+H x 9 wks FECx 3
HERA Adjuvant CT (Any) RT
N9831Sequential arm
wT x 12AC x 4
Joint analysis ofNSABP B31 & N9831
AC x 4 T x 4 + H
PACS 04 FEC/ED x 6 RT
Randomization Trastuzumab start T= paclitaxel; D= docetaxel
Concurrent administration
Sequential administration
Moja L, et al. The Cochrane Library 2012, Issue 4
Overall Survival stratified by concurrent or sequential administration
• Trastuzumab plus chemotherapy: the gold standard for
HER2 positive early breast cancer
• Improving on cardiac toxicity: different regimens and
different treatment durations
• Improving on treatment efficacy: dual blockade and new
anti-HER2 agents
• Toward personalized cancer medicine: challenging the
gold standard for specific patient subgroups
Outline
Low competing mortality risk score High competing mortality risk score
Cancer ahead pub 2010
Congestive heart failure (CHF): all studies.
Moja L, et al. The Cochrane Library 2012, Issue 4
LVEF decline-all studies.
BCIRG 006: Adjuvant Breast CancerNode Positive and High Risk Node Negative
4x AC60/600 mg/m2
4x Docetaxel100 mg/m2
HER2+(central FISH)
N+ or High risk N-
N=3,222 pts
6 x Docetaxel 75 mg/m2 +Carboplatin AUC 6
1 Year Trastuzumab
1 Year Trastuzumab
ACT
ACTH
TCH
Slamon D, NEJM 2011.
Slamon D, NEJM 2011.
Slamon et al. SABCS 2006. Abstract 52.Slamon D, NEJM 2011.
Moja L, et al. The Cochrane Library 2012, Issue 4
CHF by trastuzumab duration
Moja L, et al. The Cochrane Library 2012
DFS by trastuzumab durationLog (Hazard ratio) HR weight HR (IV,random, 95%CI)
Overall survival stratified by duration of trastuzumab treatment
Moja L, et al. The Cochrane Library 2012, Issue 4
SABCS, 2012
SABCS, 2012
www.esmo2012.org
PHARE* Trial results comparing 6 to 12 months of trastuzumab in
adjuvant early breast cancer
Xavier Pivot, Gilles Romieu, Hervé Bonnefoi, Jean-Yves Pierga, Pierre Kerbrat, Thomas Bachelot, Alain Lortholary, Marc Espié, Pierre Fumoleau,
Daniel Serin, Jean-Philippe Jacquin, Christelle Jouannaud, Maria Rios, Sophie Abadie-Lacourtoisie, Nicole Tubiana-Mathieu, Laurent Cany,
Stéphanie Catala, David Khayat, Iris Pauporté, Andrew Kramar.
Protocol of Herceptin®
Adjuvant withReduced Exposure
*lighthouse in French
www.esmo2012.org
Study design
trastuzumab 6 months
trastuzumab up to 12 months
stop trastuzumab
Clinical examLVEF
3
Mammography
6 9 12 15 18 21 24 30 mos
…
0
R
R: Randomization after informed consent
Up to 60 mos…
Stratification1. ER pos / neg2. Chemo: conco/
seq
www.esmo2012.org
Statistical Methods
• Non inferiority randomized trial– 2% variation in terms of absolute difference of recurrence– The 95% CI HR margins should not cross the 1.15 boundary– 1040 DFS events required for 80% power at 5% level
or4 years of accrual and at least 2 years of follow-up
– HR were estimated from the stratified Cox model
• Accrual target: 3400 patients
www.esmo2012.org
Equivalent
Superior
Non Inferior
Inferior
A
B
C
D
E
.85 1 1.15 1.3 1.45 1.6HR
Primary endpoint scenarii
www.esmo2012.org
Patient Characteristics12 months
n=16906 monthsn=1690
Age, median (range) 54 (21 – 86) 55 (23 – 85)
Tumor : 0 – 2 cm2 – 5 cm>5 cm
54.7%38.5%6.8%
52.4%39.8%7.8%
Nodes: negative1 – 3 nodes4 nodes
55.4%30.0%14.6%
54.7%30.2%15.1%
Positive Estrogen receptor 57.6% 58.8%
Inflammatory disease 3.5% 3.4%
SBR: IIIIII
3.1%41.0%55.6%
3.3%40.9%55.8%
www.esmo2012.org
Treatment Characteristics12 months
n=16906 monthsn=1690
Type of Chemotherapy : No AnthracyclinesAnthracyclines no
TaxanesAnthracyclines and
Taxanes
10.2%15.9%73.9%
11.8%15.5%72.7%
Concomitant ChemotherapySequential Chemotherapy
57.8%42.2%
57.7%42.3%
Radiotherapy 87.7% 88.2%
Hormonotherapy 50.6% 50.2%
Trastuzumab duration, mean (sd) 11.8 (6.3) 6.3 (1.46)
www.esmo2012.org
Cardiac toxicity
12 months(n=1690)
6 months(n=1690)
P
Cardiac events* 5.7% 1.9% <0.0001
LVEF** < 50% 6.3% 4.7% 0.04LVEF** < 50% and > 10% 4.8% 3.6% 0.071LVEF** > 50% and > 15% 7.4% 7.0% NS
* Investigator reported events (composite with clinical and LFEV finding)** Based on more than > 25,000 assessments
www.esmo2012.org
DFS Events12 mos(n=1690)
6 mos(n=1690)
DFS Events (n=395) 10.4% 13.0%
Local RecurrenceRegional RecurrenceDistant Recurrence
Controlateral Breast Cancer2nd Primary Malignancy
Death
1.1%0.6%6.4%
0.4%1.5%
0.4%
1.4%0.5%8.3%
0.7%1.5%
0.5%
42.5mos. median Follow-up
www.esmo2012.org
0.00
0.25
0.50
0.75
1.00P
roba
bilit
y
1690 1586 1353 939 526 23H 6m1690 1613 1390 980 544 18H-12m
At risk
0 12 24 36 48 60Months
H-12m H-6m
Disease Free Survival
* Cox model stratified by ER status and concomitant chemotherapy
95.5 91.2 87.8 84.9
97.0 93.8 90.7 87.8
Events HR 95%CIp-value
H 12m 176H 6m 219 1.28 (1.05 – 1.56) 0.29
www.esmo2012.org
0.00
0.25
0.50
0.75
1.00Pr
obab
ility
1690 1645 1438 1016 566 25H 6m1690 1662 1463 1042 583 19H-12m
At risk
0 12 24 36 48 60Months
H-12m H-6m
Overall Survival
* Cox model stratified by ER status and concomitant chemotherapy
42.5mos. median FU
99.3 97.2 95.2 93.1
99.9 98.7 96.9 95.0
Events HR 95%CI p-valueH 12m 66H 6m 93 1.47 (1.07 – 2.02)
www.esmo2012.org
Equivalent
Superior
Non Inferior
Inferior
A
B
C
D
E
.85 1 1.15 1.3 1.45 1.6HR
Primary endpoint scenarii
PHARE trial
Trastuzumab duration effects in patient subgroups in the
PHARE* trial
Protocol of Herceptin®
Adjuvant withReduced Exposure
*lighthouse in French
Xavier Pivot, Gilles Romieu, Hervé Bonnefoi, Jean-Yves Pierga, Pierre Kerbrat,
Thomas Bachelot, Alain Lortholary, Marc Espié, Pierre Fumoleau, Daniel Serin,
Jean-Philippe Jacquin, Christelle Jouannaud, Maria Rios, Sophie Abadie-Lacourtoisie, Nicole Tubiana-Mathieu, Laurent Cany, Stéphanie Catala, David
Khayat, Iris Pauporté, Andrew Kramar.SABCS 2012
Subgroup Results
0.00
0.25
0.50
0.75
1.00
DFS
Pro
bability
314 282 244 188 113 8T-6m312 288 254 210 130 5T-12m
Trastuzumab
0 12 24 36 48 60Months
T-12m T-6mER neg - Sequential
HR = 1.57 : 95%CI: (1.08 - 2.28)
0.00
0.25
0.50
0.75
1.00
DFS
Pro
bability
1376 1304 1109 751 413 15T-6m1378 1325 1136 770 414 13T-12m
Trastuzumab
0 12 24 36 48 60Months
T-12m T-6mOther groups
HR = 1.18 : 95%CI: (0.93 -1.49)
ER- status & Sequential modality
Other groups
Short-HER: study design
R
RT/HT
RT/HT
Trastuzumab 4 mg/kg loading dose 2 mg/kg weekly
3 mos 6 mos 9 mos 12 mos 18 mos
: LVEF measurement
PI: PF Conte
Sample size 1250 pts
FEC (600/60/600)AC60/600 orEC90/600
Trastuzumab 8 mg/kg loading dose 6 mg/kg q 3 wks
Docetaxel 100
EUDRACT-2007-004326-25, NCT00629278
Enrollment as of May, 2013
• 1176 patients– Arm A (Long) 586 patients– Arm B (Short) 590 patients
• Trastuzumab plus chemotherapy: the gold standard for
HER2 positive early breast cancer
• Improving on cardiac toxicity: different regimens and
different treatment durations
• Improving on treatment efficacy: new anti-HER2 agents
and multiple dual blockade
• Toward personalized cancer medicine: challenging the
gold standard for specific patient subgroups
Outline
TEACH Trial
Placebo qd × 1 yr
Lapatinib 1500 mg qd × 1 yr
Stratification• Time from diagnosis ≤4 vs >4 yrs
• Lymph node +ve vs -ve
• ER+ and/or PgR+ vs ER–/PgR–
4 yr
Eligibility
• HER2+ Local IHC3+ or FISH +ve
• Resected Stage I-IIIc primary BRCA
• No prior trastuzumab
• Neo-/adjuvant chemotherapy (CMF,
anthracycline, or taxane)
• Appropriate endocrine therapy
N=3147Aug 2006-May 2008
33 countries
RANDOMIZE
DiagnosisDisease-free survival (DFS):local, regional, distant recurrence,contralateral BRCA,other 2nd primary cancers,death from any cause
Goss, SABCS 2011
0.0
TEACH Primary Endpoint: K-M Plot of DFS inITT Population—Time From Randomization
ap value based on 2-sided stratified log-rank test
Lapatinib
PlaceboHR 0.83 (0.70-1.00); p=0.053a
Median Follow up: 4 years
Number of patients at risk
Lapatinib 1500 mg 1571 1431 1349 1293 1233 1168 1001 661 299
Placebo 1576 1487 1412 1343 1295 1247 1048 706 327
• No improvement in OS demonstrated with use of lapatinib:HR: 0.99 (95% CI: 0.74-1.31; P = .966)
Goss, SABCS 2011
TEACH: Forest Plot of DFS for Subgroups in ITT Population
L=lapatinib; P=placebo.
Goss, SABCS 2011
Phase III NeoALLTO study
Phase II CHER-LOB study
Dual anti-HER2 blockade (neoadjuvant studies)
Baselga J et al. Lancet 2012 Guarneri V et al, J Clin Oncol 2012
pCR (breast & axilla)
0
10
20
30
40
50
60
Arm A: CT + TArm B: CT + L Arm C: CT + T + L
Exploratory p=0.0187
Dual Anti-HER2 blockade significantly increases the pCR rate
25% 26.3%
46.7%
ALTTO study design (8000 patients)
Aphynity
R
6-8 cyclesAdj CHT
6-8 cyclesAdj CHT
52 weeks
Trastuzumab i.v. 8 mg/kg LD then 6 mg/kg, q3w Pertuzumab 840 mg i.v. LD then 420 mg, q3w
Placebo i.v., q3w
HER2+ BCN+ or high-risk N0
Expected enrollment: 3806 pts
T, P/Pl concomitant to taxane-based CT
IBCSG 39-11 / BIG 4-11 (APHINITY)
• Trastuzumab plus chemotherapy: the gold standard for
HER2 positive early breast cancer
• Improving on cardiac toxicity: different regimens and
different treatment durations
• Improving on treatment efficacy: dual blockade and new
anti-HER2 agents
• Toward personalized cancer medicine: challenging the
gold standard for specific patient subgroups
Outline
Author median FU Cohort # Relapses % P value
Amar SSABCS 2007 3 y.
HR+/HER2- 350 1.30.007HER2+ 27 7.4
TN 24 12.5
Zambelli AAIOM 2008
4 y. HER2- 309 30.038
HER2+ 31 13
Ananthakrishnan PSABCS 2008
4 y. HER2-770
3.0ns
HER2+ 9.0
Tovey SMSABCS 2008
5 y. HER2- 309 40.001
HER2+ 58 32
Curigliano GJCO 2009
4.6 y HR+/HER2- 158 1.3
0.09HER2+/HR- 71 7
HER2+/HR+ 79 7.6
TN 71 7
Gonzalez-Angulo AJCO 2009
6.2 y HER2- 867 5.9<0.001
HER2+ 98 21.4
Outcome of HER2+ T1a,b N0 tumors (w/o Trastuzumab)
Trastuzumab Adjuvant trials: subset analysis
N = node
1–3+ nodes
0 0.5 2.51.0 1.5 2.0
1–3+ nodes
≥4+ nodes
Not assessed
N9831/B-31 N–
4–9+ nodes
>10+ nodes
TCHN–
N+
N+
BCIRG 006 N–ACTH
N– HERA
Favours trastuzumab Favours no trastuzumab HR
Slamon, et al. SABCS 2006 Perez, et al. ASCO 2007; Smith, et al. Lancet 2007
32 % N0
7% N0
29% N029% N0
Characteristic Adjuvant trastuzumab trials (B31/N9831/HERA/FinHer/BCIRG006/PACS04)
Modena Cancer Registry
Age (median) 49 59
T1N0 % ~ 2 38.8
HER2+ EBC patients Adjuvant trastuzumab trials vs Modena Cancer Registry
Piccart N Engl J Med 2005; Romond N Engl J Med 2005; Joensuu N Engl J Med 2006; Slamon D, SABCS 2006; Spielmann M et al, SABCS 2007; Federico M, RTM 1998-2009
pCR by Hormone Receptor Status
Baselga J et al. SABCS 2010; Gianni et al, SABCS 2010, Guarneri et al, ASCO 2011
pCR rate*
HR + HR -
Neo-ALLTO Lapatinib (L) +paclitaxel 16.2% 33.8%
Trasuzumab (T) +paclitaxel 22.7% 36.5%
L+T+ paclitaxel 41.6% 61.3%
Cher-LOB L + P-FEC 22.7% 35.7%
T + P-FEC 25% 26.6%
L+T+ P-FEC 35.7% 56.2%
Neo-Sphere Docetaxel-T 20% 36.8%
Docetaxel + T+ Pertuzumab 26% 63.2%
T+pertuzumab 5.9% 29.1%
Docetaxel + pertuzumab 17.4% 30%
Chang, JCO 2013
Neoadjuvant trastuzumab + lapatinib w/o chemotherapy
Summary of HER2+ EBC
• CT+ 1yr trastuzumab is the standard regimen• Studies evaluating optimal trastuzumab duration in terms
of efficacy and safety are critical:• to take into account the sustainability for the NHS• to facilitate the introduction of new antiHER2 treatments
• Neoadjuvant studies are essential to rank treatment activity, prior to move to large adjuvant studies
• A dual HER2 inhibition seems a winner strategy
• New promising agents are entering the adjuvant phase
• The possibility to avoid chemotherapy in case of small T size, N0, HR+, elderly and frail patients is intriguing, but still matter of study