updates in the management of her2 positive breast canceralternative trial: de-escalating therapy in...
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Updates in the Management of HER2 Positive Breast Cancer
Hope S. Rugo, MDProfessor of Medicine
Director, Breast Oncology and Clinical Trials EducationUniversity of California San Francisco Comprehensive Cancer Center
ER+
Breast Cancer Clinical Subsets
All Breast Cancer HER2+
Triple Neg
About 20% of incident cases
are HER2+
half ER+half ER-
HER2+ Breast Cancer 2017 We are still curing most women with early stage
HER2+ breast cancer Understanding subsets is increasingly important
We are over treating at least a subset of patients Its hard to ratchet back with success
Resistance is still a problem Effective new agents are on the horizon
Key Phase III Trials for the HER2+ MBC
Trastuzumab + pertuzumab +
docetaxel
Trastuzumab + docetaxel
T-DM1
Capecitabine + lapatinib Trastuzumab+
lapatinibLapatinib
1Swain NEJM 2015; 2Diéras Lancet Oncol 2017;3Krop Lancet Oncol 2017; 4Blackwell J Clin Oncol 2012
Physician’s choiceT-DM1
1st lineCleopatra(n=808)
2nd lineEmilia
(n=991)
3rd line +TH3RESA (n= 602)
3rd/4th lineEGF 104900
(n=291)Design THP vs TH T-DM1 vs XL T-DM1 vs TPC HL vs LGain in OS 15.7 mo
(40.8 vs 56.5)4 mo
(25.9 vs 29.9)6.9 mo
(15.8 vs 22.7)4.5 mos
Side effects Minimallyincreased
In favor of T-DM1
In favor of T-DM1
Minimallyincreased
Prior trastuzumab?
Minimal (10%)and interval of
≥12 mos required
100%[if adjuvant,
free int < 6m](= 16% of pts)
Prior Trastuzumab and Lapatinib
100%(≥ 3 regimens)
T=docetaxel, H=trastuzumab, P=pertuzumab, L=lapatinib, TPC=Rx of physicians choice
Overall survivalMedian FU 50 mo. (0-70)
CLEOPATRA1st-line Pertuzumab + Trastuzumab
(10% prior trastuzumab)
Median follow-up: 30 months. PFS, progression-free survival; OS, overall survival.
Progression-free survival (inv assessed)
Pertuzumab+trastuzumab+docetaxel
Placebo+trastuzumab+docetaxel
Hazard ratio P-value
ORR1 80.2% 69.3% 0.0001
PFS1 18.7 months 12.4 months 0.69 <0.0001
OS2 56.5 months 40.8 months 0.66 0.0001
Most common adverse events ≥Grade 3 in the pertuzumab+trastuzumab+docetaxel group:1 Neutropenia (48.9%), febrile neutropenia (13.8%), leukopenia (12.3%) and diarrhoea (7.9%)
1. Baselga et al. N Engl J Med 2012;366:109; 2. Swain et al. NEJM 2015;724:734.
PFS: HR HR+ 0.72 vs 0.55 in HR-OS: HR HR+ 0.71 vs 0.61 in HR-
TH3RESA Trial HER2+ MBC with >2 HER2 directed therapies in the
advanced stage setting (T and L) T-DM1 vs TPC 2:1 randomization; 47% xover to T-DM1 3 mo improvement in PFS, less toxicity overall
Krop et al, Lancet Oncol
2017
Further Explorations Marianne trial (Perez et al, JCO 2017) T-DM1 = T-DM1/pertuzumab =
trastuzumab/taxane PFS 14.1 vs 15.2 vs 13.7 mo. QOL maintained for longer, and toxicity lower
with T-DM1
Pherexa (Urruticoechea A et al, JCO 2017) Does pertuzumab improve outcome in the 2nd
line setting after trastuzumab/taxane? Capecitabine/trastuzumab +/- pertuzumab PFS equivalent, OS numerically improved but NS 28.1 vs 37.2 mos. (HR 0.76)
Urruticoechea A et al, ASCO 2018
ER+/HER2+ Metastatic Breast Cancer: Should Treatment Differ?
Luminal intrinsic subtype more commen HER2 amplification results in relative resistance to
hormone therapy Improved PFS when hormone therapy combined with
HER2 targeted therapy, no impact on OS Tandem trial N=207 Median PFS 2.4 → 4.8 mos, HR 0.63; p=.0016
Lapatinib plus letrozole N=1286, 219 HER2+ Median PFS 3.0 → 8.2 months, HR = 0.71; P=0.019
Kaufman, JCO 2009, Johnston JCO 2009
Alternative Trial: De-Escalating Therapy in HR+ Disease (Johnston et al, JCO 2018)
355 women, HR+/HER2+ MBC, prior rx with trastuzumab/chemo, hormone therapy Randomized to L/T/AI vs T/AI vs L/AI
Grade 3 diarrhea 13 vs 6%
Clinical Pathway HER2+ MBC: 2015
First-line: Add hormone therapy to HP after response, and stop chemotherapyPertain trial (Rimawi, SABCS 2016)
2018
Targeting HER2: New Directions
Antibody-drug conjugate
(maytansineanalogue conjugated
to trastuzumab)
Small molecule kinase inhibitors
Humanized monoclonal Ab to HER2 extracellular domain
Neratinib
Humanized monoclonal Ab, blocks heterodimerization
Agents Antibody drug conjugates
Trastuzumab DS-8201
SYD 985
Novel antibodies Margetuximab
Bispecific antibodies: ZW25
Oral tyrosine kinase inhibitors Tucatinib
Neratinib
Pyrotinib
Poziotinib
Checkpoint inhibition
Biosimilars! Multiple approved in US and EU
Trastuzumab deruxtecan (DS-8201a) in subjects with HER2-expressing advanced solid tumors: Long-term efficacy and safety
from a first-in-human phase 1 study with multiple expansion cohorts
DS-8201a was designed with the goal of improving critical attributes of an ADCIwata et al, ASCO 2018
Phase I Trial Design
*Subjects in part 1 were not required to have HER2-positive (IHC 3+ or IHC2+/ISH+) tumors.HER2, human epidermal growth factor receptor 2; HNSTD, highest non-severely toxic dose; IHC, immunohistochemistry; ISH, in situ hybridization; IV, intravenous; PK, pharmacokinetic; Q3W, once every 3 weeks; RD, recommended dose for dose expansion; T-DM1, trastuzumab emtansine.
Response Across Tumor TypesHER2 low=1/2+ by IHC and FISH neg
-1 0 0
-8 0
-6 0
-4 0
-2 0
0
2 0
4 0
6 0
8 0
Chan
ge fr
om b
asel
ine
(%) HER2-Positive Breast
Cancer N = 104
-1 0 0
-8 0
-6 0
-4 0
-2 0
0
2 0
4 0
6 0
8 0
Chan
ge fr
om b
asel
ine
(%) HER2-Low Breast
Cancer N = 33
-1 0 0
-8 0
-6 0
-4 0
-2 0
0
2 0
4 0
6 0
8 0
Chan
ge fr
om b
asel
ine
(%) HER2-Positive Gastric
Cancer N = 44
-1 0 0
-8 0
-6 0
-4 0
-2 0
0
2 0
4 0
6 0
8 0
Chan
ge fr
om b
asel
ine
(%)
C o lo re c ta l
N S C L C
O th e r
Other CancersN = 37
• Overall, 86.3% of subjects experienced tumor shrinkage• Confirmed ORR* in the overall population is 49.3%• Median PFS in HER2+ NR, and in HER2 low is 12.9 months
Toxicity 10 (4.1%) TEAEs
leading to death
23 (9.5%) leading to Rx discontinuation
Events of ILD/pneumonitis including 5 fatal cases were observed
All grades Grade ≥3Nausea 166 (68.9) 6 (2.5)Vomiting 84 (34.9) 4 (1.7)Diarrhea 64 (26.6) 2 (0.8)Constipation 51 (21.2) 0 (0.0)Stomatitis 43 (17.8) 0 (0.0)Decreased appetite 134 (55.6) 8 (3.3)Anemia 77 (32.0) 36 (14.9)Platelet count decreased 69 (28.6) 25 (10.4)Neutrophil count decreased
61 (25.3)37 (15.4)
White blood cell count decreased58 (24.1) 30 (12.4)
Alopecia 87 (36.1) 0 (0.0)Fatigue 67 (27.8) 4 (1.7)Malaise 50 (20.7) 1 (0.4)Pyrexia 25 (10.4) 1 (0.4)Dysgeusia 24 (10.0) 0 (0.0)
Phase II Destiny Trial
Baselga et al, ASCO 2018
SYD 985 Phase I Expansion Study Trastuzumab duocarmazine
Pro-drug (seco-DUBA) of DNA alkylating agent
Responses HER2+: 24% (TDM1 rxd, 9/38) HER2 low/HR+: 20% (6/30)
TNBC: 27% (4/15)
Toxicity (grade 3) Neutropenia: 6% Conjunctivitis/keratitis: 5%
All grade ocular toxicities up to 29%
Phase III TULIP trial (vs TPC)
Saura et al, ASCO 2018
Synthon Pharmaceuticals
Margetuximab: Fc-Optimized anti-HER2 Monoclonal Antibody
Margetuximab (MGAH22) Derived from 4D5 with Fc domain engineered to
increase binding to isoforms of the activating Fcγreceptor CD16A
Antiproliferative in cell lines resistant to anti-HER2 ab
More potent than trastuzumab surrogate in ADCC assays
Phase I data encouraging Safety similar to trastuzumab Of 27 with breast cancer: 4 Partial Responses, 2 each in low affinity
CD16 F/F and F/V genotypes 3 ongoing on single agent study therapy at
41, 47, and 56 months (F/V, F/F, F/F)Bang et al, Ann Oncol 2017
SOPHIA Study to Establish Superiority Over Trastuzumab
1:1 Randomization(n = 530)
HER2+ mBC, 1-3 anti-HER2 lines in metastatic setting,
including pertuzumab
Arm 1margetuximab + chemotherapy
Arm 2trastuzumab + chemotherapy
PI Choice of Chemotherapy(capecitabine, eribulin,
gemcitabine or vinorelbine)R
Sequential Primary Endpoints: Progression-Free Survival (PFS, N=257, HR=0.67, α=0.05, power=90%) then Overall Survival (OS, N=385, HR=0.75, α=0.05, power=80%)
Phase 3 – Randomized Trial of Margetuximab in Third-Line Metastatic Breast Cancer
Stratification:• Type of chemotherapy• Lines of prior chemotherapy (≤2 vs >2)• Metastatic sites (≤2 vs >2)
ONT-380 (Tucatinib) Selective small molecule TKI more selective for
HER2 than EGFR Primary toxicity is elevation of transaminases 11% grade 3 diarrhea
With cape only
Treatment ONT-380/capecitabine/trastuzumab
HER2Climb Ongoing randomized phase II trial: cape/trast +/- ONT
Murthy et al, Lancet Oncol 2018
Her2-Directed Tyrosine Kinase Inhibitors: Activity in the CNS
Agent Target Phase of Development CNS ORR (Monotherapy) CNS ORR in combination with capecitabine
Lapatinib HER1/HER2 FDA Approved 6%1 20%2, 66%3
Neratinib HER1/HER2/HER4 FDA Approved(Adjuvant)Phase 3 (Metasatic)
8%4 49%5
Tucatinib HER2 Phase 3 5-9%6 (+ trastuzumab) 42%7 (+trastuzumab) 1
Pyrotinib HER1/HER2 Phase 3 NA NA
Poziotinib HER1/HER2/HER4 Phase 2 NA NA
Afatinib Phase 3 negative– No further development in breast
0%8 NA
1Lin et al, CCR 2009, 2Lin et al, CCR 2009, 3Bachelot et al, Lancet Oncol 2013, 4Freedman et al, JCO 2016, 5Freedman et al, ASCO 2017, 6Metzger et al, SABCS 2016, 7Hamilton et al, SABCS 2016, 8Cortes et al, Lancet Oncol 2015
Preclinical synergy with IO and HER2-directed agents A single dose of pre-operative trastuzumab can
change the immune profile within a tumor JAVELIN 3.8% ORR with avelumab1
Metastatic PANACEA 15% ORR with trastuzumab + pembrolizumab2
Numerous IO studies are planned or underway
Checkpoint Blockade in HER2-Positive Disease
1Dirix SABCS 2016; 2Loi SABCS 2017
PD-L1 positive (n=44)
• Median PFS 2.7(+) vs 2.5 mo(-)• Mean DOR: 10 months • 5 patients (10.8%) continue with no
progression at time of reporting• Higher TILS correlated with response
and DOR• Higher in PD-L1+ and in lung and
nodes
PD-L1 +Phase Ib,
n=6
PD-L1 +Phase II,
n=40
PD-L1 -Phase II,
n=12
ORR n (%) [90%CI]
1 (17%) [1-58]
6 (15%) [7-29]
0 (0%) [0-18]
OS
Panacea: Phase Ib/II Trial of Pembrolizumaband Trastuzumab in HER2+ MBC
Loi et al, SABCS 2017
BCRF Funded AVIATOR Trial (TBCRC 045) Addition of a 4-1BB Agonist to a Trastuzumab/anti-PD-L1
Combination in HER2+ MBC
• Advanced HER2+ cancer
• No prior immunotherapy
• PD-L1 unselected
Vinorelbine +trastuzumab+ avelumab
Vinorelbine +trastuzumabN=20
Vinorelbine +trastuzumab+ avelumab +
Utomilumab
Trastuzumab + avelumab +Utomilumab
Tumor tissue
Fresh or ≤1y old
TumorTissue
N=40
N=40
Vinorelbine 25mg/m2 D1,D8,D15Trastuzumab D1, D15Avelumab D1, D15 10mg/kg IVUtomilumab D1 100mg IV28d cycle
TumorTissue
PI: Ian Krop
Advances in Adjuvant Therapy for HER2+ Disease: How Much, How
Long?
Have we reached the ceiling of incremental benefits?
How do we de-escalate?
Adjuvant Trastuzumab Improves DFS and OS
1. Piccart-Gebhart MJ, et al; N Engl J Med 2005; 353:1659-1672; 2. Smith I, et al. Lancet 2007; 369:29-36; 3. Gianni L, et al; Lancet Oncol 2011; 12:236-244; 4. Goldhirsch A, et al. Lancet 2013; 5.Cameron et al, Lancet 2017
6. Romond EH, et al. N Engl J Med 2005; 353:1673-1684; 7. Perez EA, et al. J Clin Oncol 2011; 29:3366-3373; 8. Romond EH, et al. SABCS 2012; 9. Slamon D, et al. N Engl J Med 2011; 365:1273-1283; 10. Slamon et al, SABCS 2015
DFS OS
StudyFollow-up
(years) N HR p value HR p value
HERA1–5
CT+/–RTH vs. CT+/–RT
1 3387 0.54 < 0.0001 0.76 0.26
2 3401 0.64 < 0.0001 0.66 0.0115
4 3401 0.76 < 0.0001 0.85 0.1087
8 3401 0.76 < 0.0001 0.76 0.0005
11 34010.76
∆ 6.8% 0.00010.74
∆ 6.5% <0.0001
NCCTG N9831/NSABP B-316–8
ACTHH vs. ACT
2 3351 0.48 < 0.0001 – –
4 4045 0.52 < 0.001 0.61 < 0.001
8.4 40460.60
∆ 11% < 0.00010.63∆ 9% < 0.0001
BCIRG 0068,9
ACTHH vs. ACT10 3222
0.72∆ 6.7 < 0.0001 0.63
∆ 7.2 < 0.0001
TCH vs. ACT 0.77∆ 5.1 0.0011 0.76
∆ 4.60.075
Optimal Duration of Adjuvant Trastuzumab?
HERA Trial: 2 vs 1 year Trastuzumab at 11 Years Median FU
Cameron et al, Lancet 2017; Joensuu et al, JCO 2009
Optimal Duration of Adjuvant Trastuzumab?Trial Duration Chemotherapy Start Accrual Status/Results
PHARE 6 vs 12 mos InvestigatorChoice (~90% anthracycline-based)
5/2006 3384 Published 20131
Non-inferiority not reached, cardiac toxbetter with shorter
Hellenic Oncology
6 vs 12 mos ddFEC/D 10/2004 481 Published 20152
Non-inferiority not reached
Short-HER 9 wks vs 1year
A=T vs T+FEC 12/2007 1253 Reported ASCO 20173
Non-inferiority not reached, cardiac toxbetter with shorter
SOLD 9 wks vs 1year
T+FEC 1/2008 2168 Reported SABCS 20174
Non-inferiority not reached, less cardiac tox with shorter
Persephone 6 vs 12 mos InvestigatorChoice
10/2007(over 8 yrs)
4000 Cardiac outcomes published 20165; DFS at ASCO 20186
1. Pivot X et al. Lancet Oncol 2013;14:741-8. 2. Mavroudis D et al. Ann Oncol 2015;26:1333-40 3. Conte PF et al. J Clin Oncol 2017;35(15s):Abs 501. 4. Joensuu et al, SABCS 2017 5. Earl HM et al. Br J Cancer 2016;115:1462-70. 6. Earl et al, ASCO 2018
Persephone Study Design
1O: DFS [Diagnosis to 1st relapse (local or distant) or death]2O: OS; Cost effectiveness; Cardiac function
Earl et al, ASCO 2017
Statistics and Patient Characteristics 4 year DFS with 12 months estimated at 80%
Non-inferiority defined as no worse than 3% below
69% hormone receptor positive
48% A/T based, 42% A based
53% sequential trastuzumab (after chemo)
67% > 50 yo
56% randomized after at least one dose of trastuzumab
59% node negative; 48% T<2cm; 67% grade III
Disease-free survival
#events HR 90% CI Non-inferiority p
12 months 247 1.07 0.93-1.24 0.01
6 months 265
96.1%95.7% 89.8%
89.4%
Non-inferiority limit
}0.4%
Pre-defined subgroup analysis
Interaction between 2 groups χ21=2.3; p=0.13
Heterogeneity between 4 groups χ23=11.1; p=0.01
Interaction between 2 groups χ21=3.2; p=0.07
Interaction between 2 groups χ21=10.8; p<0.001
Overall survival
#events HR 90% CI Non-inferiority p
12 months 156 1.14 0.95-1.37 0.0006
6 months 179
98.9%98.7% 94.8%
93.8%
Non-inferiority limit
}1.0%
Cardiotoxicity
• Cardiac function recovers post-trastuzumab (p<0.0001)
• 6-month patients had a more rapid recovery (p=0.02)
• Other toxicity was modest• 20% of sequential patients
reported G3/4 toxicity during trastuzumab (23% 12 month, 18% 6 month, p=0.004)
Random effects modelling predicted lines and 95%CIs
Stopped trastuzumab because of cardiotoxicity
- in 8% of 12-month patients - in 4% of 6-month patients(p<0.0001)
Ref: Earl et al. British Journal of Cancer (2016) 115, 1462–1470
Implications for Clinical Practice The option for shorter trastuzumab has the potential to
increase accessibility and reduce cost world-wide
In the U.S.? Is a 3% margin for non-inferiority sufficient? Pertuzumab, neratinib approved for overall differences of less
than 3% Subgroup analysis? Hard to interpret
Who is a candidate for shorter adjuvant trastuzumab? Smaller tumors, ER+, older age, cardiac risk factors
Neoadjuvant Trastuzumab Trastuzumab markedly increases pCR rates when
added to standard chemotherapy Noah trial: improved pCR translated into improved
DFS
Addition of lapatinib in multiple trials Increased toxicity, variable impact on pCR
No impact on DFS
Buzdar A, et al. JCO 2004, Gianni et al, Lancet 2010
Outcome Based on pCR: Impact of Receptor Subsets
Luminal AHR+, low grade
von Minckwitz G, et al. J Clin Oncol 2012
BasalER/PR/HER2-Neg HER2+
H, trastuzumab; P, pertuzumab; T, docetaxel given for 4 cycles, followed by surgery, then 3 cycles of fluorouracil, epirubicin and cyclophosphamide (FEC) and H for a full year
Dual HER2 Blockade and pCR: Impact of Adding Pertuzumab NeoSphere Study
p = 0.014150
40
30
20
10
0TH THP HP TP
pC
R, %
±95%
C
I
p = 0.0198
p = 0.003
29.0
45.8
16.824.0
Gianni L et al. Lancet Oncol. 2012
TRYPHAENA Trial: Anthracycline and Non-AnthracyclineComparisons With Pertuzumab-Based Therapy in All Arms
Schneeweiss A, et al. Ann Oncol 2013
Pat
holo
gic
com
ple
te r
espon
se (
%)
FEC+H+P x3→ T+H+P x3
(n = 73)
FEC x3→ T+H+P x3
(n = 75)
TCH+P x6(n = 77)
Pertuzumab is approved in the neoadjuvant setting for HER2+ breast cancer –
specifically for tumors > 2 cm and positive nodes
APHINITY: Randomized Adjuvant Phase 3 Trial
A=doxorubicin, E=epirubicin, C=cyclophosphamide, T=taxane (paclitaxel or docetaxel), F=5-fluorouracil, H=trastuzumab, P=pertuzumab
N=3800 planned (4800 enrolled)
trastuzumab + pertuzumab*x 1 year
SURGE
RY
Central confirmation
of HER2 status
ACT or TCH
trastuzumab + placebo*x 1 year
ACT or TCH
*antibody therapy starts with taxane
Node + orhigh risk node negative
Von Minckwitz et al. NEJM 2017
Demographics:• N0: 37% (25% N> 4+)• HR+: 64%• Anthracycline: 78%
APHINITY: Intent-to-Treat Primary Endpoint Analysis Invasive Disease-free Survival
Number needed to treat: 112
expected: 89.2%
4yr iDFS:HR = 0.81 (p = 0.045)
Absolute benefit = 1.7%
Δ %(H/P vs. H)
Absolute Δ
N0 96.7 v 96.2% 0.5%
N1 89.9 v 86.7% 3.2%
ER/PR+ 93 v 91.6% 1.4%
ER/PR- 91 v 88.7% 2.3%
iDFS subset analysis
*No difference in iDFS by type of chemotherapy
Additional Endpoints and Toxicity
Absolute difference in DRFI: 0.6%
Overall survival identical 97.7%
Toxicity Grade >3 diarrhea 9.8 vs 3.7% overall
18 vs 6.1% with TCH
Summary: Adjuvant Therapy
Anthracyline and non-anthracycline regimens are acceptable as (neo)adjuvant therapy Triage based on tumor and cardiac risk
12 months of trastuzumab remains the general standard 9 wks of tras in pts receiving anthracycline-based chemotherapy is
not equivalent to 12 months
Shorter duration associated with slightly less cardiac toxicity
Overall benefit from addition of pertuzumab modest at best Not surprising given huge impact of trastuzumab and excellent
outcome for patients with early stage HER2+ breast cancer
Clinical Implications Pertuzumab use should be restricted to those with high risk
cancer Definition complex: N+, ER neg – but what about N-/ER-? ER+
and one node? All neoadjuvant or just N+/HR-?
Is pertuzumab during chemotherapy enough? Do patients with moderate risk disease or pCR need one year of pertuzumab?
What about neratinib?
Neratinib as Extended Adjuvant Therapy: The ExteNET Trial
• Primary endpoint: invasive DFS (iDFS)• Secondary endpoints: DFS-DCIS, time to distant recurrence, distant DFS, CNS metastases, OS, safety• Other: Biomarkers, QOL• Stratification: nodes 0, 1-3+, vs 4+, ER/PR status, concurrent vs sequential trastuzumab
• Median time from trastuzumab N vs P: 4.4 (0.2-30.9) vs 4.6 (0.3-40.6) months Chan et al, Lancet Oncology 2016
24% node negative, 47% 1-3+ nodes; 57% HR+
5 Year Analysis: IDFS
Martin et al, Lancet Oncology 2017
iDFS by hormone receptor status (exploratory analysis)
Martin et al, Lancet Oncology 2017
Antidiarrheal Prophylaxis Reduces the Incidence and Severity of Diarrhea. ExteNET and Study 6201 (CONTROL)
Hurvitzet al,
SABCS 2017
Less is More: De-escalating Therapy for HER2+ Breast Cancer
Heterogeneity of HER2+ Disease:Intrinsic subtype distribution based on HR status
HR+/HER2+N=1,648
HR-/HER2+N=1,213
36.0%
31.8%
30.0%
2.2%
75.1%
14.8%
7.4%2.7%
Courtesy Aleix Prat
Neoadjuvant Therapy for HER2+ Early Stage Breast Cancer: a Window into Best Therapy?
Cortazar P, FDA Neoadjuvant Breast Cancer Workshop 2013, Lancet 2014
pCR Rates:Impact of Receptor Subsets
WSG ADAPT-HER2
3 arm trial (n=375) T-DM1 x 4 T-DM1/endocrine therapy Trastuzumab/endocrine therapy
Association of pCR with early response (low Ki67/cellularity)
Harbeck et al, JCO 2017
Adjuvant Paclitaxel and Trastuzumab (APT) A New Standard of Care for Low Risk HER2+
HER2+ER+ or ER-Node Negative< 3 cm
EnrollTP
TP
TP
TP
TP
TP
TP
TP
TP
TP
TP
TP
PACLITAXEL 80 mg/m2 + TRASTUZUMAB 2 mg/kg x 12
TT T T T T T T T T T T TN = 410
Median FU 7 years
Tolaney et al. NEJM 2015, ASCO 2017
Point Est. 95% Conf. Interval No. of events
3-yr DFS 98.5% 97.2% to 99.7% 6
5-yr DFS 96.3% 94.4% to 98.2% 14
7-yr DFS 93.3% 90.4% to 96.2% 23
Point Est. 95% Conf. Interval
No. of events
3-yr BCSS - - 0
5-yr BCSS 99.7% 98.1% to >99.9 % 1
7-yr BCSS 98.6% 97.0% to >99.9% 3
2 ptts with CHF (0.5%), 4 distant recurrence events (1%)
ATEMPT Trial Schema
Stage IHER2+*ER+ or ER-PS 0-1Adequate organ fx
N=500
Trastuzumab-DM1 q3weeks X17
*HER2-positive defined as IHC 3+ or FISH≥2.0; will be confirmed by central HER2 testing prior to study enrollment
Adjuvant endocrine therapy can be initiated after completion of 12 weeks of therapy
Adjuvant radiation therapy can be administered concurrently with study treatment.
Paclitaxel + Trastuzumab x12Trastuzumab q3weeks x13
N=375
N=125
R3
1
Accrual time: 30 months
PI: Sara Tolaney, MD, MPH
KRISTINE/TRIO-021 Neoadjuvant therapy: Is less good enough?
444 patients with centrally confirmed HER2+ breast cancer Randomized to TCH+P x 6 vs T-DM1+P x 6
Same treatment continued post-op Primary endpoint: pCR
Patients Median age 50, 62% ER pos, 83% stage IIA-IIIA Median FU 8.8 months
Results: toxicity and efficacy T-DM1+P: less decline in HRQoL and physical function TCH+P: more AEs and SAEs; superior pCR rate and higher BCS
Hurvitz et al, ASCO 2016
0
20
40
60
80
TCH+P T-DM1+P
pC
R (
%)a
Difference: -11.395% CI: -20.5, -2.0
Stratified 2-sided P−value: 0.0155b
Primary Endpoint: pCR (ypT0/is, ypN0)
Presented by: Dr Sara Hurvitz
123/221 99/223
apCR rate and 95% CI are shown. Patients with missing or unevaluable pCR status were considered nonresponders: TCH+P, 7 (3.2%); T-DM1+P, 18 (8.1%). Treatment discontinuation in the neoadjuvant phase for progressive disease: TCH+P, 0% of patients; T-DM1+P, 7% of patients.bCochran-Mantel-Haenszel Chi-square.
56%44%
Our challenge: to identify those who will do as well with less vs more
Reg
istr
atio
n THP x 4 cycles
Surg
ery
pCR: De-escalation: HP + ET only
No pCR
EligibilityHER2+
Stage II-IIIa(T2-3, N0-2)
Primary Aim: RFS
COMPASS: Concept in Development
ER+
ER-
R
R
SOC +CDK4/6i
Rational de-escalation and escalation in HER2+
SOC + IO?
Courtesy of Lisa Carey
Summary: Major Progress! New agents
Less is more Individualizing therapy for tumor biology and
response
More and smarter therapy for those with poorly responsive disease
Continued Progress in the Treatment of HER2+ BC
EGFR discovery
Cohen
FDA approves trastuzumab in
adjuvant setting
19851978 1998 2006 2007 2010
Her2 amplification in breast cancer
Aaronson
FDA approves trastuzumab alone for 2nd line and in with paclitaxel for
1st line MBC
FDA approves lapatinib +
letrozole for MBC
FDA approves lapatinib +
capecitabine for MBC
1987
Her2/neuamplification
correlates with shorter survival
Slamon
MBC : metastatic breast cancer; MoAb : monoclonal antibody
2012
FDA approves pertuzumab + trastuzumab +
docetaxel for MBC
2013
FDA approves trastuzumab
emtansine for MBC
Accelerated approval of
pertuzumab/ trastzumab as neoadjuvant
therapy
2017
Neratinib approved for extended
adjuvant therapy
Approval of pertuzumab/ trastzumabas adjuvant
therapy