This document provides an expert summary on adjuvant and neoadjuvant therapy options for HER2-positive early-stage breast cancer. It discusses trials demonstrating improved disease-free and overall survival with adjuvant trastuzumab-based regimens. For lower-risk early-stage HER2-positive breast cancer, 1 year of adjuvant trastuzumab with or without chemotherapy is recommended. For higher-risk disease, newer neoadjuvant and adjuvant regimens incorporating dual anti-HER2 blockade or antibody-drug conjugates are discussed. The document also reviews toxicity profiles of different therapeutic approaches.

1. Lee Schwartzberg, MD, FACP
Medical Director
West Cancer Center and Research Institute
Professor of Medicine
University of Tennessee Health Science Center
Memphis, Tennessee
Expert Guidance on the Evolving Therapeutic
Landscape for HER2-Positive Early-Stage Breast
Cancer
Supported by educational grants from
Puma Biotechnology, Inc. and Seattle Genetics, Inc.

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Slide credit: clinicaloptions.com

3. Faculty Disclosures
Lee Schwartzberg, MD, FACP, has disclosed that he has received funds
for research support from Amgen; consulting fees from Amgen,
AstraZeneca, Bristol-Myers Squibb, Genentech/Roche, Genomic Health,
Helsinn, Myriad, Napo, Spectrum, and Pfizer; and other financial or
material support from Bayer.

4. Agenda
 Assessing Risk and Planning Neoadjuvant and Adjuvant Therapy
 Managing Lower-Risk EBC
 Treatment Strategies for High-Risk EBC
 Managing AEs Associated With HER2-Targeted Therapy

5. The Prognosis of HER2+ Disease Is Poor
Without Trastuzumab
Sørlie. PNAS. 2003;100:8418. Slide credit: clinicaloptions.com
Luminal A
Luminal B
Basal
HER2+
Censored
Mos
Probability
of
OS
P < .01
0 24 48 72 96
1.0
0.8
0.6
0.4
0.2
0
Response to Chemo in Locally Advanced
Breast Cancer by Subtype (n = 72)

6. Adjuvant Trastuzumab Improves DFS and OS for
Patients With HER2+ EBC
1. Piccart-Gebhart. NEJM. 2005;353:1659. 2. Smith. Lancet. 2007;369:29. 3. Gianni. Lancet Oncol. 2011;12:236. 4. Goldhirsch. SABCS 2012.
Abstr S5-2. 5. Cameron. Lancet. 2017;389:25. 6. Romond. NEJM. 2005;353:1673. 7. Perez. JCO. 2011;29:3366. 8. Romond. SABCS 2012.
Abstr S5-5. 9. Slamon. NEJM. 2011;365:1273. 10. Slamon. SABCS 2015. Abstr S5-04. Slide credit: clinicaloptions.com
Study
F/u,
Yrs
N
DFS OS
Δ, % HR P Value Δ, % HR P Value
HERA[1-5]
CT ± RTH vs
CT ± RT
11 3401 6.8 0.76 .0001 6.5 0.74 < .0001
NCCTG N9831/
NSABP B-31[6-8]
ACTHH vs ACT
8.4 4046 11.0 0.60 < .0001 9.0 0.63 < .0001
BCIRG 006[9,10]
ACTHH vs ACT
TCH vs ACT
10 3222 6.7 0.72 < .0001 7.2 0.63 < .0001
5.1 0.77 .0011 4.6 0.76 .075

7. Adjuvant Therapy:
Patients With Lower-Risk HER2+ EBC

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Elevated Risk of Recurrence in Patients With
HER2+ T1a,bN0M0 BC
 Retrospective analysis of outcomes by HER2 status* in patients diagnosed with T1a,bN0M0 BC at MDACC from
1990-2002 (median follow-up: 74 mos)
‒ Excluded those treated with adjuvant CT; none treated with adjuvant trastuzumab
HER2 Status Events, n/N 5-Yr DFS, %
HER2 negative 51/867 93.7
HER2 positive 21/98 77.1
DFS
(Proportion)
Distant
RFS
(Proportion)
Mos Since Diagnosis Mos Since Diagnosis
DFS by HER2 Status* Distant RFS by HER2 Status*
P < .0001
*HER2 positivity defined as IHC 3+ and/or HER2/CEP17 ratio > 2.0 by FISH.
Gonzalez-Angulo. JCO. 2009;27:5700. Slide credit: clinicaloptions.com
1.0
0.8
0.6
0.4
0.2
0
60
0 12 24 36 48
HER2 Status Events, n/N 5-Yr Distant RFS, %
HER2 negative 22/867 97.2
HER2 positive 12/98 86.4
P < .0001
1.0
0.8
0.6
0.4
0.2
0
60
0 12 24 36 48
+
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+ +

9. APT Trial: Adjuvant Paclitaxel + Trastuzumab for Small
(< 3 cm), Node-Negative HER2+ EBC
 Prospective, nonrandomized trial in patients with HER2+ disease; tumor ≤ 30 mm; N0 or
completely dissected micrometastasis in 1 LN*
‒ Patients received paclitaxel 80 mg/m2 + trastuzumab 2 mg/kg† qw for 12 cycles, followed up
trastuzumab to complete 1 full yr†
*Initial protocol required histologically proven N0 disease but was amended to allow 1 LN micrometastasis if axillary dissection completed
with no further LN involvement. †Included loading dose of 4 mg/kg trastuzumab on Day 1. Adjuvant hormonal therapy recommended for HR+
after paclitaxel completed.
Tolaney. JCO. 2019;37:1868. Slide credit: clinicaloptions.com
Baseline Characteristics, % Patients (N = 406)
Size of primary tumor T1mi 2
T1a 17
T1b 31
T1c 42
T2 9
HR positive/negative 67/33

10. APT Trial: Adjuvant Paclitaxel + Trastuzumab for Small
(< 3 cm), Node-Negative HER2+ EBC: 7-Yr Report
 Patients received paclitaxel + trastuzumab Q1W x 12 wks → trastuzumab Q3W for 9 mos (N = 410)
Tolaney. JCO. 2019;37:1868. Slide credit: clinicaloptions.com
12 24
1.0
0.8
0.6
0.4
0.2
0
DFS
(Probability)
36 48 60 84
72 96 108
0
Mos
388 385 378 362 347 120
247 34 0
406
Patients at Risk, n
3-yr DFS
5-yr DFS
7-yr DFS
98.5
96.3
93.3
Point Est,
%
97.2-99.7
94.4-98.2
90.4-96.2
95% CI,
%
6
14
23
Events, n
12 24
1.0
0.8
0.6
0.4
0.2
0
36 48 60 84
72 96 108
0
Mos
126
262
126
259
123
255
119
243
111
236
43
77
73
174
10
24
0
0
134
272
Patients at Risk, n
HR negative
HR positive
10
13
Events, n
90.7
94.6
7-Yr DFS,
%
84.6-97.2
91.8-97.5
95% CI,
%
Stratum
Hazard ratio (pos : neg): 0.61 (95% CI: 0.27-1.4)
DFS
(Probability)
HR positive
HR negative

11. Structure of ado-Trastuzumab-Emtansine (T-DM1),
a HER2-Targeted ADC
 Tumor antigen: HER2
 Antibody: monoclonal antibody
trastuzumab
 Linker: systemically stable thioether, not
cleavable
 Cytotoxic drug payload: emtansine
(DM1), a highly potent tubulin
destabilizer
Trastuzumab
(HER2-targeted mAb)
Cytotoxic agent:
DM1
Thioether linker
Lewis Phillips. Cancer Res. 2008;68:9280. Slide credit: clinicaloptions.com

12. Phase II ATEMPT: Study Design
 Randomized (3:1), open-label, multicenter phase II study
Women with stage 1 HER2+ BC
with N0 or N1mic disease;
LVEF ≥ 50%; no prior invasive
BC surgery; ≤ 90 days
from last surgery
(N = 497)
Follow-up for
5 yrs after
final dose of
T-DM1 or TH
T-DM1
3.6 mg/kg IV Q3W x 17
(n = 383)
Paclitaxel 80 mg/m2 IV +
Trastuzumab 2 mg/kg IV Q1W x 12
(n = 114)
Slide credit: clinicaloptions.com
Tolaney. SABCS 2019. Abstr GS1-05. NCT01853748.
Stratified by age (< 55 vs ≥ 55 yrs), planned RT (Y/N),
planned hormonal therapy (Y/N)
Trastuzumab
6 mg/kg Q3W x 13
 Coprimary endpoints: 3-yr DFS in T-DM1; comparison of incidence of clinically relevant toxicities
with T-DM1 vs TH, including: grade ≥ 3 non-hematologic AEs, grade ≥ 2 neurotoxicity, grade ≥ 4
hematologic AEs, febrile neutropenia, and any AE requiring dose delay or discontinuation of
protocol therapy
Study not powered to assess efficacy of TH or to compare efficacy of T-DM1 to TH.

13. Characteristic T-DM1 (n = 383) TH (n = 114) All Patients (N = 497)
Median age in yrs, (range) 56 (32-85) 55 (23-82) 56 (23-85)
Tumor size in cm, n (%)
 < 0.5
 ≥ 0.5-1.0
 ≥ 1.0-1.5
 ≥ 1.5-2.0
42 (11)
121 (32)
118 (31)
102 (27)
4 (12)
38 (33)
29 (25)
33 (29)
56 (11)
159 (32)
147 (30)
135 (27)
Histologic grade, n (%)
 Well differentiated
 Moderately differentiated
 Poorly differentiated
 Unknown
11 (3)
148 (39)
219 (57)
5 (1)
4 (4)
46 (40)
62 (54)
2 (2)
15 (3)
194 (39)
281 (57)
7 (2)
HR status positive/negative, n (%) 289 (75)/94 (25) 84 (74)/30 (26) 373 (75)/124 (25)
HER2 status (central), n (%)
 1+
 2+
 3+
 FISH performed centrally without IHC
5 (1)
92 (24)
277 (72)
9 (2)
1 (1)
25 (22)
87 (76)
1 (1)
6 (1)
117 (24)
364 (73)
10 (2)
Phase II ATEMPT: Baseline Characteristics
Tolaney. SABCS 2019. Abstr GS1-05. Slide credit: clinicaloptions.com
43%
57%

14. Phase II ATEMPT: DFS in ITT Population
Tolaney. SABCS 2019. Abstr GS1-05. Slide credit: clinicaloptions.com
Cohort N Events, n 3-Yr DFS, % 95% CI
T-DM1 383 10 97.7 96.2-99.3
TH 114 7 92.8 87.8-98.1
Mos
DFS
(%)
12 18
25
0 6
0
100
50
75
24
367 227
383 375 373 325
381 140
30 36 42 48 54 60 66
85 18 1
46
Patients
at Risk, n
T-DM1
TH 104 65
114 108 106 95
110 41 31 5 2
17
DFS by Tumor Size in T-DM1
Arm, cm
Events,
n
3-Yr
DFS, %
< 1 (n = 163) 2 98.5
≥ 1 (n = 22) 8 97.1
DFS Event in T-DM1 Arm
(n = 383)
Patients,
n
Mos to
Event
Any recurrence/death 10 --
Local/regional recurrence
 Ipsilateral axilla (HER2+)
 Ipsilateral breast (HER2-)
1
1
35
11
New contralateral primary BC
 HER2+
 HER2-
0
3
--
12, 18,
21
Distant recurrence 2 22, 51
Non-BC–related death 3 12, 32,
39

15. Phase II ATEMPT: T-DM1 and TH Clinically Relevant
Toxicities
Toxicity, n (%) T-DM1 (n = 383) TH (n = 114)
Grade ≥ 3, nonhematologic 37 (10) 13 (11)
Grade ≥ 2 neurotoxicity 42 (11) 26 (23)
Grade ≥ 4, hematologic 4 (1) 0 (0)
Febrile neutropenia 0 (0) 2 (2)
Any toxicity requiring dose delay 106 (28) 30 (26)
Any toxicity requiring early d/c 67 (17) 7 (6)
Total* 176 (46) 53 (46) *P = .91
Tolaney. SABCS 2019. Abstr GS1-05. Slide credit: clinicaloptions.com
Characteristic, n (%) T-DM1 (n = 383) TH (n = 114)
Congestive heart failure, symptomatic 3 (0.8) 1 (0.9)
Asymptomatic decline in LVEF of ≥ 15% 5 (1.3) 7 (6.1)
 Cardiac toxicity evaluated using ECHO or MUGA scan at baseline, 12 wks, and 6, 9, and 12 mos
 ATEMPT did not meet coprimary endpoint of 40% relative reduction in toxicity with T-DM1

16. Neoadjuvant Therapy

17. Why Neoadjuvant Systemic Therapy
 Reduce tumor size, increasing chances that patient can have breast-conserving
surgery (lumpectomy) rather than mastectomy; potential for less axillary
surgery
 Treat patients at high risk for metastatic disease with systemic therapy without
delay
 Allows patient and doctor to see if the tumor responds to treatment (and
allows to change therapy if not working); “response-guided approach”
 Assessing pathologic response at surgery (residual cancer vs pCR) is prognostic
and can help guide treatment recommendations
 No difference in survival comparing patients who have had chemo before or
after surgery
Gralow. JCO. 2008;26:814. Kaufmann. JCO. 2006;24:1940. Slide credit: clinicaloptions.com

18. CTNeoBC Pooled Analysis: Association Between pCR,
EFS, and OS by HR Status
 Pooled analysis of 12 international clinical trials enrolling patients from January 1990 – August 2011 with
primary BC treated with preoperative CT → surgery, with median f/u ≥ 3 yrs (N = 11,955)
Cortazar. Lancet 2014;384:164. Slide credit: clinicaloptions.com
Patients With HER2+ BC Achieving pCR
Patients
(%)
30.9%
18.3%
50.3%
30.2%
0
20
40
60
80
100
HER2+/HR+, trastuzumab (n = 385)
HER2+/HR+, no trastuzumab (n = 701)
HER2+/HR–, trastuzumab (n = 364)
HER2+/HR–, no trastuzumab (n = 471)
0
20
40
60
80
100
Yrs Since Randomization Yrs Since Randomization
Patients at Risk, n
pCR
No pCR
EFS in HER+/HR+ BC EFS in HER+/HR– BC
OS in HER+ BC
OS better with pCR OS worse with pCR
HR (95% CI)
HER2+/HR+, trastuzumab (n = 385)
HER2+/HR+, no trastuzumab (n = 701)
HER2+/HR–, trastuzumab (n = 364)
HER2+/HR–, no trastuzumab (n = 471)
Event-Free
Survival
(%)

19. Who Should Be Considered for Preoperative Systemic
Therapy for EBC?
Patients with HER2+ EBC who have a tumor ≥ 2 cm (T2) diameter
or who have node-positive disease regardless of hormone receptor
status should receive neoadjuvant chemotherapy with
trastuzumab/pertuzumab
Slide credit: clinicaloptions.com
Cardoso. Ann Oncol. 2019;30:1194. American Society of Breast Surgeons. Performance and practice guidelines for the use of
neoadjuvant systemic therapy in the management of breast cancer. March 2, 2017.

20. Pivotal Studies on Neoadjuvant Trastuzumab/Pertuzumab
for Patients With HER2+ EBC
Open-Label Phase II NeoSphere Study: Neoadjuvant Trastuzumab/Pertuzumab[1]
Chemo-naive women with
HER2+ EBC (operable or
LA/inflammatory);
primary tumor > 2 cm
(N = 417)
TH x 4 cycles
(n = 107)
HP x 4 cycles
(n = 107)
THP x 4 cycles
(n = 107)
TP x 4 cycles
(n = 96)
S
U
R
G
E
R
Y
FEC Q3W x 3
Trastuzumab Q3W for 1 yr
FEC Q3W x 3
Trastuzumab Q3W for 1 yr
Docetaxel Q3W x 4 → FEC Q3W x 3
Trastuzumab Q3W for 1 yr
FEC Q3W x 3
Trastuzumab Q3W for 1 yr
Primary endpoint:
pCR in breast (ITT)
Phase II TRYPHAENA Cardiac Safety Study: Dual HER2 Targeting ± Anthracycline Tx[2]
Patients with operable,
LA/inflammatory BC
(N = 225)
FEC + HP x 3 cycles →
THP x 3 cycles
TCHP x 6 cycles
FEC x 3 cycles →
THP x 3 cycles
pCR
assessed at
surgery
Adjuvant tx to
complete 1 yr
of
trastuzumab
Primary endpoint:
Cardiac safety
1. Gianni. Lancet Oncol. 2012;13:25. 2. Schneeweiss. Ann Oncol. 2013;24:2278. Slide credit: clinicaloptions.com

21. NeoSphere: Neoadjuvant Trastuzumab/Pertuzumab + CT
Increases pCR Rates
Gianni. Lancet Oncol. 2012;13:25. Slide credit: clinicaloptions.com
pCR in ITT Population (Primary Endpoint)
P values vs TH: *P = .0141;
†P = .0198; ‡P = .003.
100
80
60
40
20
0
pCR
(%)
TH (n = 107) THP (n = 107) HP (n = 107) TP (n = 96)
29.0
45.8*
16.8†
24.0‡

22. TRYPHAENA: pCR (ypT0/is) by ER/PgR Status
Schneeweiss. Ann Oncol. 2013;24:2278. Slide credit: clinicaloptions.com
FEC + HP x 3→THP x 3
(n = 73)
pCR
±
95%
CI
(%)
FEC x 3→THP x 3
(n = 75)
TCHP x 6
(n = 77)
100
80
60
40
20
0
ypT0/is and ER and PgR negative
ypT0/is and ER and/or PgR positive
46.2
79.4
48.6
65.0
50.0
83.8

23. Standard of Care After Neoadjuvant Chemotherapy +
Anti-HER2 Antibodies
 Continue Anti-HER2 antibody therapy to complete 1 year of treatment
 Add endocrine therapy if HR+

24. Adjuvant Therapy:
Patients With Higher-Risk HER2+ EBC

25. Building on Trastuzumab: Additional HER2-Targeted
Therapy in the Adjuvant Setting
1. Neratinib PI. 2. Pertuzumab PI. 3. von Minckwitz G. NEJM. 2017;377:122. 4. Ado-trastuzumab emtansine PI.
FDA approval July 17, 2017
As extended adjuvant
treatment for patients
with HER2overexpressed/amplified
EBC following adjuvant
trastuzumab-based
therapy[1]
Neratinib
FDA approval Dec 20, 2017
Use in combination with
chemotherapy as:
 Neoadjuvant treatment of
patients with HER2+ EBC
(either > 2 cm tumor or N+)
 Adjuvant treatment of
patients with HER2+ EBC
at high risk of recurrence[2]
‒ High-risk patients
included those with HR-
or N+ breast cancer[3]
Trastuzumab/Pertuzumab
FDA approval May 3, 2019
As adjuvant therapy for
patients with HER2+ EBC
and residual invasive
disease after neoadjuvant
taxane and trastuzumab-
based treatment[4]
T-DM1
Slide credit: clinicaloptions.com

26. APHINITY: Study Design
 International, randomized, double-blind, placebo-controlled phase III trial[1]
 Primary endpoint: IDFS per modified STEEP definition[2] (excludes second primary non-BC as event)
 Secondary endpoints: IDFS per STEEP definition,[2] OS, distant recurrence-free survival, DFS,
recurrence-free interval, safety, cardiac safety, health-related QoL
1. von Minckwitz. NJEM. 2017;377:122. 2. Hudis. JCO. 2007;25:2127. 3. Piccart. SABCS 2019. Abstr GS1-04.
Patients with HER2+ EBC, no prior
invasive BC or anticancer
tx or RT, N+ any tumor size
(no T0) or N0 tumor size
> 1 cm,* BL LVEF ≥ 55%
(N = 4805)
CT† + Trastuzumab/Pertuzumab
(n = 2400)
CT† + Trastuzumab + Placebo
(n = 2405)
10-yr follow-up
Surgery
Wk 52
*Or node negative with tumors > 0.5 to ≤ 1 cm + at least 1 of following: histologic/nuclear grade 3; ER negative and PgR negative; aged < 35 yrs.
Node-negative enrollment capped after first 3655 patients randomized.
†Tx initiated ≤ 8 wks post surgery. Permitted CT: standard anthracycline or nonanthracycline regimens (FEC x 3-4  TH x 3-4; AC x 4  TH x 4; or
TCH x 6, followed by HER2-targeted therapy for total of 1 yr). Endocrine and/or radiotherapy. could be started at end of adjuvant CT.
Slide credit: clinicaloptions.com

27. APHINITY: Updated Descriptive Analysis of IDFS in
ITT Population
Piccart. SABCS 2019. Abstr GS1-04. Slide credit: clinicaloptions.com
Yr 3 Yr 6
2400
2404
Yrs From Randomization
Pertuzumab
(n = 2400)
Placebo
(n = 2404)
Events, n (%) 221 (9.2) 287 (11.9)
Stratified HR 0.76 (95% CI: 0.64-0.91)
Median follow-up, mos 74.1
6-yr duration
Difference in event-free rate, % 2.8
2277
2312
2198
2215
2122
2134
2055
2039
1978
1967
1482
1421
IDFS
(%)
100
80
60
40
20
0
6
0 1 2 3 4 5
94.1%
93.2%
90.6%
87.8%
Patients at Risk, n
Pertuzumab
Placebo

28. APHINITY: IDFS by Nodal Status in ITT Population
Piccart. SABCS 2019. Abstr GS1-04.
Mos
Slide credit: clinicaloptions.com
Yr 6
Patients at
Risk, n
1503
1502
Yrs From Randomization
1420
1439
1357
1359
1301
1288
1257
1223
1205
1176
814
741
IDFS
(%)
100
80
60
40
20
0
6
0 1 2 3 4 5
87.9%
83.4%
Pertuzumab
(n = 1503)
Placebo
(n = 1502)
Events, n (%) 173 (11.5) 239 (15.9)
Stratified HR 0.72 (95% CI: 0.59-0.87)
6-yr duration
Difference in event-free rate, % 4.5
Node-Positive Cohort
Yr 3
92.0%
90.2%
Yr 6
Patients at
Risk, n
897
902
Yrs From Randomization
857
873
841
856
821
846
798
816
773
791
668
680
IDFS
(%)
100
80
60
40
20
0
6
0 1 2 3 4 5
95.0%
94.9%
Pertuzumab
(n = 897)
Placebo
(n = 902)
Events, n (%) 48 (5.4) 48 (5.3)
Stratified HR 1.02 (95% CI: 0.69-1.53)
6-yr duration
Difference in event-free rate, % 0.1
Node-Negative Cohort
Yr 3
97.5%
98.4%

29. APHINITY: IDFS by HR Status in ITT Population
Piccart. SABCS 2019. Abstr GS1-04.
Mos
Slide credit: clinicaloptions.com
Yr 6
Patients at
Risk, n
864
858
Yrs From Randomization
821
811
796
771
759
743
732
716
708
693
520
502
IDFS
(%)
100
80
60
40
20
0
6
0 1 2 3 4 5
89.5%
87.0%
Pertuzumab
(n = 864)
Placebo
(n = 858)
Events, n (%) 90 (10.4) 106 (12.4)
Stratified HR 0.83 (95% CI: 0.63-1.10)
6-yr duration
Difference in event-free rate, % 2.5
HR-Negative Cohort
Yr 3
92.8%
91.2%
Yr 6
Patients at
Risk, n
1536
1546
Yrs From Randomization
1456
1501
1402
1444
1363
1391
1323
1323
1270
1274
962
919
IDFS
(%)
100
80
60
40
20
0
6
0 1 2 3 4 5
91.2%
88.2%
Pertuzumab
(n = 1536)
Placebo
(n = 1546)
Events, n (%) 131 (8.5) 181 (11.7)
Stratified HR 0.73 (95% CI: 0.59-0.92)
6-yr duration
Difference in event-free rate, % 3.0
HR-Positive Cohort
Yr 3
94.8%
94.4%

30. Neratinib: Mechanism of Action
 Pan-HER TKI
 Irreversible inhibition
 Different MoA than
trastuzumab and
pertuzumab
HER1 (EGFR) HER2 HER3
Trastuzumab T-DM1
Pertuzumab
Lapatinib Neratinib
Baselga. Crit Rev Oncol Hematol. 2017;119:113. Slide credit: clinicaloptions.com
Extracellular
Intracellular
TK TK
HER4
TK
P P
MEK
ERK
PI3K
AKT

31. ExteNET 5-Yr Update: Neratinib vs Placebo After
Adjuvant Trastuzumab in HER2+ EBC
 Primary endpoint: IDFS at 2 yrs
 Primary analysis of 2-yr IDFS rate: neratinib, 93.9%; placebo, 91.6%
(HR: 0.67; 95% CI: 0.50-0.91; P = .0091)
Chan. Lancet Oncol. 2016;17:367. Martin. Lancet Oncol. 2017;18:1688.
Patients with HER2+ EBC (stage I-III);
adjuvant trastuzumab completed ≤ 2 yrs
before randomization*; N+/- disease or
residual disease after neoadjuvant therapy;
known ER and PgR status
(N = 2840)
Neratinib 240 mg/day PO
(n = 1420)
Placebo
(n = 1420)
1 yr
*Amendment in Feb 2010
restricted enrollment to
patients with N+ disease who
completed trastuzumab ≤ 1 yr
before randomization.
Stratified by hormone receptor status (ER+ and/or PgR+ vs ER- and
PgR-), nodal status (0 vs 1-3 vs ≥ 4), adjuvant trastuzumab regimen
(sequential vs concurrent with CT)
Endocrine therapy given according to
local practice
Slide credit: clinicaloptions.com

32. ExteNET: 5-Yr IDFS Analysis
Martin. Lancet Oncol. 2017;18:1688.
Mos After Randomization
IDFS
(%)
Patients at Risk, n
Neratinib
Placebo
HR: 0.73 (95% CI: 0.57-0.92; P = .0083)
1420
1420
1316
1354
1272
1298
1225
1248
1106
1142
978
1029
965
1011
949
991
938
978
920
958
885
927
100
60
80
40
20
0
Neratinib
Placebo
60
0 6 18 24
12 30 36 42 48 54
97.9%
95.5%
94.3%
91.7%
92.2%
90.2%
91.2%
89.1% 87.7%
90.2%
Slide credit: clinicaloptions.com

33. ExteNET: 5-Yr IDFS Analysis by Hormone Receptor Status
Martin. Lancet Oncol. 2017;18:1688.
Mos After Randomization
IDFS
(%)
Patients at Risk, n
Hormone Receptor Positive Hormone Receptor Negative
HR: 0.95 (95% CI: 0.66-1.35)
HR: 0.60 (95% CI: 0.43-0.83)
Neratinib
Placebo
816
815
757
779
731
750
705
719
642
647
571
581
565
567
558
556
554
551
544
542
532
525
60
0 6 12 18 24 30 36 42 48 54
100
80
60
40
20
0
Neratinib
Placebo
98.1%
96.1%
95.4%
91.7%
93.6%
89.8% 88.5%
92.6% 91.2%
86.8%
Mos After Randomization
IDFS
(%)
Patients at Risk, n
Neratinib
Placebo
604
605
559
575
541
548
520
529
464
495
407
448
400
444
391
435
384
427
376
416
362
402
60
0 6 12 18 24 30 36 42 48 54
100
80
60
40
20
0
Neratinib
Placebo
97.5%
94.7%
92.8%
91.8%
90.8%
90.4% 89.3%
89.9%
88.9%
88.8%
Slide credit: clinicaloptions.com

34. ExteNET: 5-Yr IDFS by Patient Subgroup
Hormone Receptor Positive and
< 1 Yr From Last Dose of Tmab
Gnant. SABCS 2018. Abstr P2-13-01. Slide credit: clinicaloptions.com
Hormone Receptor Positive and
< 1 Yr From Last Dose of Tmab
Without pCR After Neoadjuvant Tx
Mos After Randomization
IDFS
(%)
Patients at Risk, n
Hormone receptor positive/≤ yr from trastuzumab
HR: 0.58 (95% CI: 0.41-0.82)
2-sided P = .002
Neratinib
Placebo
670
664
620
634
599
609
577
583
523
535
469
481
465
471
460
462
457
458
448
450
428
433
60
0 6 12 18 24 30 36 42 48 54
100
90
80
70
60
0
Neratinib
Placebo
50
98.1%
96.1%
94.8%
91.0%
93.1%
89.2% 87.6%
92.3% 90.8%
85.7%
∆5.1%
Mos After Randomization
Patients at Risk, n
Hormone receptor positive/≤ yr from trastuzumab without pCR
HR: 0.60 (95% CI: 0.33-1.07)
Neratinib
Placebo
131
164
126
159
121
151
113
143
100
125
94
107
93
103
91
99
91
99
88
98
84
94
60
0 6 12 18 24 30 36 42 48 54
100
90
80
70
60
0
50
98.4%
95.0%
90.8%
85.5%
88.9%
81.6% 80.0%
88.0% 85.0%
77.6%
∆7.4%

35. KATHERINE: Trastuzumab Emtansine vs Trastuzumab
as Adjuvant Therapy for HER2+ EBC
 International, randomized, open-label phase III study
Patients with HER2+ EBC (cT1-4/N0-3/M0) who had
residual invasive disease in breast or axillary nodes
after neoadjuvant chemotherapy plus HER2-targeted
therapy* at surgery
(N = 1486)
T-DM1† 3.6 mg/kg IV Q3W x 14 cycles
(n = 743)
Trastuzumab 6 mg/kg IV Q3W x 14 cycles
(n = 743)
Slide credit: clinicaloptions.com
Geyer. SABCS 2018. Abstr GS1-10. von Minckwitz. NEJM. 2019;380:617.
Stratified by clinical stage, HR status, single vs dual neoadjuvant HER2-targeted therapy,
pathologic nodal status after neoadjuvant therapy
 Primary endpoint: IDFS
 Secondary endpoints including distant recurrence-free survival, OS,
safety
Randomization occurred within 12 wks of surgery; radiotherapy and/or endocrine therapy given per local standards. *Minimum of 9 wks taxane and
trastuzumab. †Patients who d/c T-DM1 for toxicity allowed to switch to trastuzumab to complete 14 cycles.

36. KATHERINE: IDFS
Slide credit: clinicaloptions.com
von Minckwitz. NEJM. 2019;380:617.
First IDFS
Event, %
T-DM1 T
Any 12.2 22.2
Distant
recurrence
10.5* 15.9†
Locoregional
recurrence
1.1 4.6
Contralateral
breast cancer
0.4 1.3
Death without
prior event
0.3 0.4
6 12
100
80
60
40
20
0
IDFS
(%)
18 24 30 36 48
42 54 60
0
Mos Since Randomization
707
676
681
635
658
594
633
555
561
501
409
342
142
119
255
220
44
38
4
4
743
743
Patients at Risk, n
T-DM1
Trastuzumab
Events, n (%)
3-yr IDFS, %
T-DM1
(n = 743)
91 (12.2)
88.3
Trastuzumab
(n = 743)
165 (22.2)
77.0
HR: 0.50 (95% CI: 0.39-0.64; P < .001)
CNS events: *5.9% vs †4.3%.

37. KATHERINE: Secondary Endpoints
Slide credit: clinicaloptions.com
von Minckwitz. NEJM. 2019;380:617.
6 12
100
80
60
40
20
0
Freedom
From
Distant
Recurrence
(%)
18 24 30 36 48
42 54 60
0
Mos Since Randomization
707
679
682
643
661
609
636
577
564
520
412
359
143
126
254
233
45
41
4
4
743
743
Patients
at Risk, n
T-DM1
Trastuzumab
Events, n (%)
3-yr event-free rate, %
T-DM1
(n = 743)
78 (10.5)
89.7
Trastuzumab
(n = 743)
121 (16.3)
83.0
HR: 0.60 (95% CI: 0.45-0.79)
6 12
100
80
60
40
20
0
OS
(%)
18 24 30 36 48
42 54 60
0
Mos Since Randomization
719
695
702
677
693
657
668
635
648
608
508
471
195
175
345
312
76
71
12
8
743
743
Patients
at Risk, n
T-DM1
Trastuzumab
HR: 0.70 (95% CI: 0.47-1.05; P = .08)
Events, n (%)
T-DM1
(n = 743)
42 (5.7)
Trastuzumab
(n = 743)
56 (7.5)
Distant Recurrence OS
Median follow-up: 41.4 mos (range: 0.1-62.7) with T-DM1 and 40.9 mos (range: 0.1-62.6) with trastuzumab

38. So, What Do We Do?

39. Putting the Data Into Context: Higher-Risk HER2+
Adjuvant Therapy
Parameter
EXTENET[1]
(Neratinib vs Placebo)
APHINITY[2]
(Pertuzumab vs Placebo)
KATHERINE[3]
(T-DM1 vs Trastuzumab)
Study population, N 2840 4805 1486
HER2 testing Local (confirmed
centrally after)
Central Central
Entry criteria Stage I-IIIc, later
changed to II-IIIC
N+ or N- and > 1 cm tumor
or N- and < 1 cm tumor and
< 35 yrs of age or G3 or HR-
cT1-4/N0-3/M0 with
residual disease after NAC
Node negative, % 24 34 54
Prior anthracycline, % 78 75 76
HR positive, % 57 64 73
IDFS, % 5 yr: 90.2 vs 87.7 3 yr: 94.1 vs 93.2 3 yr: 88.3 vs 77.0
Hazard ratio for IDFS 0.73 (P = .0083) 0.81 (P = .045) 0.50 (P < .001)
1. Martin. Lancet Oncol. 2017;18:1688. 2. von Minckwitz. NEJM. 2017;377:122. 3. von Minckwitz. NEJM. 2019;380:617. Slide credit: clinicaloptions.com

40. cT1 a/b, cN0* ≥ cT2 or ≥ cN1
Surgery → trastuzumab-
based therapy
(observation only;
TH followed by
H* 1 yr)
Neoadjuvant
TCHP or AC-THP
Proposed Strategy for Managing Patients With
Stage I-III HER2+ EBC
Slide credit: clinicaloptions.com
cT1c cN0
Assess Risk*
and Patient
Preference
Residual invasive
disease
pCR
(ypT0/is ypN0)
H ± P‡ x 1 yr
Neratinib if HR+ Neratinib
??
HR+ HR−
H ± P
x 1 yr
T-DM1 x 14
*High-risk patients (age < 35 yrs, grade 3, hormone receptor negative,
multifocal disease) could be considered for neoadjuvant therapy.
‡In the phase II CONTROL trial assessing the effectiveness of
antidiarrheal prophylaxis for neratinib-induced diarrhea, 54% of
patients received pertuzumab as part of (neo)adjuvant therapy prior
to extended adjuvant therapy with neratinib.[1]
1. Barcenas. Ann Oncol. 2020;[Epub].

41. KAITLIN: Adjuvant T-DM1 + P vs HP + Taxane After
Anthracyclines in High-Risk Early Breast Cancer
 International, randomized, open-label phase III trial
Harbeck. ASCO 2020. Abstr 500. NCT01966471. Slide credit: clinicaloptions.com
 Coprimary endpoints: IDFS in node-positive and ITT populations
 Secondary endpoints: OS, secondary malignancies, DFS, distant RFS, safety, PROs
Patients with HER2+ EBC; if
node negative, must be HR-
with tumor > 2 cm (T2+)
(N = 1846)
T-DM1 + Pertuzumab
for up to 18 cycles (1 yr)
(n = 928)
Trastuzumab + Pertuzumab
for up to 18 cycles (1 yr) +
Taxanes x 3-4 cycles or 12 wks
(n = 918)
Anthracyclines*
x 3-4 cycles
Anthracyclines*
x 3-4 cycles
Stratified by region (US/Canada vs Western EU/Aus/NZ vs Asia vs rest
of world), nodal status (0 vs 1-3 vs ≥ 4), HR status (ER and/or PgR pos
vs ER/PgR neg), anthracycline (doxorubicin vs epirubicin)
Surgery
*Investigator’s choice: FEC, AC, or EC.

42. Primary Analysis of KAITLIN: Outcomes
 Trial failed to meet coprimary endpoints: T-DM1 + P after anthracyclines did not significantly
reduce risk of IDFS event vs HP + taxanes in node-positive or ITT populations
 No new safety signals observed
 Lower risk of deterioration in QoL observed in those treated with T-DM1 + P
‒ Difference likely driven by treatment with taxanes in comparator arm
Harbeck. ASCO 2020. Abstr 500. Slide credit: clinicaloptions.com
IDFS
(Coprimary Endpoints)
Node-Positive Disease ITT Population
HP + Taxanes
(n = 826)
T-DM1 + P
(n = 832)
HP + Taxanes
(n = 918)
T-DM1 + P
(n = 928)
Events, n (%) 82 (9.9) 80 (9.6) 88 (9.6) 86 (9.3)
Stratified HR 0.97 (95% CI:0.71-1.32; P = .8270) 0.98 (95% CI: 0.72-1.32)
3-yr IDFS, % 94.1 92.8 94.2 93.1

43. Managing AEs Associated With
HER2-Targeted Therapy in EBC

44. AEs of Interest
 Cardiac toxicity (rare)
 Infusion reactions (rare)
 Diarrhea
 Cardiac toxicity (rare)
 Diarrhea
 Rash
 Liver toxicity (rare)
 Drug interactions:
‒ Gastric acid–reducing
agents
‒ CYP3A4
inhibitors/inducers
‒ P-glycoprotein substrates
Neratinib PI. Pertuzumab PI. Ado-trastuzumab emtansine PI. Slide credit: clinicaloptions.com
Trastuzumab/Pertuzumab Neratinib
 Thrombocytopenia
 Increased AST/ALT
 Neuropathy
 Hepatic toxicity (rare)
 Cardiac toxicity (rare)
 Infusion reactions (rare)
T-DM1

45. Considerations for Management of Pertuzumab-
Induced Diarrhea
 Diarrhea more common with
trastuzumab/pertuzumab vs
trastuzumab/placebo
‒ Any grade: 71.2% vs 45.2%
‒ Grade ≥ 3: 9.8% vs 3.7%
 Episodes of diarrhea most frequent
during cycle 1 of pertuzumab and
when given concurrently with chemo
 Treatment delay or discontinuation
generally not necessary for
pertuzumab-associated diarrhea
Incidence of Grade ≥ 3
Diarrhea (APHINITY)
Patients
(%)
8%
3%
18%
6%
0
5
10
15
20
25
Anthracycline  taxane + trastuzumab/pertuzumab (n = 1834)
Anthracycline  taxane + trastuzumab/placebo (n = 1894)
Taxane/carboplatin + trastuzumab/pertuzumab (n = 528)
Taxane/carboplatin + trastuzumab/placebo (n = 510)
von Minckwitz. NEJM. 2017;377:122. Slide credit: clinicaloptions.com

46. Phase II CONTROL Trial: Antidiarrheal Prophylaxis for
Neratinib-Associated Diarrhea
 An international, sequential-cohort, open-label phase II study in patients
who completed adjuvant trastuzumab-based treatment in ≤ 1 yr
All prophylaxis cohorts Neratinib 240 mg/day (13 cycles)
Loperamide LPM 4 mg TID D1-14, then BID D15-56
Barcenas. Ann Oncol. 2020;[Epub]. Slide credit: clinicaloptions.com
LPM + Budesonide
LPM 4 mg TID D1-14, then BID D15-56
Budesonide 9 mg QD for 1 cycle
LPM + Colestipol
LPM 4 mg TID D1-14, then BID D15-28
Colestipol 2 g BID for 1 cycle
Colestipol + LPM prn
Colestipol 2 g BID for 1 cycle;
LPM as needed (16 mg/day max)
Neratinib dose-escalation cohorts
0 1 2 3 4 5 6 7 8 9 10 11 12 13 0 1 2 3 4 5 6 7 8 9 10 11 12 13
Neratinib 120 mg/day D1-7  160 mg/day D8-14
 240 mg/day (13 cycles)
Neratinib 160 mg/day D1-14  200 mg/day D15-28
 240 mg/day (13 cycles)
LPM as needed (16 mg/day max)
LPM as needed (16 mg/day max)

47. Sales
None Grade 1 Grade 2 Grade 3
ExteNET vs CONTROL: Antidiarrheal Prophylaxis
Reduces Incidence, Severity of Diarrhea With Neratinib
 All preventive strategies in CONTROL reduced incidence of grade ≥ 3 diarrhea compared with
phase III ExteNET trial as historical control (40%)
Barcenas. Ann Oncol. 2020;[Epub]. Slide credit: clinicaloptions.com
ExteNET*: Adj Neratinib in
Trastuzumab-Treated HER2+ EBC
(N = 1408)
20% 8% 4%
Discontinuation rate
due to diarrhea:
*Grade 4 diarrhea: ExteNET, n = 1 (< 1%); CONTROL, none.
CONTROL*
Incidence of Diarrhea
Loperamide
n = 137
Loperamide + Budesonide
n = 64
Loperamide + Colestipol
n = 136
40%
33%
23%
5%
31%
25%
24%
20%
28%
33%
25%
14%
None Grade 1 Grade 2 Grade 3
35%
28%
17%
21%
3%
Neratinib Dose Escalation
+ loperamide PRN n = 60
15%
42%
42%
2%

48. Neratinib-Induced Diarrhea Over Time:
ExteNET and CONTROL Trials
100
90
80
70
50
60
40
30
20
10
0
1
1408
137
64
26
2
1146
90
57
18
3
1074
85
53
11
4
1033
79
51
4
5
1006
78
48
0
6
971
78
35
0
7
935
79
25
0
8
924
74
18
0
9
911
74
9
0
10
888
72
6
0
11
873
72
2
0
12
863
67
0
0
Mos
Patients
With
Diarrhea
(%)
ExteNET
Loperamide
LPM + budesonide
LPM + colestipol
No grade 4 events occurred in the CONTROL study
Grade 2 Grade 3
ExteNET
CONTROL: Loperamide
CONTROL: LPM + budesonide
CONTROL: LPM + colestipol
Patients at Risk, n
Ibrahim. AACR 2017. Abstr CT128. Slide credit: clinicaloptions.com

49. Considerations for Management of Neratinib-Induced
Diarrhea: Prophylaxis
Start Loperamide at
First Dose of Neratinib
 Give patients instructions for use of
loperamide (potential to adjust dose if
constipation occurs)
 Add budesonide or colestipol to manage
loperamide-refractory diarrhea
Neratinib Dose Modifications for Diarrhea
Hold neratinib for any grade 2 events lasting
≥ 5 days or grade 3 events lasting ≥ 2 days or
any grade with complicated features*
Time Loperamide Dose Dose Frequency
Wks 1-2 4 mg 3 times per day
Wks 3-8 4 mg 2 times per day
Wks 9-52 4 mg
As needed to achieve 1-2
BM per day, no more
than 16 mg/day
Resume neratinib
at same dose
Resume neratinib
at reduced dose
(200/160/120 mg/day)
Resolves to grade ≤ 1
in ≤ 7 days
Resolves to grade ≤ 1
in 8-21 days
*Dehydration, fever, hypotension, renal failure, or grade 3/4
neutropenia.
Neratinib PI. Slide credit: clinicaloptions.com
If grade 4 diarrhea occurs or diarrhea recurs at grade
≥ 2 at 120 mg dose; permanently discontinue neratinib

50. Considerations for Cardiac Dysfunction During Adjuvant
Trastuzumab/Pertuzumab or T-DM1
 Both HER2-targeted therapy and anthracyclines can result in decreased
LVEF and CHF (subclinical or clinical cardiac failure)
Pretreatment:
LVEF ≥ 55% or
≥ 50% after anthracyclines
For LVEF decrease to
< 50% with ≥ 10%
decrease from baseline:
hold HER2-targeted tx for
at least 3 wks
Resume tx if
LVEF improves to
≥ 50% or < 10%
below baseline
Monitor LVEF every 12 wks during therapy
Baseline Assessment of LVEF
Pertuzumab PI. Ado-trastuzumab emtansine PI. Slide credit: clinicaloptions.com
T-DM1
Trastuzumab/Pertuzumab
Pretreatment:
LVEF ≥ 50%
For LVEF decrease of
< 40% or 45% with
≥ 10% decrease from
baseline: hold T-DM1 for
at least 3 wks
Resume tx if
LVEF improves to
≥ 40% or within
10% of baseline
Monitor LVEF at regular intervals during therapy
Baseline Assessment of LVEF

51. clinicaloptions.com/oncology
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