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2020 Spring Oncology Conference
Key Updates in the Treatment of HER2-Positive Breast Cancer
3
• Apply current evidence and guideline recommendations to identify the appropriate
use of and optimally sequence HER2-targeted agents in the treatment of HER2-
positive metastatic breast cancer
• Evaluate emerging research, the mechanisms of action, and the role of novel
HER2-targeted therapies in clinical investigation for patients with HER2-positive
metastatic breast cancer
• Implement best practices for the management of HER2-positive breast cancer
brain metastases
• Develop strategies to effectively manage adverse events associated with
treatments for HER2-positive breast cancer
Learning Objectives
HER2 = human epidermal growth factor receptor 2.
4
Targeted Therapies for HER2+ Breast Cancer
ADC = antibody–drug conjugate; mAb = monoclonal antibody; TKI = tyrosine kinase inhibitor.
Gajria. Expert Rev Anticancer Ther. 2011;11:263. Pernas. Ther Adv Med Oncol. 2019;11:1758835919833519.
Tucatinib
T-DM1
T-DXd
T-DM1
T-DXd
HER2-Targeted ADCsHER2-Targeted mAbs
TrastuzumabPertuzumab
Lapatinib
NeratinibHER2-Targeted
TKIsProteasome
HER2HER2
HER2HER2HER3
P
P P PP
P13K
AKT
mTOR
MK-2206 BKM120
BEZ235
Everolimus
Temsirolimus
hsp90
inhibitor
hsp90
Breakdown
of HER2 P
Endosome
T-DM1
T-DXd
5
Preferred regimens*
• Taxane + trastuzumab + pertuzumab (THP)†
Guideline-Recommended Regimens for HER2-Positive Recurrent or Stage IV Breast Cancer
Other Recommended Regimens*
• Ado-trastuzumab emtansine (T-DM1)
• Trastuzumab deruxtecan (T-DXd)
• Trastuzumab + chemotherapy‡§
• Trastuzumab + lapatinib (without cytotoxic
therapy)
• Trastuzumab + other agents§
• Lapatinib + capecitabine
• Neratinib + capecitabine
• Trastuzumab + capecitabine + tucatinib
*An FDA-approved biosimilar is an acceptable substitute for trastuzumab. †Docetaxel or paclitaxel. ‡Paclitaxel ± carboplatin, docetaxel, vinorelbine,
capecitabine. §Anthracyclines should be avoided due to significant cardiotoxicity.
Wang. Signal Transduct Target Ther. 2019;4:34. Pernas. Ther Adv Med Oncol. 2019:11:1758835919833519.
6
0 10 20 30 40 50 60 70 80 90 100 110 120
CLEOPATRA: Standard First-line Treatment for HER2+ MBC With Docetaxel/Trastuzumab/Pertuzumab
H = trastuzumab; HR = hazard ratio; ITT = intention-to-treat; OS = overall survival; P = pertuzumab; Pbo = placebo; T = docetaxel.
Swain. ASCO 2019. Abstr 1020.
*Crossover patients were analyzed in the placebo arm.
57.1
40.8
Median OS,
Mos
HR: 0.69 (95% CI: 0.58-0.82)
100
80
60
40
20
0130
OS
(%
)
MosPatients at Risk, n
THPTH + Pbo
402406
371350
318289
269230
228181
188149
165115
15096
13788
12075
7144
2011
01
00
THP
TH + Pbo
End of Study OS in ITT Population*8 yrs
Landmark OS: 37%Events: 235 (58.5%)
Landmark OS: 23%Events: 280 (69.0%)
7
MARIANNE: First-line T-DM1 ± Pertuzumab versus Docetaxel/Trastuzumab in HER2+ MBC
T-DM1 = trastuzumab emtansine.
Perez. Cancer. 2019;125:3974.
TH (n = 365) T-DM1 (n = 367) T-DM1 + P (n = 363)
Median OS, mos 50.9 53.7 51.8
Events, n 169 175 168
Stratified HR vs HT (97.5% CI) -- 0.93 (0.73-1.20) 0.86 (0.67-1.11)
Stratified HR vs T-DM1 (97.5% CI) -- -- 1.00 (0.78-1.28)
100
80
60
40
20
0
Day 1
OS
(%
)
12 Mos 24 Mos 36 Mos 48 Mos 60 Mos 72 Mos
TH
T-DM1
T-DM1 + P
Patients at Risk, nTH
T-DM1T-DM1 + P
365367363
303322309
251264257
197216217
155176172
283741
8
MARIANNE: Grade ≥ 3 AEs
Grade ≥ 3 AE, %Trastuzumab + Taxane
(n = 353)
T-DM1
(n = 361)
T-DM1 + Pertuzumab
(n = 366)
Any 55.8 47.1 48.6
Alopecia 60.1 7.2 9.0
Neutropenia 19.3 4.4 3.8
Febrile neutropenia 6.5 0 0
Diarrhea 4.2 0.3 2.7
Hypertension 3.1 4.7 5.5
Anemia 2.8 5.0 7.1
ALT increase 0.8 4.4 6.0
AST increase 0.3 6.9 3.3
GGT increase 0.3 3.3 2.5
Thrombocytopenia 0 6.6 9.0
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CT = chemotherapy; GGT = gamma-glutamyl transferase.
Perez. Cancer. 2019;125:3974.
Greater incidence
with trastuzumab +
CT
Greater incidence
with T-DM1
9
100
80
60
40
20
Physician’schoiceT-DM1
HR: 0.68 (95% CI: 0.54-0.85; P = .0007)
22.7
15.8
Median OS, mos
T-DM1
Physician’s choice
00 2 4 6 8 10 12 14 16 18 20 22 24 26
OS
(%
)
Mos
28 30 32 34 36
198 (0)
404 (0)
38 40
150 (28)
368 (17)
122 (31)
321 (29)
107 (33)
280 (35)
80 (34)
226 (43)
66 (36)
192 (44)
59 (37)
167 (45)
39 (45)
132 (66)
16 (68)
54 (138)
1 (80)
12 (172)
0
0
EMILIA[1]: Randomized phase III study of T-DM1 vs lapatinib +
capecitabine for HER2+ MBC with progression on trastuzumab +
taxane (N = 991)
EMILIA and TH3RESA: Standard Second-line Therapy for HER2+ MBC With T-DM1 After Progression on HER2-Targeted Agents
TH3RESA[2]: Randomized phase III study of T-DM1 vs physician’s
choice for HER2+ MBC with progression on a taxane, lapatinib, and
≥2 HER2-targeted regimens including trastuzumab (N = 602)
Cape = capecitabine; MBC = metastatic breast cancer; T-DM1 = trastuzumab emtansine.
1. Verma. NEJM. 2012;367:1783. 2. Krop. Lancet Oncol. 2017;18:743.
30.9
25.1
Median OS, mos
T-DM1
Lapatinib + Cape
HR: 0.68 (95% CI: 0.55-0.85; P < .001)
Efficacy stopping boundary: HR of 0.73 or P = .0037
100
80
60
40
20
00 2 4 6 8 10 12 14 16 18 20 22 24 26
OS
(%
)
Mos
28 30 32 34 36
Patients at Risk, n
496
495
471
485
453
474
435
457
403
439
368
418
297
349
240
293
204
242
159
197
133
164
110
136
86
111
63
86
45
62
27
38
17
28
7
13
4
5
85.2%
64.7%78.4%
51.8%
Lapatinib + cape
T-DM1
Patients at Risk, n (censored)
10
• HER2 TKIs
‒ Neratinib
‒ Tucatinib (FDA approved 4/2020)
• HER2 ADCs
‒ Trastuzumab deruxtecan (T-DXd; approved 12/2019)
‒ Trastuzumab duocarmazine/trastuzumab-vc-seco-DUBA (SYD985)
What’s New in HER2-Targeted Agents?
ADC = antibody–drug conjugate; mAb = monoclonal antibody; TKI = tyrosine kinase inhibitor.
11
Case Study: Sonia
• 49-yr-old woman presents with back pain and left breast mass (4 cm)
‒ She has no significant family history or past medical history
‒ Core biopsy of breast mass: invasive ductal carcinoma; ER: 0%, PgR: 0%, HER2: 3+
‒ PET/CT: 3 liver lesions (largest 2 cm); several vertebral lesions in the thoracic and lower
spine
• She receives docetaxel/trastuzumab/pertuzumab (THP) and achieves PR in liver after 3 mos
on therapy
‒ 18 mos later, progression is noted in liver (new 3-cm lesion, other lesions stable)
• Receives T-DM1 and achieves PR in liver, with stable bone lesions
‒ 10 mos later, she complains of headache
‒ MRI of the brain: 3 lesions (1 cm) in the left frontal lobe with minimal edema
‒ PET/CT: liver lesions remain unchanged, no new liver lesions; bone lesions stable
ER = estrogen receptor, PgR = progesterone receptor, PR = partial response; T-DM1 = trastuzumab emtansine.
12
Optimal Sequence of HER2-Targeted Agents for Patients With HER2-Positive MBC
• Multiple treatment options are available for patients with HER2-positive MBC
• Clinicians should reassess risks and benefits of additional lines of therapy
based on patient’s fitness, comorbidities, and preferences at progression
• If additional treatment is indicated, select therapy based on disease features as
well as patient’s fitness, comorbidities, and preferences
13
• ≥ 50% of patients with HER2+ MBC will develop
brain metastases[1]
• Lapatinib + capecitabine approved in this
setting but few patients respond
‒ In a pooled analysis, CNS ORR was 21.4%,
median PFS was 4.1 mos, median OS was
11.2 mos[1]
• Neratinib + capecitabine approved in this
setting in Feb 2020
• Trastuzumab + capecitabine + tucatinib
approved in this setting in April 2020
• T-DM1, trastuzumab, and pertuzumab do not
penetrate the CNS under normal conditions
In HER2+ MBC, CNS Disease Remains Incurable Despite Current Treatment Options
CNS = central nervous system; ECOG = Eastern Cooperative Oncology Group; MBC = metastatic breast cancer; OR = odds ratio;
PS = performance status; T-DM1 = trastuzumab emtansine.
1. Petrelli. Eur J Cancer. 2017;84:141. 2. Hurvitz. Clin Cancer Res. 2019;25:2433.
Risk of CNS Metastasis in HER2+ MBC by Subgroup[2]
Ethnicity: Hispanic/Latino No vs Yes
RaceOther vs black/African AmericanWhite vs black/African American
Age at MBC diagnosis50-69 vs ≥ 70 years< 50 vs ≥ 70 years
ECOG PS1 vs 0≥ 2 vs 0
MBC diagnosis typeRecurrent vs de novo
Hormone receptor statusNegative vs positive
1.181 (0.718-1.943)
1.268 (0.580-2.769)1.619 (1.072-2.444)
2.042 (1.248-3.341)3.128 (1.852-5.284)
1.192 (0.876-1.622)1.900 (1.125-3.201)
1.650 (1.239-2.196)
1.841 (1.359-2.494)
0 1 2 3 4 5
Higher Risk of CNS MetastasisLower Risk of CNS Metastasis
OR (95% CI)
14
OSNo CNS Mets
(n = 678)
CNS Mets
at Dx
(n = 87)
CNS Mets
After Dx
(n = 212)
Median OS, mos NE 30.2 38.3
HR(95% CI)
vs no CNS mets--
2.86
(2.05-4.00)
P < .0001
1.94
(1.52-2.49)
P < .0001
SystHERs Registry Analysis: PFS and OS by CNS Metastasis in HER2+ MBC
CNS = central nervous system; Dx = diagnosis; MBC = metastatic breast cancer; mets = metastases; NE = not estimable.
Hurvitz. Clin Cancer Res. 2019;25:2433.
PFSNo CNS Mets
(n = 678)
CNS Mets
at Dx
(n = 87)
CNS Mets
After Dx
(n = 212)
Median PFS, mos 19.1 9.2 9.9
HR (95% CI)
vs no CNS mets--
2.49
(1.93-3.20)
P < .0001
2.52
(2.13-2.99)
P < .0001
1.0
0.6
0.8
0
0.2
0.4
Mos on Study Since MBC Diagnosis
0 4 8 12 16 20 24 28 5632 36 40 44 48 52 6860 64
1.0
0.6
0.8
0
0.2
0.4
Mos on Study Since MBC Diagnosis
0 4 8 12 16 20 24 28 5632 36 40 44 48 52 6860 64
Pro
po
rtio
n W
ith
PF
S
Pro
po
rtio
n S
urv
ivin
g
15
• Randomized phase III study
• Primary endpoint: CNS as first site of relapse
• Secondary endpoints: PFS, OS
Lapatinib 1250 mg/day +
Capecitabine 2000 mg/m2/day
on Days 1-14
CEREBEL: CNS Metastasis at First Relapse in HER2+ MBC With Lapatinib/Cape vs Trastuzumab/Cape
• Trial closed early for futility in lapatinib
+ capecitabine arm
Patients with HER2+ MBC,
any line of tx, including
prior anthracyclines or
taxanes; no CNS
metastasis
(N = 540)
EndpointL + Cape
(n = 251)
T + Cape
(n = 250)
P
Value
CNS as first
site of progression, n (%)
8 (3) 12 (5) .360
Incidence of CNS
progression at any time, n (%)
17 (7) 15 (6) .865
Median time to first
CNS progression, mos (range)
5.7
(2-17)
4.4
(2-27)
NR
Median PFS, mos
• Trastuzumab naive
6.6
6.3
8.1
10.9
.021
NR
Median OS, mos 22.7 27.3 .095
ORR, % 27 32 NR
Cape = capecitabine; CNS = central nervous system; L = lapatinib; MBC = metastatic breast cancer; NR = not reported; T = trastuzumab; tx = therapy.
Pivot. JCO. 2015;33:1564.
Stratified by prior trastuzumab, lines of prior tx for MBC (0 vs ≥ 1)
*Loading dose of 8 mg/kg.
21-day
cycle
Trastuzumab* 6 mg/kg Q3W +
Capecitabine 2500 mg/m2/day
on Days 1-14
16
• Pan-HER TKI
• Irreversible inhibition
• Different MoA than trastuzumab
and pertuzumab
Neratinib: Mechanism of Action
HER1 (EGFR) HER2 HER3 HER4
TrastuzumabT-DM1
Pertuzumab
MoA = mechanism of action; T-DM1 = trastuzumab emtansine; TKI = tyrosine kinase inhibitor.
Baselga. Crit Rev Oncol Hematol. 2017;119:113.
Lapatinib Neratinib
17
Neratinib + paclitaxel
Trastuzumab + paclitaxel
TBCRC 022 Cohort 3[2]: Single-arm 2-stage phase II study of
neratinib/capecitabine in HER2+ MBC with CNS disease (n = 49)
NEfERT-T and TBCRC 022: Neratinib in HER2+ MBC
NEfERT-T[1]: Randomized phase III study of
neratinib/paclitaxel vs trastuzumab/paclitaxel in previously
untreated, HER2+ locally recurrent or MBC (N = 479)
Cape = capecitabine; CNS = central nervous system; MBC = metastatic breast cancer; N = neratinib; NE = not estimable; P = paclitaxel;
RANO-BM = Response Assessment in Neuro-Oncology Brain Metastases criteria; T = trastuzumab.
1. Awada. JAMA Oncol. 2016;2:1557. 2. Freedman. JCO. 2019;13:1081.
Events Median Time to CNS Progression
N + P (n = 242) 20 NE
T + P (n = 237) 41 NE
18 responses by volumetric criteria;
CNS ORR: 49% (95% CI: 32-66)
Best CNS Volumetric Response With Neratinib + Cape
in Lapatinib-Naive Patients (n = 37*)
*n = 6 who did not reach first reimaging assigned 0.†CNS response by RANO-BM criteria.
†
CNS ORR with prior
lapatinib: 33% (95%
CI: 10-65)
0 4 8 12 16 20 24 28 5632 36 40 44 48 52
1.0
0.6
0.8
0
0.2
0.4
HR:0.449 (95% CI: 0.259-0.780;log-rank P = .0036)
No
CN
S
Pro
gre
ssio
n (
%)
Mos
100
60
80
0
20
40
Ch
an
ge
Fro
m B
ase
line
(%
)
†††
†††††
-20
-60
-40
-100
-80
18
• International, open-label, randomized phase III trial
NALA: Neratinib/Cape vs Lapatinib/Cape in HER2+ MBC With ≥ 2 Prior Lines of HER2-Targeted Agents
Cape = capecitabine; CBR = clinical benefit rate; CNS = central nervous system; DoR = duration of response; MBC = metastatic breast cancer;
PD = progressive disease; PRO = patient-reported outcomes.
Saura. ASCO 2019. Abstr 1002. NCT01808573.
Patients with centrally confirmed
HER2+ MBC; previously treated
with ≥ 2 lines of HER2-targeted
agents for MBC; asymptomatic,
stable brain metastases allowed
(N = 621)
Until PD
Survival
follow-up
Stratified by no. prior HER2-targeted therapies, disease
location, hormone receptor status, geographic location
• Coprimary endpoints: OS, PFS (centrally confirmed)
Study positive if either endpoint statistically significant (OS, P < .04; PFS, P < .01)
• Secondary endpoints: PFS (locally determined), ORR, DoR, CBR, intervention for CNS metastases, safety, PRO
• No endocrine therapy permitted
*BID in 2 evenly divided doses. †Loperamide administered at 4 mg with first neratinib dose followed by 2 mg
Q4H for first 3 days, followed by 2 mg every 6-8 hrs through end of cycle 1; as needed thereafter.
21-day cycle
Lapatinib 1250 mg/day PO continuously +
Capecitabine* 2000 mg/m2 PO on Days 1-14
(n = 314)
Neratinib 240 mg/day PO continuously +
Capecitabine* 1500 mg/m2 PO on Days 1-14†
(n = 307)
19
NALA: Baseline Characteristics
MBC = metastatic breast cancer; T-DM1 = trastuzumab emtansine.
Saura. ASCO 2019. Abstr 1002.
Characteristic, n (%)Neratinib + Capecitabine
(n = 307)
Lapatinib + Capecitabine
(n = 314)
Age < 65 yrs 244 (79) 248 (79)
Geographic region
• Europe
• North America
• Rest of world
121 (39)
59 (19)
127 (41)
123 (39)
65 (21)
126 (40)
Hormone receptor+ (ER+ and/or PgR+) 181 (59) 186 (59)
Visceral disease at enrollment 247 (80) 253 (81)
De novo metastatic disease 139 (45) 136 (43)
No. prior HER2-targeted therapies for MBC
• 2
• ≥ 3
215 (70)
92 (30)
215 (68)
99 (32)
Prior HER2-targeted therapies for MBC
• Trastuzumab only
• Trastuzumab + pertuzumab
• Trastuzumab + T-DM1
• Trastuzumab + pertuzumab + T-DM1
124 (40)
24 (8)
58 (19)
101 (33)
113 (36)
23 (7)
64 (20)
114 (36)
20
0 3 6 9 12 15 18 21 24 27 30 330
NALA: Survival
Cape = capecitabine; L = lapatinib; N = neratinib.
Saura. ASCO 2019. Abstr 1002.
PFS (Prespecified Means Analysis) OS (Coprimary Endpoint)
Pro
babili
ty o
f P
FS
Mos Since Randomization
Neratinib + capecitabine
Lapatinib + capecitabine
Restriction:
24 mos
307
314
183
183
113
82
69
39
54
24
35
9
20
8
13
3
9
2
7
2
3
2
2
2
2
1
Patients
at Risk, n
N + Cape
L + Cape
HR (95% CI)
0.88 (0.72-1.07)
Log-Rank
P Value
.208624.0
22.2
Pro
babili
ty o
f O
S
Mos Since Randomization
1.0
0.8
0.6
0.4
0.2
0 3 6 9 12 15 18 21 24 27 30 36 39 42 45 48 51 54
Restriction:
48 mos
Mean OS,
Mos
Neratinib + capecitabine
Lapatinib + capecitabine
307
314
294
303
275
273
244
240
220
208
182
170
142
132
112
107
82
84
64
67
47
47
34
36
28
27
Patients
at Risk, n
N + Cape
L + Cape18
22
15
17
13
12
6
8
4
4
2
3
1
1
8.8
6.6
Mean PFS, Mos
1.7 mos
2.2 mos
Restricted mean
analysis P = .0003
573336
1.0
0.8
0.6
0.4
0.2
0
21
NALA: Time to Intervention for CNS Metastases
CNS = central nervous system.
Saura. ASCO 2019. Abstr 1002.
Intervention, %
Radiation therapy
Surgery/procedure
Anticancer medication
Neratinib + Capecitabine
(n = 55/307)
11
2
1
Lapatinib + Capecitabine
(n = 75/314)
15
3
1
100
80
60
40
0
Cum
ula
tive incid
ence (
%)
0 6 12 18 24 30 36 42 48 54 60
Mos Since Randomization
Neratinib + capecitabine
Lapatinib + capecitabineOverall cumulative incidence (Gray’s test): 22.8% vs 29.2%; P = .043
20
22
NALA: Safety
*No grade 4 diarrhea observed.
AE = adverse event.
Saura. ASCO 2019. Abstr 1002.
Treatment-Emergent AE, %Neratinib + Capecitabine (n = 303) Lapatinib + Capecitabine (n = 311)
All Grade Grade 3/4 All Grade Grade 3/4
Overall 100 61 99 60
• Diarrhea 83 24* 66 13*
• Hand–foot syndrome 46 10 56 11
• Hypokalemia 12 5 14 6
• Nausea 53 4 42 3
• Vomiting 46 4 31 2
• Fatigue 34 3 31 3
• Neutropenia 7 3 5 2
• Asthenia 12 3 12 2
• Decreased appetite 35 3 22 2
• Dehydration 6 2 6 2
• Median duration of treatment numerically longer with
neratinib vs lapatinib (5.7 vs 4.4 mos)
• Discontinuation due to treatment-emergent AEs:
neratinib arm, 10.9%; lapatinib arm, 14.5%
23
0 1 2 3 4 5 6 7 8 9 10 11 12 13 1 2 3 4 5 6 7 8 9 10 11 12 130
Loperamide (LPM) LPM 4 mg TID D1-14, then BID D15-56
• Open-label phase II trial enrolled adults with stage I-IIIC HER2+ BC who completed trastuzumab-
based adjuvant therapy* within 1 yr or who d/c due to AE (N = 501)
Phase II CONTROL Trial: Antidiarrheal Prophylaxis for Neratinib-Associated Diarrhea in Early HER2+ BC
All prophylaxis cohorts Neratinib 240 mg/day (13 cycles)
LPM + BudesonideLPM 4 mg TID D1-14, then BID D15-56
Budesonide 9 mg QD for 1 cycle
LPM + ColestipolLPM 4 mg TID D1-14, then BID D15-28
Colestipol 2 g BID for 1 cycle
Colestipol + LPM prnColestipol 2 g BID for 1 cycle;
LPM as needed (16 mg/day max)
Neratinib dose-escalation cohorts
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)
*28-day cycles. Treatment-emergent diarrhea also managed with neratinib interruption/reduction, BSC. Data cutoff: August 26, 2019.;
*Includes trastuzumab, trastuzumab + pertuzumab, and T-DM1.
BC = breast cancer; AE = adverse event; d/c = discontinued; LPM = loperamide; tx = treatment.
Chan. SABCS 2019. Abstr P5-14-03. Chan. Lancet Oncol. 2016;17:367. Hurvitz. SABCS 2017. P3-14-01.
24
• All preventive strategies in CONTROL reduced incidence of grade ≥ 3 diarrhea compared
with phase III ExteNET trial as historical control (40%)
*n = 1 grade 4 diarrhea on ExteNET, none on CONTROL.
Adj = adjuvant; EBC = early breast cancer.
Chan. SABCS 2019. Abstr P5-14-03. Chan. Lancet Oncol. 2016;17:367. Hurvitz. SABCS 2017. P3-14-01.
20.4% 10.9% 3.7%Discontinuation rate
due to diarrhea:
CONTROL*
Loperamide
(n = 137)
LPM + Budesonide
(n = 64)LPM + Colestipol
(n = 136)
40%
32%
23%
5%
31%
25%
24%
20%28%
33%
25%
14%
None Grade 1 Grade 2 Grade 3
35%28%
17%21%
3.3%
Neratinib Dose Escalation
+ LPM prn (n = 60)
15%
42%
40%
3%
ExteNET vs CONTROL: Antidiarrheal Prophylaxis Reduces Incidence, Severity of Diarrhea With Neratinib
ExteNET*: Adj Neratinib in
Trastuzumab-Treated HER2+ EBC
(N = 1408)
25
60
• Less EGFR-associated toxicity than other
HER2-targeted TKIs
• CNS penetration
• Well tolerated and active in combinations (eg,
with T-DM1, capecitabine, or trastuzumab)
Tucatinib: HER2-Selective TKI
AgentCellular Selectivity, IC50 (nM)
HER2 EGFR
Tucatinib 8 4000
Neratinib 7 8
Lapatinib 49 31
CNS = central nervous system; MBC = metastatic breast cancer; T-DM1 = trastuzumab emtansine; TKI = tyrosine kinase inhibitor.
Borges. ASCO 2016. Abstr 513. Borges. JAMA Oncol. 2018;4:1214-1220.
Phase Ib: Tucatinib + T-DM1 in HER2+ MBC
Overall Response in Patients with Measurable Disease
40
20
0
-20
-40
-60
-80
-100
O
N NH
N N
HN
O N
NN
1 prior HER2 agent
≥ 2 prior HER2 agents
Max c
hange in s
um
of
dia
mete
r of
targ
et
lesio
ns (
%)
26
Phase Ib Study: Tucatinib + Capecitabine/Trastuzumab in HER2+ MBC
Cape = capecitabine; CNS = central nervous system; mDoR = median duration of response; MBC = metastatic breast cancer;
mets = metastases; RP2D = recommended phase II dose; Tz = trastuzumab.
Hamilton. SABCS 2016. Abstr P24-21-01. Murthy. Lancet Oncol. 2018;19:880.
No brain mets (n = 14)
Brain mets (n = 9)
P Prior pertuzumab (n = 18)
Tucatinib + Capecitabine/Trastuzumab (n = 23)
ORR: 61% (14/23)
mDoR: 10 mos (95% CI: 2.8-19.3)
Bars represent change in measurable lesions, but some patients
also have nonmeasurable lesions. n = 4 patients with
nonmeasurable lesions only not included here.
Tucatinib at RP2D in Evaluable Patients With
Measurable CNS Disease (n = 12)
CNS ORR: 42% (5/12)
n = 29 of 52 patients had brain mets at baseline,
17 with nonmeasuarable lesions only
n = 1 patient did not have follow-up scan
-100
40
20
0
-20
-40
-60
-80
Ma
x C
ha
ng
e i
n S
um
of
Tu
mo
r D
iam
ete
rs (
%)
PP
P P
PP
PP P P
P
P PP
P
P
P P
-100
40
20
0
-20
-40
-60
-80
Tucatinib + cape
Tucatinib + Tz
Tucatinib + cape + TzScreening Post Cycle 6
(Images selected to demonstrate
longest axis of lesions)
Ma
x C
ha
ng
e i
n S
um
of
Tu
mo
r D
iam
ete
rs (
%)
27
• Randomized, double-blind, placebo-controlled, active comparator phase II trial at 155 sites in 15
countries (February 2016 to May 2019); data cutoff: September 4, 2019; median f/u: 14.0 mos
HER2CLIMB: Phase II Study Design
Patients with HER2+ MBC;
prior trastuzumab, pertuzumab,
and T-DM1; ECOG PS 0/1;
brain mets allowed*
(N = 612)
Tucatinib 300 mg PO BID +
Trastuzumab 6 mg/kg Q3W (loading dose: 8 mg/kg C1D1) +
Capecitabine 1000 mg/m2 PO BID on Days 1-14
(n = 410)
Placebo PO BID +
Trastuzumab 6 mg/kg Q3W (loading dose: 8 mg/kg C1D1) +
Capecitabine 1000 mg/m2 PO BID on Days 1-14
(n = 202)
*Including previously treated stable mets, untreated
mets not needing immediate local therapy, and
previously treated progressing mets not needing
immediate local tx.
21-day cyclesStratified by brain mets (yes vs no), ECOG PS
(0 vs 1), and region (US or Canada vs rest of
world)
BICR = blinded independent central review; ECOG = Eastern Cooperative Oncology Group; f/u = follow-up; MBC = metastatic breast cancer; mets =
metastases; RECIST = Response Evaluation Criteria in Solid Tumors; PS = performance status; T-DM1 = trastuzumab emtansine; tx = treatment.
Murthy. SABCS 2019. Abstr GS1-01. Murthy. NEJM. 2019;382:597.
• Primary endpoint: PFS (RECIST v 1.1 by BICR) among first 480 randomized patients
90% power with 288 events at α = 5%, HR: 0.67
• Secondary endpoints (total population): OS, PFS in patients with brain mets, ORR in patients with measurable disease, safety in patients who received ≥ 1 dose of study tx
28
HER2CLIMB: Baseline Characteristics (Total Population)
ECOG = Eastern Cooperative Oncology Group; PS = performance status.
Murthy. SABCS 2019. Abstr GS1-01. Murthy. NEJM. 2019;382:597.
CharacteristicTucatinib + Trastuzumab/Capecitabine
(n = 410)
Placebo + Trastuzumab/Capecitabine
(n = 202)
Female, n (%) 407 (99) 200 (99)
Median age, yrs (range) 55.0 (22-80) 54.0 (25-82)
ECOG PS 0/1, n (%) 204 (50)/206 (50) 94 (47)/108 (54)
Stage IV at initial diagnosis, n (%) 143 (35) 77 (39)
Hormone receptor status, n (%)
▪ ER and/or PgR positive
▪ ER and PgR negative
243 (60)
161 (40)
127 (63)
75 (37)
Median prior lines of therapy, n (range)
▪ Overall
▪ Metastatic setting
4.0 (2-14)
3.0 (1-14)
4.0 (2-17)
3.0 (1-13)
Presence or history of brain metastases, n (%)
▪ Treated, stable
▪ Untreated
▪ Treated, progressing
198 (48)
118 (59.6)
44 (22.2)
36 (18.2)
93 (46)
55 (59.1)
22 (23.7)
16 (17.2)
• Baseline characteristics balanced between endpoint populations and treatment arms
29
46.3
HER2CLIMB: PFS (Primary Endpoint Population)
Cape = capecitabine.
Murthy. SABCS 2019. Abstr GS1-01. Murthy. NEJM. 2019;382:597.
Events,
n/N
7.8 (7.5-9.6)
5.6 (4.2-7.1)
Median PFS,
Mos (95% CI)
Tucatinib + Trastuzumab/Cape
Placebo + Trastuzumab/Cape
178/320
97/160
33 (27-40)
12 (8-21)
1-Yr PFS,
% (95% CI)
46% reduction in risk of disease progression
HR: 0.54 (95% CI: 0.42-0.71; P < .00001)
100
80
60
40
20
0 3 6 9 12 15 18 21 24 27 30 36
Patients
Aliv
e a
nd F
ree F
rom
Dis
ease P
rogre
ssio
n (
%)
Mos Since RandomizationPatients
at Risk, n
Tucatinib arm
Placebo arm
320
160
235
94
152
45
98
27
40
629
4
15
210
1
8
1
4
0
2
0
1
0
0
0
62.9
12.3
33.1
33
0
30
HER2CLIMB: PFS in Patients With Brain Metastases (Total Population)
Cape = capecitabine.
Murthy. SABCS 2019. Abstr GS1-01. Murthy. NEJM. 2019;382:597.
Events,
n/N
7.6 (6.2-9.5)
5.4 (4.1-5.7)
Median PFS,
Mos (95% CI)
Tucatinib + Trastuzumab/Cape
Placebo + Trastuzumab/Cape
106/198
51/93
25 (17-34)
0
1-Yr PFS,
% (95% CI)
52% reduction in risk of disease progression
HR: 0.48 (95% CI: 0.34-0.69; P < .00001)
100
60
40
20
0
0 3 6 9 12 18 21 24 27 30 33 36
Patients
Aliv
e a
nd F
ree F
rom
Dis
ease P
rogre
ssio
n (
%)
Mos Since RandomizationPatients
at Risk, n
Tucatinib arm
Placebo arm
60.4
33.9
0
24.9
198
93
144
49
78
12
45
4
14
08
0
2
01
0
1
0
1
0
1
0
1
00
0
80
15
31
100
80
60
40
20
0
0 3 6 9 12 15 18 21 24 27 30 33 36
26.6
HER2CLIMB: OS (Total Population)
Cape = capecitabine.
Murthy. SABCS 2019. Abstr GS1-01. Murthy. NEJM. 2019;382:597.
21.9 (18.3-31.0)
17.4 (13.6-19.9)
Median OS,
Mos (95% CI)
Tucatinib + trastuzumab/cape
Placebo + trastuzumab/cape
130/410
85/202
45 (37-53)
27 (16-39)
2-Yr OS,
% (95% CI)
HR: 0.66 (95% CI: 0.50-0.88); P = .0048)
34% reduction in risk of death
Events,
n/N
Patients
Aliv
e (
%)
Mos Since Randomization
410
202
388
191
322
160
245
119
178
77123
48
80
3251
19
34
7
20
5
10
2
4
1
0
0
44.9
75.5
62.4
Patients
at Risk, n
Tucatinib Arm
Placebo Arm
32
Favors Tucatinib Arm Favors Placebo Arm
HER2CLIMB: OS Subgroup Analysis
SubgroupTotalAge
≥ 65 yrs< 65 yrs
RaceWhiteNonwhite
Hormone receptor statusPositive for ER, PgR, or bothNegative for ER and PgR
Baseline brain metastasisYesNo
ECOG PS01
Geographic regionUnited States and CanadaRest of world
0.1 1.0 10.0
Event/N215/612
53/116162/496
160/44455/168
128/37087/242
114/291101/319
81/298134/314
148/36967/243
OS in Total Population
0.66 (0.50-0.88)
0.58 (0.32-1.06)0.69 (0.50-0.95)
0.69 (0.50-0.96)0.51 (0.28-0.93)
0.85 (0.59-1.23)0.50 (0.31-0.80)
0.58 (0.40-0.85)0.72 (0.48-1.08)
0.51 (0.33-0.80)0.84 (0.59-1.20)
0.68 (0.48-0.95)0.63 (0.39-1.03)
HR for Death (95% CI)
ECOG = Eastern Cooperative Oncology Group; PS = performance status.
Murthy. SABCS 2019. Abstr GS1-01. Murthy. NEJM. 2019;382:597.
33
100
HER2CLIMB: Most Common Adverse Events (≥ 20% in Tucatinib Arm)
ALT = alanine aminotransferase; AST = aspartate aminotransferase; Cape = capecitabine; PPE = palmar–plantar erythrodysesthesia.
Murthy. SABCS 2019. Abstr GS1-01.
Grade
1
Grade
≥ 3
Tucatinib + trastuzumab/cape
Placebo + trastuzumab/cape
Grade
2
Fre
qu
en
cy (
%)
80
60
40
20
0
34
Optimal Use of HER2-Targeted TKI for Patients With HER2-Positive MBC and Brain Metastases
• HER2 TKIs known to have CNS penetration, data from clinical trials show systemic benefit as
well as CNS benefit
• Standard of care for patients with single or limited brain metastases continues to be
radiotherapy of CNS lesions followed by continuation of current systemic therapy
• For patients with progressive brain metastases despite initial radiotherapy, consider switching
to systemic therapy with HER2 TKI
• HER2 TKIs may also be an option for patients without brain lesions due to overall systemic
benefit observed in clinical trials
• On April 17, 2020, the FDA approved tucatinib in combination with trastuzumab/capecitabine
for treatment of advanced, unresectable or metastatic HER2+ BC, including patients with brain
metastases, who have received ≥ 1 previous HER2-targeted therapy in the metastatic setting
CNS = central nervous system; MBC = metastatic breast cancer; TKI = tyrosine kinase inhibitor.
35
• On April 17, 2020, the FDA approved tucatinib in combination with trastuzumab/capecitabine
for treatment of advanced, unresectable or metastatic HER2+ BC, including patients with brain
metastases, who have received ≥ 1 previous HER2-targeted therapy in the metastatic setting
‒ Administration: 300 mg taken orally twice daily with or without food
• Reduce dose to 200 mg orally twice daily for patients with severe hepatic impairment
‒ Tucatinib can cause severe diarrhea; administer antidiarrheal treatment as clinically
indicated
‒ Tucatinib can cause severe hepatotoxicity; monitor ALT, AST, and bilirubin prior to starting
tucatinib, every 3 weeks during treatment, and as clinically indicated
‒ Management of AEs may require temporary interruption, dose reduction, or discontinuation
• Approval based on efficacy data from randomized phase II HER2CLIMB trial
Tucatinib Approval
AEs = adverse events; ALT = alanine aminotransferase; AST = Aspartate transaminase; BC = breast cancer.
Tucatinib PI.
36
Case Study: May
• 60-yr-old woman presents with back pain and right breast mass (2 cm)
‒ She has no significant family history or past medical history
‒ Core biopsy of breast mass: invasive ductal carcinoma; ER: 0%, PgR: 0%, HER2: 2+; FISH
ratio: 3.4 with copy number of 7
‒ PET/CT: 3 liver lesions (largest 3 cm); several vertebral lesions in the thoracic and lumbar
spine
• She receives docetaxel/trastuzumab/pertuzumab (THP) and achieves PR in liver after 4 mos
• 16 mos later, she experiences progression in liver (new 2.5-cm lesion, other lesions stable)
• She receives T-DM1 and achieves PR in liver, with stable bone lesions
• 12 mos later PET/CT shows increase in liver lesions to 3 cm, no new liver lesions, and bone
lesions remain stable
‒ No brain lesions on MRI
RCB = residual cancer burden; T-DM1 = trastuzumab emtansine.
37
Optimal Sequence of HER2-Targeted Agents for Patients With HER2-Positive MBC
• For patients who have received multiple lines of therapy including
trastuzumab, pertuzumab, and T-DM1, consider treatment with next-
generation ADC T-DXd
‒ T-DXd was granted accelerated FDA approval in Dec 2019 for
treatment of unresectable or metastatic HER2-positive breast cancer
after ≥ 2 previous lines of anti–HER2-based regimens for metastatic
disease
ADC = antibody–drug conjugate; MBC = metastatic breast cancer; T-DM1 = trastuzumab emtansine; T-DXd = trastuzumab deruxtecan.
38
• Tumor antigen: abundant in tumors,
minimal in normal tissues; internalized
upon ADC binding
• Antibody: high affinity, avidity for
antigen; optimal PK; internalized
• Linker: stable in plasma; efficient
release of cytotoxic agent inside tumor
cells
• Payload: drug cytotoxic to targeted
tumor cells; not hydrophobic; must be
potent since limited number of
molecules can be attached to antibody
Structure of Antibody–Drug Conjugates
ADC = antibody–drug conjugate; mAb = monoclonal antibody; PK = pharmacokinetics.
Thomas. Lancet Oncol. 2016;17:e254.
Antigen-
binding SitemAb that targets
tumor-specific or
tumor-associated
antigens
Potent
cytotoxic
payload
Stable linker
releases
payload only
in target cell
Tumor antigen
39
Mechanism of Action of HER2-Directed ADCs
ADC = antibody–drug conjugate.
Image from Rinnerthaler. Int J Mol Sci. 2019;20:1115. HER2 directed antibody-drug-conjugates beyond T-DM1 in
breast cancer. Licensed under Creative Commons Attribution 3.0 Unported License (CC BY 3.0).
40
• Early generation
‒ Mouse antibodies; immunogenic
‒ Unstable in circulation
‒ Unable to release cytotoxic drug within
tumor cell
‒ Cytotoxic payload: chemotherapy drugs
such as doxorubicin, vinca alkaloids
(eg, vinblastine), or methotrexate
Early- vs New-Generation Antibody–Drug Conjugates
• New generation
— Chimeric or humanized antibodies;
reduced immunogenicity
— Stable in circulation
— Efficient linker technology able to
release cytotoxic drug within tumor cell
(eg, disulfide, dipeptide, or hydrazone
linkage)
— Cytotoxic payload: highly potent agents
with subnanomolar IC50 such as
calicheamicin, maytansine derivative
(eg, DM1, DM4), or auristatin (eg,
MMAE, MMAF)
Thomas. Lancet Oncol. 2016;17:e254.
41
• Tumor antigen: HER2
• Antibody: monoclonal antibody
trastuzumab
• Linker: systemically stable thioether,
not cleavable
• Cytotoxic drug payload: Emtansine
(DM1), a highly potent tubulin
destabilizer
Structure of ado-Trastuzumab-Emtansine (T-DM1), a HER2-Targeted ADC
ADC = antibody–drug conjugate.
Lewis Phillips et al. Cancer Res. 2008;68:9280.
Trastuzumab
(HER2-targeted mAb)
Cytotoxic agent:
DM1
Thioether linker
42
• High drug:antibody
ratio: ~ 8
• Stable linker-payload
• Tumor-selectable
cleavable linker
• High potency,
membrane-permeable
payload with short
systemic half-life
• Bystander killing effect
HER2-Targeted ADC: Trastuzumab Deruxtecan (DS-8201)
ADC = antibody–drug conjugate; mAb = monoclonal antibody.
Nakada. Chem Pharm Bull (Tokyo). 2019;67:173. Trail. Pharmacol Ther. 2018;181:126. Ogitani. Cancer Sci. 2016;107:1039.
Humanized anti-HER2 IgG1 mAb with same
amino acid sequence as trastuzumab
Tetrapeptide-based cleavable linker
Cysteine residue
Drug/linker
Topoisomerase I inhibitor (DXd) payload(exatecan derivative)
HOO
F
NH
O
O
O
NN
OH
OH
HN
OO
O
O
O
O
O
O
O
OO
O
HN
NH
NH
NH
N
N
N
F
HNCys
43
• Open-label, multicenter, 2-part phase II study
DESTINY-Breast01: Trastuzumab Deruxtecan (T-DXd) in Advanced HER2+ Breast Cancer
CBR = clinical benefit rate; d/c = discontinuation; DCR = disease control rate; DoR = duration of response; ECOG = Eastern Cooperative Oncology
Group; ICR = independent central review; ILD = interstitial lung disease; PD = progressive disease; PK = pharmacokinetics; PS= performance status;
RP2D = recommended phase II dose; RECIST = Response Evaluation Criteria in Solid Tumors; R/R = resistant/refractory.
Krop. SABCS 2019. Abstr GS1-03. Modi. NEJM. 2020;382:610-621.
Adult patients with
HER2+ unresectable
and/or metastatic
BC; prior T-DM1;
ECOG PS 0/1;
stable, treated brain
metastases allowed;
history of significant
ILD excluded
Newly
enrolled
patients
Pharmacokinetics (n = 65)
• Primary endpoint: ORR by ICR (RECIST v1.1)
• Secondary endpoints: investigator-assessed ORR, DCR, DoR, CBR, PFS, OS, PK, safety
*5.4 mg/kg confirmed as RP2D.
Dose Finding* (n = 54) Continuation (n = 134)
Part 1 Part 2
Total enrolled at 5.4 mg/kg: n = 184
T-DM1
Intolerant
(n = 4)
T-DM1
R/R
(n = 249)
• Data cutoff: August 1, 2019
‒ 79 (42%) continuing treatment
‒ 105 (57.1%) d/c (mostly for PD, 28.8%)
T-DXd 6.4 mg/kg
(n = 22)
T-DXd 7.4 mg/kg
(n = 23)
T-DXd 5.4 mg/kg
(n = 22)
T-DXd 5.4 mg/kg
(n = 28)
T-DXd 6.4 mg/kg
(n = 26)
T-DXd 5.4 mg/kg
(n = 130)
T-DXd 5.4 mg/kg
(n = 4)
44
DESTINY-Breast01: Baseline Characteristics
ECOG = Eastern Cooperative Oncology Group; PS = performance status; T-DM1 = trastuzumab emtansine; T-DXd = trastuzumab deruxtecan.
Krop. SABCS 2019. Abstr GS1-03. Modi. NEJM. 2020;382:610.
CharacteristicT-DXd 5.4 mg/kg
(N = 184)
Median age, yrs (range) 55 (28-96)
Female, % 100
Region, %
▪ Asia
▪ North America
▪ Europe
34.2
28.8
37.0
ECOG PS, %
▪ 0/1
▪ 2
55.4/44.0
0.5
Hormone receptor status, %
▪ Positive
▪ Negative
▪ Unknown
52.7
45.1
2.2
CharacteristicT-DXd 5.4 mg/kg
(N = 184)
Median prior lines of treatment, n (range)
▪ Trastuzumab, %
▪ T-DM1, %
▪ Pertuzumab, %
▪ Other anti-HER2 therapy, %
▪ Hormone therapy, %
▪ Other systemic therapy, %
6 (2-27)
100
100
65.8
54.3
48.9
99.5
Visceral disease, % 91.8
History of brain metastases, % 13.0
HER2 expression, %
▪ IHC 3+
▪ IHC 2+, ISH+
▪ IHC 1+, ISH+
83.7
15.2
1.1
45
100
80
60
40
20
0
-100
-80
-60
-40
-20
DESTINY-Breast01: Response
CBR = clinical benefit rate; DCR = disease control rate; DoR = duration of response; ICR = independent central
review; ITT = intention-to-treat; PD = progressive disease; SD = stable disease; T-DXd = trastuzumab deruxtecan.
Krop. SABCS 2019. Abstr GS1-03. Modi. NEJM. 2020;382:610.
Response (ITT)T-DXd 5.4 mg/kg
(N = 184)
ORR* (by ICR; n = 112), %
(95% CI)60.9 (53.4-68.0)
• CR (n = 11) 6.0
• PR (n = 101) 54.9
• SD (n = 67) 36.4
• PD (n = 3) 1.6
• Not evaluable (n = 2) 1.1
DCR, % (95% CI) 97.3 (93.8-99.1)
6-mo CBR, % (95% CI) 76.1 (69.3-82.1)
Median DoR,
mos (95% CI)14.8 (13.8-16.9)
Median time to response,
mos (95% CI)1.6 (1.4-2.6)
Best Change in Tumor Size
(by ICR; n = 168)
Line at 20% indicates PD; line at −30% indicates PR.
Patients (N = 168)B
est P
erc
enta
ge C
hange F
rom
Ba
se
line
in
Su
m o
f D
iam
ete
rs
*Patients who received T-DXd 5.4 mg/kg.
46
100806040200 70503010 90
DESTINY-Breast01: ORR by Subgroup
ECOG = Eastern Cooperative Oncology group; HT = hormone therapy;
PS = performance status; tx = therapy.
Modi. NEJM. 2020;382:610.
Yes
No
Positive
Negative
≥ 3
< 3
Yes
No
Yes
No
Asia
North America
Europe
0
1
Yes
No
IHC 3+
IHC 1+ or 2+, ISH positive
112/184
78/121
34/63
56/97
55/83
99/167
13/17
14/24
98/160
102/169
10/15
37/63
33/53
42/68
67/102
45/81
36/56
76/128
97/154
13/28
Objective Response, % (95% CI)
61 (53-68)
64 (55-73)
54 (41-67)
58 (47-68)
66 (55-76)
59 (51-67)
76 (50-93)
58 (37-78)
61 (53-69)
60 (53-68)
67 (38-88)
59 (46-71)
62 (48-75)
62 (49-73)
66 (56-75)
56 (44-67)
64 (50-77)
59 (50-68)
63 (55-71)
46 (28-66)
Subgroup Events/ Total Patients, n/N
All patients
Previous pertuzumab use
Hormone receptor
No. of regimens excluding HT
Brain metastasis
Presence of visceral disease
Geographic region
ECOG PS
T-DXd tx immediately after T-DM1
HER2-positive tumor
47
00
1.0
0.8
0.6
0.4
0.2
00 1 2
0.4
DESTINY-Breast01: Survival
Mets = metastases; mPFS = median PFS; NR = not reached; T-DXd = trastuzumab deruxtecan.
Modi. NEJM. 2020;382:610.
mPFS: 16.4 mos (95% CI: 12.7-NR)
mPFS in 24 patients with brain mets:
18.1 mos (95% CI: 6.7-18.1)
PFS OS
mOS: NR
Censored: 68.5%
Events: 31.5%
Pro
babili
ty o
f P
FS
Mos
184 182 174 155 153 135 121 107 103 94 69 54 38 17 11 10 9 4
3 1 0
3 4 5 6 7 8 9 1011121314151617181920
Patients
at Risk,
n
10
Censored: 86.4%
Events: 13.6%
184 183 182 179 174 171 167 161 155 147 133 101 66 36 21 16 12 9 8
4 0
1.0
0.8
0.6
0.2
1 2 3 4 5 6 7 8 9 11121314151617181920
Mos
Pro
babili
ty o
f O
S
Patients
at Risk,
n
• Median follow-up: 11.1 mos (range: 0.7-19.9)
48
Cough
0
DESTINY-Breast01: AEs in Overall Population
AE = adverse events; WBC = white blood cell count.
Krop. SABCS 2019. Abstr GS1-03. Modi. NEJM. 2020;382:610.
Nausea
Fatigue
Alopecia
Vomiting
Constipation
Neutropenia
Decreased appetite
Anemia
Diarrhea
Decreased WBC count
Thrombocytopenia
Headache
10 20 4030 50 60 70 9080 100
Grade 1/2
Grade ≥ 3
49
Case Study: May
• After progressing on THP and T-DM1, she begins therapy with trastuzumab
deruxtecan (T-DXd) 5.4 mg IV Q3W
‒ Treatment is generally tolerated well with minimal diarrhea and alopecia
• At 3 months, PET/CT shows PR in liver, stable bone lesions
• At 6 months, PET/CT shows continued PR but hazy infiltrates in upper lobes of both
lungs
‒ She has no apparent symptoms and reports no shortness of breath or dyspnea on
exertion
T-DM1 = trastuzumab emtansine; THP = docetaxel/trastuzumab/pertuzumab, Q3W = every 3 weeks.
50
• Among the 25 ILD events:
‒ Median time to investigator-reported onset: 193 days (range: 42-535)
‒ 17/20 patients with grade ≥ 2 ILD received glucocorticoids
‒ 7 patients recovered, 2 were recovering, 12 were unknown/not followed to ILD resolution, 4 had
died
• For 4 fatal cases, onset was from 63-148 days and death 9-60 days after ILD diagnosis (3
received steroids)
• Recommendation: monitor for symptoms; hold T-DXd and re-image for grade 1 ILD; discontinue T-
DXd and start steroids immediately upon suspecting grade 2 or greater ILD
DESTINY-Breast01: Interstitial Lung Disease
AE, n (%)T-DXd 5.4 mg/kg (N = 184)
Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Any Grade
ILD 5 (2.7) 15 (8.2) 1 (0.5) 0 4 (2.2) 25 (13.6)
AE = adverse events; ILD = interstitial lung disease; T-DXd = trastuzumab deruxtecan.
Krop. SABCS 2019. Abstr GS1-03.
51
Strategies to Manage ILD Associated with T-DXd Therapy in HER2-Positive MBC
• Monitor for ILD and promptly investigate signs and symptoms including cough,
dyspnea, fever, and other new or worsening respiratory symptoms
‒ Evaluate with imaging and consider pulmonology consult
• For patients with asymptomatic ILD, hold T-DXd and re-image in 4 wks
‒ Consider corticosteroid treatment, if necessary
‒ If resolved, restart T-DXd with dose reduction
• For patients with symptomatic ILD, discontinue T-DXd and initiate steroids
‒ Consider pulmonary consult
ILD = interstitial lung disease; MBC = metastatic breast cancer; T-DXd = trastuzumab deruxtecan.
52
Grade 1 Grade 2 Grade 3/4
• Monitor with close follow-up in 2-7 days for
onset of clinical symptoms, pulse oximetry
• Consider follow-up imaging in 1-2 wks (or as
clinically indicated)
• Consider initiating systemic steroids (≥ 0.5
mg/kg/day prednisone or equivalent) until
improvement, followed by gradual taper over
at least 4 wks
• If ILD worsens despite initiation of
corticosteroids, follow grade 2 guidelines
• Restart T-DXd if ILD resolves within 28 days
after onset
• Restart T-DXd at reduced dose if ILD resolves
> 28 days after onset
• Permanently discontinue T-DXd if grade 1 ILD
occurs beyond cycle Day 22 and has not
resolved within 49 days from last infusion
• Immediately begin systemic steroids (≥ 1
mg/kg/day prednisone or equivalent) until
clinical improvement, followed by gradual
taper over at least 4 wks
• Monitor symptoms closely
• Re-image as clinically indicated
• For worsening symptoms or no improvement
within 5 days:
⎻ Consider increasing dose of steroids to 2 mg/kg/day prednisone or equivalent and/or switch to IV administration with methylprednisolone
⎻ Reconsider additional workup for alternative etiologies as described above
⎻ Escalate care as clinically indicated
• Permanently discontinue T-DXd
• Hospitalization required
• Immediately begin empiric high-dose methylprednisolone IV (500-1000 mg/day for 3 days), followed by ≥ 1 mg/kg/day of prednisone (or equivalent) until clinical improvement, followed by gradual taper over at least 4 wks
• Re-image as clinically indicated
• For no improvement within 3-5 days:
⎻ Reconsider additional workup for alternative etiologies as described above
⎻ Consider other immunosuppressants and/or treat per local practice
• Permanently discontinue T-DXd
Guidelines for the Management of Trastuzumab Deruxtecan–Induced Interstitial Lung Disease
ILD = interstitial lung disease; T-DXd = trastuzumab deruxtecan.
Krop. SABCS 2019. Abstr GS1-03.
53
• On December 20, 2019, the FDA approved fam-trastuzumab deruxtecan-nxki for treatment
of patients with unresectable or metastatic HER2+ BC who have received ≥ 2 previous
HER2-targeted therapies in the metastatic setting
‒ Administration/dose: IV 5.4 mg/kg QW3
‒ Monitor CBC prior to each administration; assess LVEF prior to initiation and at regular
intervals during treatment as clinically indicated; monitor for ILD and pneumonitis during
treatment
‒ Management of AEs may require temporary interruption, dose reduction, or
discontinuation
• Based on ORR and DoR data from randomized phase II DESTINY-Breast01 trial
Trastuzumab Deruxtecan Approval
AE = adverse event; BC = breast cancer; CBC = complete blood count; DoR = duration of response; ILD = interstitial lung disease;
LVEF = left ventricle ejection fraction.
Trastuzumab deruxtecan PI.
Future Directions in HER2+ MBC
55
• Randomized, double-blind, phase III trial
HER2CLIMB-02: Tucatinib or Placebo + T-DM1 in Unresectable HER2-Positive Breast Cancer
Patients with HER2+ unresectable LA
or metastatic BC; previous treatment
with trastuzumab and a taxane;
previous pertuzumab permitted but not
required; untreated brain mets not
requiring immediate therapy or
previously treated and stable brain
mets permitted
(planned N = 460)
Placebo 300 mg PO BID +
T-DM1 3.6 mg/kg IV Q3W
AE = adverse event; BC = breast cancer; BICR = blinded independent central review; CBR = clinical benefit rate; DoR = duration of response;
LA = locally advanced; mets = metastases; RECIST = Response Evaluation Criteria in Solid Tumors; T-DM1 = trastuzumab emtansine.NCT03975647.
• Primary endpoint: PFS (RECIST v 1.1 by investigator assessment)
• Secondary endpoints: OS, PFS (BICR), ORR, DoR, CBR, rate of AEs
Placebo 300 mg PO BID +
T-DM1 3.6 mg/kg IV Q3W
Tucatinib 300 mg PO BID +
T-DM1 3.6 mg/kg IV Q3W
56
• Randomized, open-label, active-controlled phase III trial
Investigator’s Choice of Trastuzumab/Cape
or Lapatinib/Cape
(planned n = 200)
Trastuzumab Deruxtecan 5.4 mg/kg IV Q3W
(planned n = 400)
DESTINY-Breast02: T-DXd vs Trastuzumab/Cape or Lapatinib/Cape in HER2+ MBC With Prior T-DM1
Patients with HER2+, unresectable
and/or metastatic BC; at least third
line; progression on prior HER2-
targeted agents including T-DM1;
no prior capecitabine;
no CNS metastases
(planned N = 600)
BC = breast cancer; BICR = blinded independent central review; Cape = capecitabine; CBR = clinical benefit rate; CNS = central nervous system;
DoR = duration of response; MBC = metastatic breast cancer; RECIST = Response Evaluation Criteria in Solid Tumors; T-DM1 = trastuzumab emtansine.
NCT03523585.
• Primary endpoint: PFS (RECIST v 1.1 by BICR)
• Secondary endpoints: OS, PFS by investigator assessment, ORR, DoR, CBR
Stratified by hormone receptor status, prior pertuzumab, history of visceral disease
57
• Primary endpoint: PFS (RECIST v 1.1 by BICR)
• Secondary endpoints: OS, ORR, DoR, CBR, PFS (investigator assessment)
• Randomized, open-label phase III trial at ~160 sites in North America and Europe
DESTINY-Breast03: Second-line T-DXd vs T-DM1 in HER2+ MBC After Progression on Trastuzumab/Taxane
Patients with HER2+,
unresectable and/or metastatic
BC; previous treatment with
trastuzumab and a taxane; no
prior HER2-targeted ADC; CNS
metastases allowed
(planned N = 500)
ADC = antibody–drug conjugate; BC = breast cancer; BICR = blinded independent central review; CBR = clinical benefit rate; CNS = central nervous
system; DoR = duration of response; MBC = metastatic breast cancer; RECIST = Response Evaluation Criteria in Solid Tumors; T-DM1 = trastuzumab
emtansine; T-DXd = trastuzumab deruxtecan.
NCT03529110.
Stratified by hormone receptor status, prior
pertuzumab, history of visceral disease
T-DM1 3.6 mg/kg IV Q3W
(Planned n = 250)
Trastuzumab Deruxtecan 5.4 mg/kg IV Q3W
(Planned n = 250)
58
Efficacy of Trastuzumab Deruxtecan in HER2-Low MBC
BL = baseline; DoR = duration of response; ILD = interstitial lung disease; MBC = metastatic breast cancer; NR = not reported; PD = progressive disease.
Modi. JCO. 2020: JCO1902318.
Efficacy in HER2-Low MBC Confirmed ORR, % Median DoR, Mos Median PFS, Mos
All (N = 54) 37.0 10.4 11.1
IHC 2+ (n = 26) 38.5 -- --
IHC 1+ (n = 28) 35.7 -- --
HR+ (n = 47) 40.4 -- --
Prior CDK4/6 inhibitor (n = 16) 43.8 -- --
Be
st %
Ch
an
ge
in
Tu
mo
r S
ize
Fro
m B
L
Ch
an
ge
in
Tu
mo
r
Siz
e F
rom
BL (
%)
% Change in Tumor Size by
HER2 IHC Status
Line at 20% indicates PD; line at -30% indicates PR.
Best % Change in Tumor Size by
HER2 IHC Status
*Hormone receptor negative
n = 48
* * * * * *
80
60
40
20
0
-20
-40
-60
-80
-100
IHC 2+
IHC 1+
100
80
60
40
20
0
-20
-40
-60
-80
-100
10 20 30 40 50 60 70 80 90 120110100
IHC 2+
IHC 1+
Time (weeks)
**
*
*x
*
59
• Randomized, open-label, active-controlled phase III trial
Physician’s Choice of CT:
Capecitabine, Eribulin, Gemcitabine, Paclitaxel or nab-Paclitaxel
(planned n = 180)
Trastuzumab Deruxtecan 5.4 mg/kg IV Q3W
(planned n = 360)
DESTINY-Breast04: T-DXd vs Chemotherapy in Unresectable HER2-Low Breast Cancer
Patients with HER2-low (IHC1+ or
IHC2+/ISH-), unresectable and/or
metastatic BC; previous treatment
with trastuzumab and a taxane;
progression on endocrine therapy;
no prior HER2 positivity
(planned N = 540)
BC = breast cancer; BICR = blinded independent central review; CT = chemotherapy; DoR = duration of response; HR = hormone receptor;
RECIST = Response Evaluation Criteria in Solid Tumors; T-DM1 = trastuzumab emtansine; T-DXd = trastuzumab deruxtecan.
NCT03734029.
• Primary endpoint: PFS (RECIST v 1.1 by BICR)
• Secondary endpoints: OS, PFS (investigator assessment), ORR, DoR
Stratified by HER2 IHC status, no. of prior lines of CT, HR status (HR+
without previous CDK4/6i vs HR+ with previous CDKi vs HR-)
60
• HER2 antibody with same amino acid sequence as trastuzumab
• Proteolytic cleavage of linker in tumor microenvironment leads to activation of prodrug payload
• Active toxin (DUBA) alkylates DNA, kills dividing and nondividing cells
• Bystander killing effect
HER2-Targeted ADC: Trastuzumab Duocarmazine (SYD985)
ADC = antibody–drug conjugate.
Dokter. Mol Cancer Ther. 2014;13:2618. Elgersma. Mol Pharm. 2015;12:1813.
Trastuzumab-vc-seco-duocarmycin-hydroxybenzamide-azaindole
O
HN
O
N OH
OH
HN
O
O
O
OO
O
O
O
OO
O
O
HN
NH
N N
N
S O
NH2
NN
HN
~2.8
CI
SYD985
Antibody Linker ProdrugTrastuzumab Maleimide
linkerProtease-cleavable
linker
Self-elimination
spacers
Seco-duocarmycin progrug
Valine
CitrullinePABC Cyclization
spacer
61
• Most drug-related TEAEs mild to moderate
⎻ Ocular toxicity reported in 2/3 of patients; most common reason for treatment discontinuation
⎻ Ocular toxicity, neutropenia most common reason for dose modifications
ORR: 33% (95% CI: 20.4-48.4)
Phase I Study: Trastuzumab Duocarmazine in Locally Advanced or Metastatic HER2+ Breast Cancer
AE = adverse event; BL = baseline; TEAE = treatment-emergent adverse event.
Banerji. Lancet Oncol. 2019;20:1124.
Be
st C
ha
ng
e in
Tu
mo
r S
ize
Fro
m B
L (
%)
*Dose-expansion phase. n = 5 patients with 0% best percentage change.
Drug-Related AE, n (%)Dose-Expansion Cohorts (n = 146)
Grade 1/2 Grade 3
Fatigue 43 (29) 5 (3)
Conjunctivitis 41 (28) 4 (3)
Dry eye 44 (30) 1 (1)
Increased lacrimation 29 (20) 0
Dry skin 26 (18) 0
Decreased appetite 27 (18) 2 (1)
Alopecia 26 (18) 0
Nausea 27 (18) 0
Stomatitis 24 (16) 0
Neutropenia 14 (10) 9 (6)
Vomiting 17 (12) 0
Anemia 13 (9) 2 (1)
Pyrexia 9 (6) 0
Best % Change in Tumor Size in HER2+ Cohort
* * * * *
80
60
40
20
0
-20
-100
-80
-60
-40
100
62
• Randomized, active-controlled phase III trial
TULIP: Trastuzumab Duocarmazine vs Physician’s Choice of Tx in Locally Advanced or Metastatic Breast Cancer
Patients with HER2+,
unresectable, locally
advanced and/or metastatic
BC; progression on or after ≥
2 HER2-targeted regimens or
after T-DM1;
ECOG PS 0-2
(planned N = 345)
BC = breast cancer; ECOG = Eastern Cooperative Oncology Group; f/u = follow-up; PD = progressive disease; PRO = patient-reported outcomes;
PS = performance status; QoL = quality of life; RECIST = Response Evaluation Criteria in Solid Tumors; T-DM1 = trastuzumab emtansine.
NCT03262935.
• Primary endpoint: PFS (RECIST v 1.1)
• Secondary endpoints: OS, PFS (investigator assessment), ORR, PROs/QoL
Until PD,
toxicity, or
withdrawal
Survival f/u
Q3M
Tumor evaluation Q6W
Physician’s Choice: Lapatinib/Capecitabine,
Trastuzumab/Capecitabine, Trastuzumab/Vinorelbine,
Trastuzumab/Eribulin
(planned n = 115)
Trastuzumab Duocarmazine Q3W
(planned n = 230)
63
• Margetuximab has the same specificity,
affinity to HER2 as trastuzumab with similar
ability to disrupt signaling
• However, via Fc engineering with intent to
activate immune responses, margetuximab
has altered Fc receptor affinity
‒ Trastuzumab: WT IgG1 effector domains;
binds and activates immune cells
‒ Margetuximab: Increased affinity for
activating Fcγ RIIIA (CD16A) and
decreased affinity for inhibitory Fcγ RIIB
(CD32B)
Margetuximab: Novel HER2-Targeted Monoclonal Antibody
ADCC = Antibody-dependent cellular cytotoxicity; APC, antigen presenting cell; WT = wildtype.
Nordstrom. Breast Cancer Res. 2011;13:R123. Stavenhagen. Cancer Res. 2007;67:8882.
Nordstrom. ASCO 2019. Abstr 1030. Clynes. Nat Med. 2000;6:443.
HER2-specific
Lymphocyte
Proliferation
CD32B
TAA
CD16A
Cancer Cell
DestructionHER2
Increased CD16A Affinity:
Enhance Innate Immunity/More Potent ADCC Stimulation
Perforins
Granzymes
Decreased CD32B Affinity:
Enhance Adaptive Immunity/Increase Immune Activation
HER2+Cancer
Cell
T-cell
APC
NK Cell
64
• Sequential primary endpoint: PFS, OS
• Secondary endpoints: ORR by central blinded analysis, investigator-assessed PFS
• Tertiary and exploratory endpoints: investigator-assessed CBR, DoR, safety, and effect ofCD16A, CD32A, and CD32B alleles on margetuximab efficacy
• Randomized, open-label phase III trial (data cutoff: September 30, 2019)
SOPHIA: Margetuximab vs Trastuzumab in HER2+ Advanced Breast Cancer After ≥ 2 HER2 Therapies
BC = breast cancer; CBR = clinical benefit rate; CT = chemotherapy; DoR = duration of response; tx = treatment.
Rugo. SABCS 2019. Abstr GS1-02.
Patients with HER2+ advanced BC with
≥ 2 previous anti-HER2 therapies,
including pertuzumab; 1-3 prior lines of
tx for metastatic disease;
prior brain metastasis allowed if
treated/stable
(N = 536)
Stratified by CT, no. of prior lines of tx (> 2 vs ≤ 2),
no. of metastatic sites (> 2 vs ≤ 2)
*Investigators choice of CT: capecitabine, eribulin, gemcitabine, or vinorelbine.
Trastuzumab 8 mg/kg loading → 6 mg/kg Q3W +
CT* in 3-wk cycles
(n = 270)
Margetuximab 15 mg/kg Q3W + CT*
in 3 wk cycles
(n = 266)
65
3020100
100
80
60
40
20
0
++
++
+
SOPHIA: Investigator-Assessed PFS
CT = chemotherapy.
Rugo. SABCS 2019. Abstr GS1-02.
Mos From Randomization
PF
S (
%)
Margetuximab + CT
Trastuzumab + CT
266
270
210
192
137
108
100
72
62
42
36
2025
8
14
4
11
3
6
2
5
23
1
2
0
2 0
++++
+
+
++++
+
++
+
+
+
++
++
+
+++ +++ ++ + + +++
++
+++
++
++
++
+
+++
+
+
5.7 (5.22-6.97)
4.4 (4.14-5.45)
Median PFS,
Mos (95% CI)
208
222
HR: 0.71 (95% CI: 0.58-0.86; P = .0006)
29% reduction in risk of disease progression
Events,
n
Margetuximab + CT (n = 266)
Trastuzumab + CT (n = 270)
Mos From Randomization
PF
S (
%)
Margetuximab + CT
Trastuzumab + CT
266
270
206
184
155
130
112
87
72
59
61
45
33
25
32
21
13
5
16
10
8
4
7
3
3
1
2
1
2
1
+
+++
+
+
+
++++++
++
+++++
+
++++++
++++
++
+++
++++++
++++
5.6 (5.06-6.67)
4.2 (3.98-5.39)
Median PFS,
Mos (95% CI)
160
177
HR: 0.70 (95% CI: 0.56-0.87; P = .001)
30% reduction in risk of disease progression
Events,
n
Margetuximab + CT (n = 266)
Trastuzumab + CT (n = 270)
Investigator-Assessed PFS (Sep 2019 Cutoff)Investigator-Assessed PFS (Oct 2018 Cutoff)
0
1
0
1
0
0
+++++++++ ++
++++++++
+ +
+++++
++
++++++ + +
+ ++
0
0
100
5 2010
80
60
40
20
15 25
66
OS
(%
)
3020100
Mos From Randomization
100
80
60
40
20
040
Median difference: 1.8 mos
Median follow-up: 15.6 mos
+
SOPHIA: Interim OS Analyses (ITT)
266
270
Margetuximab + CT
Trastuzumab + CT
+++
+++++++++++++
+ ++
+
++++
++
++++
++++ +++++++
+ +
++
++++
++
++++++
+++
++++
+
+
0
259
260
249
246
230
218
214
205
159
160
131
126
107
102
64
57
47
43
35
30
22
16
14
10
9
6
0
1
3
2
2
2
2
2
239
235
186
183
80
74
31
22
21.6 (18.86-24.05)
19.8 (17.54-22.28)
Median OS,
Mos (95% CI)
Margetuximab + CT (n = 266)
Trastuzumab + CT (n = 270)
131
139
Events,
n
HR: 0.89 (95% CI: 0.69-1.13; P = .326)
Second Interim OS Analysis (Sep 2019 Cutoff)First Interim OS Analysis (Oct 2018 Cutoff)
OS
(%
)
Mos From Randomization
20
3020100
100
80
60
40
0
266
270
Margetuximab + CT
Trastuzumab + CT
Median difference: 1.7 mos
+++++
+
+++
++++++
+
++
+
++++++++++++++
241
237
174
163
85
92
57
63
42
37
29
24
8
6
3
3
0
0
2
2
0
1
209
194
125
122
17
14
18.9 (16.16-25.07)
17.2 (15.80-33.31)
Median OS,
Mos (95% CI)
Margetuximab + CT (n = 266)
Trastuzumab + CT (n = 270)
78
80
Events,
n
HR: 0.95 (95% CI: 0.69-1.31; P = .758)
+
+++ ++++++++++ ++ +
++
+
+
+++ ++++++++++++++++++
++++++
++
Median follow-up: 9.2 mos
++++++++++++++++++++++++++
+++
+++++++++
+
+++++++++++++++++++++++
+++ +
CT = chemotherapy; ITT = intention-to-treat.
Rugo. SABCS 2019. Abstr GS1-02.
67
100
80
60
40
20
03020100 40
SOPHIA: Prespecified Exploratory OS in CD16A-158F Carriers
CT = chemotherapy.
Rugo. SABCS 2019. Abstr GS1-02.
23.7 (18.89-28.32)
19.4 (16.85-22.28)
Median OS,
Mos (95% CI)
Margetuximab + CT (n = 221)
Trastuzumab + CT (n = 216)
103
114
HR: 0.79 (95% CI: 0.61-1.04; P = .087)
Median follow-up: 15.6 mos
Events,
n
0
Mos From Randomization
OS
(%
)
221
216
219
210
212
201
204
192
196
176
157
145
135
123
111
98
91
81
68
57
42
30
31
21
27
16
19
11
0
1
13
9
8
6
1
2
1
2
2
2
+
+
+
+
++
+
+++
++
++++
++ +++
+
+++ + ++
+ +
+++
+
++++
+++
+++
+
+
+++++ ++++
+
++
+
+++
+
+++
+ +
+++
+++
+
Median difference: 4.3 mos
Margetuximab + CT
Trastuzumab + CT
++
+
++
+++++
+++++++
++ +
+
+ +++++
181
165
55
43
Data Cutoff: September 2019.
• CD16A-158F carriers (FF or FV): 437/506 (86%) of genotyped patients
68
SOPHIA: Safety
AEs, n (%)Margetuximab + CT
(n = 264)
Trastuzumab + CT
(n = 265)
Any grade 260 (98.5) 261 (98.1)
Any margetuximab- or trastuzumab-related AE 160 (60.6) 132 (49.6)
Grade ≥ 3 AE 142 (53.8) 140 (52.6)
Grade ≥ 3 margetuximab- or trastuzumab-related AE 34 (12.9) 22 (8.3)
Any serious AE 43 (16.3) 49 (18.4)
Any margetuximab- or trastuzumab-related serious AE 5 (1.9) 4 (1.5)
AE leading to treatment discontinuation 8 (3.0) 7 (2.6)
AE resulting in death* 3 (1.1) 2 (0.8)
AEs of special interest
• IRR
• Discontinuation due to IRR
• LV dysfunction resulting in delayed dosing or discontinuation
All Grade
35 (13.3)
2 (0.6)
4 (1.5)
Grade ≥ 3
4 (1.5)
0
0
All Grade
9 (3.4)
0
6 (2.3)
Grade ≥ 3
0
0
0
*Deaths due to pneumonia (n = 2), pneumonia aspiration (n = 1) in margetuximab arm; pneumonia (n = 1), acute kidney injury (n =1) in trastuzumab
arm. None related to study treatments. Data cutoff: April 2019.
AE = adverse event; CT = chemotherapy; IRR = infusion-related reaction; LV = left ventricle.
Rugo. SABCS 2019. Abstr GS1-02.
69
• HER2-targeted TKIs are a reasonable therapy for HER2+ MBC in the third-line
setting and beyond
‒ Tucatinib data are particularly strong and may be a good option for patients with
progressive brain metastases
• Trastuzumab deruxtecan is a major new therapy approved for HER2+ MBC in the
third-line setting, likely to move to earlier settings
‒ Post neoadjuvant therapy
‒ Second-line T-DXd vs T-DM1 (DESTINY-Breast03)
‒ Also being looked at for HER2-low disease (DESTINY-Breast04)
• Margetuximab is of unclear benefit (perhaps in CD16A-F allele carriers?)
Implications for Practice
MBC = metastatic breast cancer; T-DM1 = trastuzumab emtansine; T-DXd = trastuzumab deruxtecan; TKI = tyrosine kinase inhibitor.
70
PCE Action Plan
✓ Clinicians should reassess risks and benefits of additional lines of therapy
based on patient’s fitness, comorbidities, and preferences at progression
✓ If additional treatment is indicated, select therapy based on disease features as
well as patient’s fitness, comorbidities, and preferences
✓ For patients with brain metastases, consider treatment with HER2 TKI-based
therapy
✓ After ≥ 2 previous lines of anti–HER2-based therapy, consider T-DXd for eligible
patients
✓ For patients receiving T-DXd, monitor for signs of interstitial lung disease and
manage ILD using recommended guidelines
PCE Promotes Practice Change
ILD = interstitial lung disease; T-DXd = trastuzumab deruxtecan; TKI = tyrosine kinase inhibitor.
2020 Spring Oncology Conference
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