2020 spring oncology conference - practicingclinicians.com · 4/25/2020 · gajria. expert rev...

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.


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


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


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.


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



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.


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)



*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.


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.


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)



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)


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)



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 (

%)


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.


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


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.


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.


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 +


Tucatinib 300 mg PO BID +


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


• 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


(Planned n = 250)


(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)


(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.


• 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)


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.


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)


Events,

n

Margetuximab + CT (n = 266)

Trastuzumab + CT (n = 270)


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)


Events,

n



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


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)



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

(%

)


20

3020100

100

80

60

40

0

266

270

Margetuximab + CT

Trastuzumab + CT


+++++

+

+++

++++++

+

++

+

++++++++++++++

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)



78

80

Events,

n

HR: 0.95 (95% CI: 0.69-1.31; P = .758)

+

+++ ++++++++++ ++ +

++

+

+

+++ ++++++++++++++++++

++++++

++


++++++++++++++++++++++++++

+++

+++++++++

+

+++++++++++++++++++++++

+++ +

CT = chemotherapy; ITT = intention-to-treat.


67

100

80

60

40

20

03020100 40

SOPHIA: Prespecified Exploratory OS in CD16A-158F Carriers

CT = chemotherapy.


23.7 (18.89-28.32)

19.4 (16.85-22.28)

Median OS,

Mos (95% CI)



103

114

HR: 0.79 (95% CI: 0.61-1.04; P = .087)


Events,

n

0


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

+

+

+

+

++

+

+++

++

++++

++ +++

+

+++ + ++

+ +

+++

+

++++

+++

+++

+

+

+++++ ++++

+

++

+

+++

+

+++

+ +

+++

+++

+


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.


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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