CNS Control in Subgroup DESTINY Trial Oral Present

European Society for Medical Oncology (ESMO) Breast Cancer Virtual Meeting, 23-24 May 2020
CNS Metastases in HER2-Positive

Metastatic Breast Cancer Treated With
Trastuzumab Deruxtecan:
DESTINY-Breast01 Subgroup Analyses
Guy Jerusalem, Yeon Hee Park, Toshinari Yamashita, Sara A. Hurvitz,
Shuquan Chen, Jillian Cathcart, Caleb Lee, Christophe Perrin
On behalf of the DESTINY-Breast01 investigators
This presentation is the intellectual property of the author/presenter. Contact them at g.jerusalem@chuliege.be for permission to reprint and/or distribute.
Disclosures
Research grant/Funding (self), Non-remunerated activity/ies, personal fees and non-financial

support: Daiichi Sankyo; Research grant/Funding (self), Research grant/Funding (institution),
Non-remunerated activity/ies, grants, personal fees and non-financial support: Novartis;
Research grant/Funding (self), Research grant/Funding (institution), Non-remunerated
activity/ies, grants, personal fees and non-financial support: Roche; Research grant/Funding
(self), Research grant/Funding (institution), Non-remunerated activity/ies, grants, personal
fees and non-financial support: Pfizer; Research grant/Funding (self), Non-remunerated
activity/ies, personal fees and non-financial support: Lilly; Research grant/Funding (self),
Non-remunerated activity/ies, personal fees and non-financial support: Amgen; Research
grant/Funding (self), Non-remunerated activity/ies, personal fees and non-financial support:
BMS; Research grant/Funding (self), Non-remunerated activity/ies, personal fees and non-
financial support: AstraZeneca; Research grant/Funding (self), personal fees: AbbVie; Non-
remunerated activity/ies, non-financial support: Med-Immune; Non-remunerated
activity/ies, non-financial support: Merck KGaA.
This presentation is the intellectual property of the author/presenter. Contact them at g.jerusalem@chuliege.be for permission to reprint and/or distribute. 2
Trastuzumab Deruxtecan (T-DXd) is a Novel ADC Designed to

Deliver an Optimal Antitumor Effect
T-DXd is an ADC with 3 components: Payload MOA:
• A humanized anti-HER2 IgG1 mAb with the same topoisomerase I inhibitor
amino acid sequence as trastuzumab
• A topoisomerase I inhibitor payload, an exatecan derivative High potency of payload
• A tetrapeptide-based cleavable linker

High drug to antibody ratio ≈ 8
Humanized anti-HER2 Deruxtecan1,2,4

Payload with short systemic half-life
IgG1 mAb1-3
Stable linker-payload
Tetrapeptide-Based Cleavable Linker Tumor-selective cleavable linker

Topoisomerase I Inhibitor payload
(DXd)
Membrane-permeable payload
The clinical relevance of these features is under investigation.

ADC, antibody-drug conjugate; HER2, human epidermal growth factor receptor 2; IgG1, immunoglobulin G1; mAb, monoclonal antibody; MOA, mechanism of action.
1. Nakada T, et al. Chem Pharm Bull (Tokyo). 2019;67(3):173-185. 2. Ogitani Y, et al. Clin Cancer Res. 2016;22(20):5097-5108. 3. Trail PA, et al. Pharmacol Ther. 2018;181:126-142. 4. Ogitani Y, et al. Cancer Sci. 2016;107(7):1039-1046.
T-DXd Activity in HER2-Positive Breast Cancer
PHASE 2 STUDY of T-DXd: 5.4 mg/kg every 3 weeks (N=184)1
Confirmed ORR (by ICR): 60.9% (95% CI, 53.4%-68.0%)
Median DOR: 14.8 months (95% CI, 13.8-16.9)
Median PFS: 16.4 months (95% CI, 12.7-NE)

Gastrointestinal and hematologic,
Most common TEAEs:
generally low grade
Important identified risk: Interstitial lung disease (ILD)
• T-DXd was approved for the treatment of unresectable or metastatic HER2-positive breast
cancer after ≥2 prior anti–HER2-based regimens (US)2 or after prior chemotherapy (Japan)3
1. Modi S, et al. N Engl J Med. 2020; 382(7):610-621; 2. Enhertu (trastuzumab deruxtecan) [US package insert]. 2019; 3. Enhertu for intravenous drip infusion 100 mg. Japan Prescribing Information.
DESTINY-Breast01 Study Design:

An Open-Label, Multicenter, Phase 2 Study
PART 1 PART 2
Population PK Stage Dose-Finding Stage Continuation Stage

(n=65) (n=54) (n=134)
• ≥18 years of age
• Unresectable and/or
metastatic BC T-DM1 R 5.4 mg/kg
Resistant/Refractory 1:1:1 (n=22)
• HER2 positive (centrally 5.4 mg/kg
(n=249)
confirmed on archival (n=28) PART 2a
6.4 mg/kg R
tissue) (n=22) 1:1 5.4 mg/kg
• Prior T-DM1 6.4 mg/kg (n=130)
(n=26)
• Excluded patients with 7.4 mg/kg
(n=21)
history of significant ILD T-DM1 PART 2b
• Stable, treated brain Intolerant 5.4 mg/kg
metastases were allowed (n=4) (n=4)
184 patients
enrolled at 5.4 mg/kg
Endpoints Data Cutoff: August 1, 2019
• Primary: confirmed ORR by independent central review per RECIST v1.1 • 24 patients (13.0%) had CNS metastases at baseline
• Secondary: investigator-assessed ORR, DCR, DOR, CBR, PFS, OS, PK and – 11 (45.8%) ongoing
safety – 13 (54.2%) discontinued, primarily for progressive disease (6/24, 25.0%)
Modi S, et al. N Engl J Med. 2020; 382(7):610-621;
DESTINY-Breast01 Study Design:

An Open-Label, Multicenter, Phase 2 Study
PART 1 PART 2
Population Patients were included if: PK Stage Dose-Finding Stage Continuation Stage
(n=65) (n=54) (n=134)
• ≥18 years of age • They had brain metastases that were treated,
• Unresectable and/or asymptomatic, or did not require therapy to control
metastatic BC T-DM1
symptoms R 5.4 mg/kg
Resistant/Refractory 1:1:1 (n=22)
• HER2 positive (centrally • They had radiation, surgery, or other therapy 5.4 mg/kg
(n=249)
confirmed on archival (including steroids or anticonvulsants) to controlR (n=28) PART 2a
6.4 mg/kg
tissue) symptoms more than 60 days before (n=22)randomization
1:1 5.4 mg/kg
• Prior T-DM1 6.4 mg/kg (n=130)
• Brain imaging was performed every 6 weeks for (n=26)
• Excluded patients with 7.4 mg/kg
patients with a history of brain metastases
(n=21)
history of significant ILD T-DM1 PART 2b
• Stable, treated brain Intolerant 5.4 mg/kg
metastases were allowed (n=4) (n=4)
184 patients
enrolled at 5.4 mg/kg
Endpoints Data Cutoff: August 1, 2019
• Primary: confirmed ORR by independent central review per RECIST v1.1 • 24 patients (13.0%) had CNS metastases at baseline
• Secondary: investigator-assessed ORR, DCR, DOR, CBR, PFS, OS, PK and – 11 (45.8%) ongoing
safety – 13 (54.2%) discontinued, primarily for progressive disease (6/24, 25.0%)
Modi S, et al. N Engl J Med. 2020; 382(7):610-621;
DESTINY-Breast01
Patient Baseline Characteristics
CNS Subgroup All Patients
% (n=24) (N=184)
Age, median (range), years 58.0 (33-85) 55.0 (28-96)

Female 100 100
Region
37.5 / 37.5 / 25.0 34.2 / 37.0 / 28.8
Asia / Europe / North America
ECOG performance status 0 / 1 / 2 62.5 / 37.5 / 0 55.4 / 44.0 / 0.5
HR positive / negative / unknown 37.5 / 58.3 / 4.2 52.7 / 45.1 / 2.2
HER2 expressiona
IHC 3+ 79.2 83.7
IHC 2+; ISH+ / IHC 1+; ISH+ 20.8 / 0 15.2 / 1.1
Presence of visceral disease 100 91.8
All patients received ≥1 dose of T-DXd 5.4 mg/kg.

a HER2 status was centrally assessed on archival tissue according to guidelines of the American Society of Clinical Oncology–College of American Pathologists.
DESTINY-Breast01
Prior Therapies
Prior Treatment, % (n=24) (N=184)
Median, n (range)a 6 (3-16) 6 (2-27)
Trastuzumab 100 100
T-DM1 100 100
Pertuzumab 62.5 65.8
HER2 TKI 62.5 50.5
Hormone therapy 45.8 48.9
Other systemic therapy 100 99.5
Radiation therapy 88.3 70.7
a Therapies for locally advanced or metastatic breast cancer, including hormone therapy.
DESTINY-Breast01
Primary Endpoint: Objective Response Rate
Intent-to-Treat Analysis (n=24) (N=184)
58.3% (n=14) 60.9% (n=112)
Confirmed ORR by ICR
(95% CI, 36.6%-77.9%) (95% CI, 53.4%-68.0%)
CR 4.2% (n=1) 6.0% (n=11)
PR 54.2% (n=13) 54.9% (n=101)
SD 33.3% (n=8) 36.4% (n=67)
PD 4.2% (n=1) 1.6% (n=3)
Not evaluable 4.2% (n=1) 1.1% (n=2)
DCR 91.7% (n=22) 97.3% (n=179)
Duration of response (CR or PR), median 16.9 months (95% CI, 5.7-16.9) 14.8 months (95% CI, 13.8-16.9)
• Median time to response was 2.8 months (95% CI, 1.3-4.1 months) for the CNS subgroup and 1.6 months
(95% CI, 1.4-2.6 months) for all patients
DESTINY-Breast01
Best Change in Tumor Size
n=168
Best % Change From Baseline in the Sum
of Diameters of Measurable Tumors
Non-CNS patients (n=117)

CNS subgroup (n=21)
Includes patients who had both baseline and postbaseline target lesion assessments by ICR.
The line at 20% indicates PD; the line at −30% indicates PR.
DESTINY-Breast01
Progression-Free Survival
CNS Subgroup (n=24) All Patients (N=184)
Median: 18.1 months (95% CI, 6.7-18.1) Median: 16.4 months (95% CI, 12.7-NE)
Probability of Progression-Free Survival
Probability of Progression-Free Survival

1.0 1.0
0.8 0.8
0.6 0.6
0.4 0.4
0.2 0.2
Censored: 68.5%
Events: 31.5%
0.0 0.0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Months Months
No. at risk: 24 23 22 18 18 17 17 14 13 13 11 10 6 2 1 1 1 1 1 0 0 No. at risk: 184 182 174 155 153 135 121 107 103 94 69 54 38 17 11 10 9 4 3 1 0
Median follow-up, 11.0 months (range, 0.7-19.6 months) Median follow-up, 11.1 months (range, 0.7-19.9 months)
Patients who received T-DXd 5.4 mg/kg.
DESTINY-Breast01
Sites of Progression
CNS Subgroup Non-CNS All Patients
Site of PD (n=24) Patients (n=160) (N=184)
• Sites of progression were
Patients with progression on study, n (%) 8 (33.3) 40 (25.0) 48 (26.1) similar among all patients
Lung 3 (12.5) 17 (10.6) 20 (10.9) and the CNS subgroup
Liver 2 (8.3) 12 (7.5) 14 (7.6)
Brain 2 (8.3) 2 (1.3) 4 (2.2) • Overall, only 4 of 48

Bone 1 (4.2) 2 (1.3) 3 (1.6) patients had progression in
Lymph node 1 (4.2) 11 (6.9) 12 (6.5)
the CNS
Pleura 1 (4.2) 1 (0.6) 2 (1.1)
Soft tissue 1 (4.2) 0 1 (0.5) • CNS progression events:

– At 78 and 85 days in the
Chest wall 0 4 (2.5) 4 (2.2) CNS subgroup
Muscle 0 1 (0.6) 1 (0.5) – At 323 and 498 days in
patients without a history of
Peritoneum 0 1 (0.6) 1 (0.5) CNS metastases
For patients in the CNS subgroup, a CT or MRI of the brain was mandatory every 6 wks (±7 days).
DESTINY-Breast01
Safety Summary
CNS Subgroup Non-CNS All Patients
Type of Adverse Event, n (%)a (n=24) Patients (n=160) (N=184) • Median treatment duration
Any TEAE 24 (100) 159 (99.4) 183 (99.5)
Drug-related 24 (100) 159 (99.4) 183 (99.5)
– All patients: 10.0 months (range, 0.7-20.5)
– CNS subgroup: 11.0 months (range, 0.7-20.2)
TEAE grade ≥3 13 (54.2) 92 (57.5) 105 (57.1)
Drug-related 10 (41.7) 79 (49.4) 89 (48.4)
• The TEAEs in the CNS subgroup were
Serious TEAE 3 (12.5) 39 (24.4) 42 (22.8)
Drug-related 1 (4.2) 22 (13.8) 23 (12.5) generally consistent with the overall
patient population and were
Dose adjustments
predominantly gastrointestinal or
TEAE associated with discontinuation 2 (8.3) 26 (16.3) 28 (15.2)
Drug-related 2 (8.3) 25 (15.6) 27 (14.7) hematologic in nature
TEAE associated with dose reduction 5 (20.8) 38 (23.4) 43 (23.4) • TEAEs associated with discontinuation in
Drug-related 4 (16.7) 36 (22.5) 40 (21.7)
≥2 patients included:
TEAE associated with dose interruption 9 (37.5) 56 (35.0) 65 (35.3)
Drug-related 8 (33.3) 45 (28.1) 53 (28.8) – Pneumonitis (n=11) and interstitial lung
disease (n=5)
Death
– 2 patients in the CNS subgroup discontinued
TEAE associated with deathb 2 (8.3) 7 (4.4) 9 (4.9) due to different TEAEs
Drug-related 1 (4.2) 1 (0.6) 2 (1.1)
a Relationshipto study drug was determined by the treating investigator.
b Eachof the following TEAEs was associated with a fatal outcome: in the CNS subgroup, respiratory failure and disease progression (each, n=1); in the non-CNS subgroup, acute respiratory failure, general
physical health deterioration, lymphangitis, pneumonia, pneumonitis, and shock hemorrhagic (each n=1) and 1 patient had 2 TEAEs associated with death (acute kidney injury and acute hepatic failure).
DESTINY-Breast01
Case Report: 55% Regression of a Metastatic Brain Lesion
Baseline scan
• 48-year-old woman with HER2-positive
(IHC 3+)/HR-negative metastatic BC
• 16 prior lines of treatment, including
T-DM1, pertuzumab, trastuzumab, and
lapatinib
• Prior brain lesion treatment included:
– WBRT 5 years prior to enrollment
– Stereotactic radiosurgery 3 years
prior to enrollment
• Target lesions at baseline in brain,
lymph nodes, and retroperitoneum
• Nontarget lesions in lung, pancreas,
bone, and axillary lymph node
WBRT, whole-brain radiotherapy.
DESTINY-Breast01
6-week scan
• Brain lesion reduced by 36% from
baseline at 6-week scan
– PR in all target lesions
– Overall non-target lesion
response: non-CR/non-PD
• Status improved, allowing for
reduction in pain medication
DESTINY-Breast01
12-week scan
• Brain lesion reduced by 55% from
baseline at 12-week scan
– PR in all target lesions
– Overall non-target lesion
response: non-CR/non-PD
– New lesions in chest wall
DESTINY-Breast01
CNS Subgroup Conclusions
• T-DXd demonstrated efficacy in patients who had stable, treated brain metastases at baseline
that was similar to its efficacy in the overall population
– Median DOR, 16.9 months
– Median PFS, 18.1 months
– Progression in the brain was noted in only 8% of patients. Among 40 patients without brain lesions at
baseline who had progressive disease, only 2 had new brain lesions and both were late events
• The safety profile in the CNS subgroup is consistent with the non-CNS subgroup and overall
population
• Phase 3 studies in HER2-expressing BC are ongoing

– DESTINY-Breast02: vs standard of care after T-DM1 (HER2 positive)
– DESTINY-Breast03: vs T-DM1 (HER2 positive)
– DESTINY-Breast04: vs chemotherapy (HER2 lowa)
a IHC 2+/ISH− or IHC 1+.
Acknowledgments
We would like to thank:
The patients
& The study site staff
and their families for their contributions
for their participation
This study was sponsored and designed by:

Daiichi Sankyo, Inc.
Collaborator:
AstraZeneca
Medical writing support was provided by:
John Togneri, PhD (Articulate Science LLC), and was funded by Daiichi Sankyo, Inc.
DESTINY-Breast01 Investigators United States

Italy Haythem Yousif Ali
Giulia Bianchi Vasileios Assikis
Japan France Marina Cazzaniga Adam Brufsky
Kenjiro Aogi Fabrice Andre Giuseppe Curigliano Mahmoud Charif
Naoki Hayashi Marjorie Baciuchka-Palmaro Luca Gianni David Chu
Tsutomu Iwasa You Benoit Neelima Denduluri
Hiroji Iwata Elsa Curtit Stephen Dyar
Yoshinori Ito Julien Grenier Jami Fukui
Toru Mukohara William Jacot Musaberk Goksel
Yasuaki Sagara Claire Jamet
Belgium Sara Hurvitz
Toshimi Takano Christophe Perrin Jean-Luc Canon Ian Krop
Kenji Tamura Luis Teixeira Guy Jerusalem Reshma Mahtani
Eriko Tokunaga Jill Wagemans Omkar Marathe
Toshinari Yamashita Hans Wildiers Marc Matrana
Wim W. Wynendaele Shanu Modi
Spain Rashmi Murthy
Maria Fernandez Abad Cynthia Osborne
Republic of Korea Jose Manuel Perez Garcia Haeseong Park
Yee Soo Chae Joaquin Gavila Gregori Amir Abdul Rasheed
Seock-ah Im Xavier Gonzalez Farre Jane Raymond
United Kingdom Charles Redfern
Jee Hyun Kim Ignacio Delgado Mingorance
Sung-Bae Kim Manuel Ruiz-Borrego Timothy Crook Donald Richards
Keun Seok Lee Cristina Saura Peter Hall Hope Rugo
Kyong Hwa Park Silvia Vazquez Srinivisan Madhusudan Rachel Swart
Yeon Hee Park Rebecca Roylance Julie Taguchi
Joohyuk Sohn Peter Schmid Grace Wang

CNS Control in Subgroup DESTINY Trial Oral Present

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CNS Control in Subgroup DESTINY Trial Oral Present

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European Society for Medical Oncology (ESMO) Breast Cancer Virtual Meeting, 23-24 May 2020

CNS Metastases in HER2-Positive

On behalf of the DESTINY-Breast01 investigators

Research grant/Funding (self), Non-remunerated activity/ies, personal fees and non-financial

Trastuzumab Deruxtecan (T-DXd) is a Novel ADC Designed to

• A tetrapeptide-based cleavable linker

Humanized anti-HER2 Deruxtecan1,2,4

Tetrapeptide-Based Cleavable Linker Tumor-selective cleavable linker

The clinical relevance of these features is under investigation.

T-DXd Activity in HER2-Positive Breast Cancer

PHASE 2 STUDY of T-DXd: 5.4 mg/kg every 3 weeks (N=184)1

Confirmed ORR (by ICR): 60.9% (95% CI, 53.4%-68.0%)

Median DOR: 14.8 months (95% CI, 13.8-16.9)

Median PFS: 16.4 months (95% CI, 12.7-NE)

DESTINY-Breast01 Study Design:

Population PK Stage Dose-Finding Stage Continuation Stage

DESTINY-Breast01 Study Design:

Age, median (range), years 58.0 (33-85) 55.0 (28-96)

All patients received ≥1 dose of T-DXd 5.4 mg/kg.

Median, n (range)a 6 (3-16) 6 (2-27)

Trastuzumab 100 100

T-DM1 100 100

Pertuzumab 62.5 65.8

HER2 TKI 62.5 50.5

Hormone therapy 45.8 48.9

Other systemic therapy 100 99.5

Radiation therapy 88.3 70.7

Non-CNS patients (n=117)

Probability of Progression-Free Survival

Patients who received T-DXd 5.4 mg/kg.

Brain 2 (8.3) 2 (1.3) 4 (2.2) • Overall, only 4 of 48

Soft tissue 1 (4.2) 0 1 (0.5) • CNS progression events:

• Phase 3 studies in HER2-expressing BC are ongoing

We would like to thank:

This study was sponsored and designed by:

DESTINY-Breast01 Investigators United States

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