DESTINY-Breast03 Phase 3 Study Results
Poster 17
Dose-finding and expansion studies of
trastuzumab deruxtecan in combination with
other anticancer agents in patients with
advanced/metastatic HER2+ (DESTINY-Breast07)
and HER2-low (DESTINY-Breast08) breast cancer
Fabrice André, MD, PhD; Erika P. Hamilton, MD²; Sherene Loi, MD, PhD³; Seock-Ah Im, MD, PhD; Joohyuk Sohn, MD, PhD5;
Ling-Ming Tseng, MD, Carey K. Anders, MD; Peter Schmid, MD, PhD, FRCP; Sarice Boston, PhD; Annie Darilay, PhD;
Pia Herbolsheimer, MD, PhD; Adam Konpa, MBA, MPH, MBBS10; Gargi Patel, MD, PhD, BChir, FRCP11; Magdalena Wrona,
PharmDev 10 Shoubhik Mondal, PhD; Komal L. Jhaveri, MD, FACP12
1Gustave Roussy, Université Paris-Sud, Villejur, France; Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN "Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; *Department of
Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; "Yonse Cancer Center, Seoul, Republic of Korea; *Talpel Veterans General Hospital. Talpel, Talwan: "Duke Cancer
Institute, Durham, NC; "Barts Cancer Institute, Centre for Experimental Cancer Medicine, London, UK; "AstraZeneca Pharmaceuticals LP, Gaithersburg, MD, 10AstraZeneca, Warsaw, Mazowieckie, Poland;
"AstraZeneca Pharmaceuticals LP, Cambridge, UK; Memorial Sloan Kettering Cancer Center, New York, NY
Introduction
⚫ T-DXd is an antibody-drug conjugate composed of a humanized anti-HER2
monoclonal antibody and a topoisomerase I inhibitor payload1.2
⚫ T-DXd is approved in the US for patients with unresectable or metastatic HER2+
breast cancer who have received a prior anti-HER2-based regimen either in the
metastatic setting, or in the neoadjuvant or adjuvant setting and have developed
disease recurrence during or within 6 months of completing therapy³
o T-DXd is also approved in multiple countries for patients with unresectable or
metastatic HER2+ breast cancer with 22 prior anti-HER2-based therapies+
. In the phase 3 DESTINY-Breast03 trial, T-DXd has shown lower risk of disease
progression or death vs T-DM1 in patients with HER2+ metastatic breast cancer
previously treated with trastuzumab and a taxane
T-DXd demonstrated preliminary antitumor activity in patients with HER2-low
advanced/metastatic breast cancer in a phase 1 trial and improved PFS and OS vs
physician's choice of chemotherapy in patients with HER2-low unresectable and/or
metastatic breast cancer in the phase 3 DESTINY-Breast04 trial?
• Combinations of T-DXd with anticancer therapies are being assessed in 2 ongoing,
open-label, multicenter, modular clinical trials in patients with advanced/metastatic
HER2+ breast cancer (DB-07) or HER2-low-expressing breast cancer (DB-08)
Each trial has a dose-finding phase (part 1) and a dose-expansion phase (part 2)
© Here we report preliminary results from the dose-finding phase of DB-07
(module 2: T-DXd+pertuzumab) and DB-08 (module 4: T-DXd + anastrozole;
module 5: T-DXd + fulvestrant), including safety and RP2D (DB-07)/
recommended doses for expansion (DB-08)
Methods
Data are reported for the following part
1 modules of DB-07 (phase 1b/2;
NCT04538742) and DB-08 (phase 1b;
NCT04556773; Figures 1 and 2)
© DB-07 module 2: T-DXd 5.4 mg/kg
Q3W+pertuzumab 420 mg Q3W
(pertuzumab loading dose: 840 mg)
⚫ DB-08 module 4: T-DXd 5.4 mg/kg
Q3W + anastrozole 1 mg daily
• DB-08 module 5: T-DXd 5.4 mg/kg
Q3W + fulvestrant 500 mg Q4W
(fulvestrant loading dose: 500 mg on
C1D15)
The part 1 primary objective was to
assess safety and tolerability and
determine the RP2D/recommended
doses for expansion according to the
modified toxicity probability interval-2
algorithm
• Study design details (parts 1 and 2) can
be found in the supplemental materials
using the QR code
Figure 1. DB-07 study design (part 1)
Part 1: Dose findinga
Population
⚫ HER2+ (IHC 3+ or IHC 2+/ISH+) advanced/unresectable or
metastatic breast cancer
• ≥1 prior treatment line in the metastatic setting
Patents in
*The doses administered in the part-2 expansion phase will be based on the RP20s determined in part 1.
Patents were followed up beyond the 21-day in a pesarate study (BEGONIA; NCT03742102)
es in modue 2 ved the
2 received spuma loading dose of an
Figure 2. DB-08 study design (part 1)
Part 1: Dose finding
Population
• HER2-low (IHC 1+ or IHC 2+/ISH-) advanced/metastatic
breast cancer
Modules 1 to 3: HR+ or HR-
• Modules 4 and 5: HR+
⚫HR+ patients: 21 prior line of endocrine therapy® and 21
prior line of chemotherapy for metastatic disease
• HR- patients: ≥1 prior line of chemotherapy for metastatic
disease
*The doses administered in the part-2 expansion phase will be based on the recommended dose for expansion determined in part 1.
Patients were folowed up beyond the 21-day DLT period (28 days for T-xd+vestrant) for safety events.
With or without a targeted therapy (such as CDK4/6, mTOR, or PBK inhibitors)
Patients in module 5 received a fulvestrant leading dose of 500 m on CID15
Module 1: T-DXd + durvalumab
Module 2: T-DXd 5.4 mg/kg Q3W+pertuzumab 420 mg
Q3W (data cutoff: October 15, 2021)
Module 3: T-DXd + paclitaxel
Module 4: T-DXd + durvalumab + paclitaxel
Module 5: T-DXd + tucatinib
O Module 1: T-DXd+capecitabine
Module 2: T-DXd + durvalumab + paclitaxel
Module 3: T-DXd+capivasertib
Module 4: T-DXd 5.4 mg/kg Q3W + anastrozole 1 mg daily
(data cutoff: January 20, 2022)
Module 5: T-DXd 5.4 mg/kg Q3W + fulvestrant 500 mg Q4Wc
(data cutoff: January 20, 2022)
Primary objectives and
endpoints for part 1
-Safety, tolerability, and
RP2D assessed by AES,
serious AEs, DLTs, and
laboratory findings
Primary objective and
endpoints for part 1
• Safety, tolerability, and
recommended dose for
expansion assessed by
AES, serious AEs, DLTs.
and laboratory findings
aiichi-Sankyo
Objective
•The primary objective of part 1 of the ongoing DESTINY-Breast07 (DB-07) and DESTINY-Breast08 (DB-08) clinical
trials is to investigate the safety and tolerability and determine the recommended phase 2 dose (RP2D; DB-07)
and recommended doses for expansion (DB-08) of combinations of T-DXd with anticancer therapies in patients
with HER2+ breast cancer (DB-07) or HER2-low-expressing breast cancer (DB-08)
Conclusions
•For the following T-DXd combination therapies, the RP2D (DB-07) and recommended doses for expansion
(DB-08) were the standard doses for breast cancer for each individual drug:
⚫ DB-07: T-DXd 5.4 mg/kg Q3W + pertuzumab 420 mg Q3W (pertuzumab loading dose: 840 mg)
• DB-08: T-DXd 5.4 mg/kg Q3W + anastrozole 1 mg daily
DB-08: T-DXd 5.4 mg/kg Q3W + fulvestrant 500 mg Q4W (fulvestrant loading dose: 500 mg on C1D15)
•These doses of these T-DXd combination regimens were well tolerated and will serve as the doses for further
evaluation in part 2
⚫DB-07 (NCT04538742) and DB-08 (NCT04556773) are ongoing, with additional T-DXd combinations being
evaluated and further follow-up underway
Plain language summary
600
Why did we perform this research?
Some breast cancers have high levels of the HER2 protein (HER2+) and some have lower levels (HER2 low). T-
DXd is an anticancer drug designed to target and kill cancer cells that express HER2.1. It is being studied for the
treatment of HER2+ breast cancer³ and HER2-low-expressing breast cancer. 4.5 We wanted to find out if T-DXd
can be used to treat HER2+ and HER2-low-expressing breast cancer in combination with other drugs that are
already used to treat breast cancer and experimental drugs that could potentially be used to treat breast cancer.
How did we perform this research?
In the ongoing DESTINY-Breast07 and DESTINY-Breast08 trials, we are assessing T-DXd by itself and in
combination with other anticancer drugs in patients with HER2+ (IHC 3+ or IHC 2+/ISH+) and HER2-low-
expressing (IHC 1+ or IHC 2+/ISH-) breast cancer, respectively. In part 1 of both trials, we are assessing the
safety of different doses of each combination treatment; results will be used to decide what dose to use for each
combination in part 2. In part 2, we will further assess how safe and effective these drug combinations are for
treating patients with HER2+ or HER2-low-expressing breast cancer.
What were the findings of this research and what are the implications?
In part 1 of DESTINY-Breast07, 7 patients were treated with T-DXd 5.4 mg/kg Q3W + pertuzumab 420 mg Q3W
(pertuzumab loading dose: 840 mg). In part 1 of DESTINY-Breast08, 6 patients each were treated with T-DXd
5.4 mg/kg Q3W combined with either anastrozole 1 mg daily or fulvestrant 500 mg Q4W (fulvestrant loading dose:
500 mg on day 15 of cycle 1). These preliminary results show that T-DXd can be combined with pertuzumab,
anastrozole, or fulvestrant. These doses were determined to be the recommended doses to use in part 2 of these
trials, where their safety and efficacy (antitumor activity) will be evaluated further. T-DXd combined with other
anticancer drugs is also being assessed in both trials.
Where can I access more information?
DESTINY-Breast07: ClinicalTrials.gov. A Phase 1b/2 Study of T-DXd Combinations in HER2-positive Metastatic
Breast Cancer (DB-07). https://clinicaltrials.gov/ct2/show/NCT04538742
DESTINY-Breast08: ClinicalTrials.gov. A Phase 1b Study of T-DXd Combinations in HER2-low Advanced or
Metastatic Breast Cancer (DB-08). https://clinicaltrials.gov/ct2/show/NCT04556773
These studies were funded b AstraZeneca. In March 2019, AstraZeneca entered into a global development and commercialization colaboration agreement with Dalichi Sankyo for T-DXd (DS-8201).
References: 1. Nakada T, et al. Chem Pharm BUN (Tokyo). 2019;67(3):173-185.2.0
2. ograni Y, et al. Cin cancer Res. 2016,22,20:5097-5108. 3. Cortes J, et al. N Engl J Med. 2022 386(12):1143-1154.
4. Modi S, et al. J Can Oncol. 2020;38(17):1887-1896. 5. AstraZeneca. News release. Accessed March 31, 2022. https://www.astrazeneca.com/media-centre/press-releases/2022/enhertu-improves-prs-and-
-in-her-low-ohmitt-text-Positive20high%20level%20re20from
Poster
Plain language
summary
Supplementary material (Study
design details, parts 1 and 2)
Please scan this quick response (QR) code with your smartphone
camera or app to obtain a copy of these materiale. Alternatively,
please click on the link below.
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This presentation is the intellectual property of the authors/presenter. Please contact Dr Fabrice André at [email protected] for permission to
reprint and/or distribute.
Poster presented at ASCO Annual Meeting, June 3-7, 2022; Chicago, IL, and virtual.
Corresponding author email address: FABRICE [email protected]
.
Results and interpretation
DB-07 part 1: T-DXd + pertuzumab
Patients
As of the data cutoff, 7 patients were assigned to the T-DXd +
pertuzumab module and received the initial dose level (Table 1)
о Treatment ongoing: n=5 (71.4%)
о
Treatment discontinued: n=2 (28.6%; discontinued both T-DXd
and pertuzumab)
Withdrawal by patient: n=1 (14.3%)
AE: n=1 (14.3%; ejection fraction decreased)
Treatment duration is reported in Figure 3
Table 1. Patient demographics and disease characteristics
Age, mean (range), years
Female, n (%)
Race, n (%)
Asian
HER2 status, n (%)
IHC 3+
IHC 2+/ISH+
N=7
.
54.3 (38-66)
7 (100.0)
Dose modifications: T-DXd+pertuzumab
DB-08 part 1: T-DXd + anastrozole and T-DXd + fulvestrant
Patients
T-DXd+anastrozole
• As of the data cutoff, 6 patients were assigned to the T-DXD +
anastrozole module and received the initial dose level (Table 3)
Treatment ongoing: n-3 (50.0%)
Dose modifications: T-DXd + fulvestrant
Patients with:
Patients with:
≥1 dose
delaya
21 dose
reduction
≥1 dose
delay
≥1 dose
reduction
≥1 dose
interruption
Treatment discontinued: n=3 (50.0%; discontinued both T-DXd
and anastrozole)
T-DXd
2 (33.3)
Reason: AE (n=1)
other (n=2)
3 (50.0%)
1 (14.3%)
1 (14.3%)
T-DXd
0
Reason: other'
Reason: AE
Fulvestrant
0
0
Dose modifications
not allowed per
protocol
0
Pertuzumab
*Evaluation for potential pneumonits
* Grade 3 platelet count decreased.
Safety
°
objective disease
21 dose
interruption
0
Six patients were evaluable for DLTS (1 was not evaluable for DLTS
due to using G-CSF for grade 3 neutropenia); no DLTs were reported
- Objective disease progression: n=2 (33.3%)
Clinical disease progression: n=1 (16.7%)
T-DXd+fulvestrant
As of the data cutoff, 6 patients were assigned to the T-DXd+
fulvestrant module and received the initial dose level
o Treatment ongoing: n=5 (83.3%)
Treatment discontinued: n=1 (16.7%; discontinued T-DXd due
to AE [pneumonitis] and fulvestrant due
progression)
Treatment duration is reported in Figure 4
Table 3. Patient demographics and disease characteristics
Reason: AE (n=3)d
Dose modifications
not allowed per
protocol
1 (16.7%)
Reason: other
*Reasons for dose delays were not mutually exclusive; patients with multiple dose delays were counted only once per category.
Nausea (vas updated from a dose interruption after the data cutor). Public holiday (n-1) and assessment of possible disease
progression (n=1; was updated from a dose interruption after the data cutof). "Nausea (n-2) and platelet count decreased (n-1).
Assessment of possible disease progression
Safety
.
All patients were evaluable for DLTS; no DLTs were reported in either
module
Both combination treatments were generally well tolerated (Table 4)
T-DXd+ anastrozole
One patient (16.7%) died 226 days after the first dose due to disease
progression; no patients had ILD/pneumonitis
T-DXd+fulvestrant
No patients died; 1 patient (16.7%) experienced drug-related
ILD/pneumonitis outside the 28-day DLT cycle
.
.
The combination treatment was generally well tolerated (Table 2)
There were no deaths; no patients experienced ILD/pneumonitis
6 (85.7)
T-DXd+
anastrozole
N=6
T-DXd+
fulvestrant
N=6
.
White
1 (14.3)
Table 2. Safety with RP2D
Age, mean (range), years
57.7 (47-71)
Patients, n (%)
N=7
Primary tumor location at diagnosis, n (%)
Breast
Female, n (%)
6 (100.0)
59.0 (46-74)
6 (100.0)
Any AE
7 (100.0)
7 (100.0)
Race, n (%)
Any grade 23 AE
3 (42.9)
Asian
6 (100.0)
4 (66.7)
Hematologic
White
0
2 (33.3)
5 (71.4)
Neutrophil count decreased
2 (28.6)
Primary tumor location, n (%)
Patients, n (%)
Table 4. Safety with recommended doses for expansion
T-DXd+
anastrozole
T-DXC +
fulvestrant
1 (14.3)
White blood cell count decreased
2 (28.6)
N=6
N=6
Breast
6 (100.0)
6 (100.0)
Anemia
1 (14.3)
Any AE
6 (100.0)
6 (100.0)
Missing
1 (14.3)a
HER2 status, n (%)
Febrile neutropenia
1 (14.3)
ECOG performance status, n (%)
IHC 2+/ISH-
3 (50.0)
4 (66.7)
Any grade ≥3 AE
2 (33.3)
3 (50.0)
Platelet count decreased
1 (14.3)
IHC 1+
3 (50.0)
2 (33.3)
Hematologic
0
4 (57.1)
Non-hematologic
ECOG performance status, n (%)
Anemia
2 (33.3)
1 (16.7)
1
3 (42.9)
Ejection fraction decreased.
1 (14.3)
0
5 (83.3)
4 (66.7)
Hypokalemia
1 (14.3)
1
1 (16.7)
2 (33.3)
Platelet count decreased
Non-hematologic
0
1 (16.7)
Serious AEs
1 (14.3)
AEs leading to treatment discontinuation
Femoral neck fracture
1 (14.3)
1 (16.7)
0
Hypokalemia
1 (16.7)
1 (16.7)
7.5 (range, 3-11) months
Nausea
0
1 (16.7)
7.0 (range, 2-11) months
Serious AEs
2 (33.3)
1 (16.7)
7.5 (range, 7-10) months
AEs leading
treatment discontinuation
0
1 (16.7)
AEs of special interest
8.0 (range, 7-10) months
ILD/pneumonitis
Deaths
0
1 (16.7)
1 (16.7)e
0
ore patient (16.7%)
"The HER2 status for this patient was missing at the time of the data cutoff and was later confirmed to be HC 3-
Figure 3. Median actual treatment duration"
T-DXd+
pertuzumab
(N=7)
T-DXd
Pertuzumab
*Dose delays were excluded in the analysis of actual treatment duration.
Acknowledgments
AES of special interest
ILD/pneumonitis
7.6 (range, 2.8-7.7) months
Left ventricular ejection fraction decreased
Deaths
7.3 (range, 2.8-7.7) months
We thank the patents who are participating in these studies as well as their families and caregivers
These studies are sponsored by AstraZeneca. In March 2019, AstraZeneca entered into a global development and
commercialization collaboration agreement with Daichi Sankyo for trastuzumab derurtecan (T-DXd; DS-8201)
The authors thank Tinghul Yu, PhD (formerly an employee of AstraZeneca) and Caron Lloyd AstraZenecal for their
contributions to this work. Medical wrting support was provided by Christopher Edwards, PhD, CMPP (Articulate Science, LLC),
and was unded by Aazeneca
References
1. Natada T, et al. Chem Pram Bull (Tokyo). 2010;67(2):172- Cortes et al. N Engl J Med. 2022,206(12):1142-1154
2 Ogitani Y, et al. Clin Cancer Res. 2016;22(205097-5108
3. Ennertu (tan-trastuzumat deruxtecan-Prescribing
Information Dalich Sankyo, Inc: 2022
4 Enhertu (trastuzumab denate car) Summary of product
characteristics. Daichi Sankyo Europe GmbH; 2021.
6. Nodi S, et al. J Clin Oncol. 2020;38(17):1887-1896
7. AstraZeneca. News release. Accessed March 31, 2022
hps://www.asazeneca.commedia centrepress
releases/2022 entertu-improves-pfs-and-os-in-her-low-
bc.mtext-Positive%20high%20level%209620from
8. Guo W, et al. Contemp Clin Titals. 2017;58:23-33
Figure 4. Median actual treatment duration²
0
T-DXd
1 (14.3)
T-DXd+
anastrozole
(N=6)
Anastrozole
0
T-DXd
Fulvestrant
*Febrile neutropenia.
One patient (14.3%) experienced a nonserous AB
AE of rade 3 election fraction decreasect it was considered related to T-DX
but not to pertuzumab, led to discontinuation of T-Dxd and pertuzumab, and was not resolved by the data cutof
RP2D was
TDXd+
fulvestrant
(5=N
T-DXd 5.4 mg/kg Q3W + pertuzumab 420 mg Q3W
(pertuzumab loading dose: 840 mg)
Abbreviations
AE, adverse event, C. cycle; COK, cyclin-dependent kinase; D, day; DB-17, DESTINY-Breast 7; DB-08, DESTINY-Breast08; DLT,
dose-limiting toxicity: ECOG. Fastem Cooperative Oncology Group: G-CSF. granulocyte-colony stimulating factor: HER2, human
epderma growth factor receptor 2; HR, hormone receptor, IHC, Immunohistochemistry; ILD, interstal lung disease; ISH, In situ
hybridization: mTOR, mechanistic target of momych kinase Os overal survival: PFS progression three survival: P
phosphoinositide 3-kinase; Q3W, every 3 weeks; Q+W, every weeks, RF2D, recommended phase 2 dose, T-DX,
deurtean; T-DM1, trastuzumab emtansine
*Dose delays and interruptions were excuded is the analysis of actual treatment duration
Dose modifications: T-DXd + anastrozole
Patients with:
Disclosures
Fabrice André reports travel, accommodations, and/or expenses from Novartis, Roche, GSK, and AstraZeneca; stock and other
ownership interests in regacy and research funding from Novaras, Roche, Arazeneca, Pitzer,uty, and palchi sankyo
0
21 dose
delaya
≥1 dose
reduction
≥1 dose
interruption
T-DXd
4 (66.7%)
Reasons: AE (n=3);"
other (n=1)
0
Dose modifications
2 (33.3%)
Reason: AE (n=2)
not allowed per
protocol
1 (16.7%)
Reason: AE
Anastrozole
*Reasons for dose delays were not mutually exclusive in patients who had mutiple dose delays; patients were counted only
pricamont (n-1) Medication error (1)
once per category. Anemia (1), femoral nech fracture (1), and vomiting and prica
Vomiting and pneumonies (n-1) and nasopharyngitis (n-1). "Nasopharyngitis
entenced a serious AES, vomiting and anemia; neither were considered related to study arug
patient delayed TOXd and anastrozole treatment due to the vomitsa: the patient had eered related to stay aras, the
anemia had not resolved by the data cutoff. One (16.7%) patient experienced a serious AE of femoral neck fracture that was not
considered related to study drugs: the patentdel
ntdelayed T-DX treatment and the event was not resolved by the data cutoff. One
patient (16.7%) experienced a serious AE of seizure that was not considered related to study drugs; the seizure hadresolved by
the data cutoff. Pneumonits. Occurred outside 20-day DLT period. Due to disease progression, 226 days after frat doss
Recommended doses for expansion were
T-DXd 5.4 mg/kg Q3W + anastrozole 1 mg daily
and T-DXd 5.4 mg/kg Q3W+ fulvestrant 500 mg Q4W
(fulvestrant loading dose: 500 mg on C1D15)
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