Daiichi Sankyo : ASCO presentation materia

ASCO 2024 Presentation Materials

• DESTINY-Breast06
• • Curigliano, G. et al., ASCO 2024 #LBA1000 Oral
• DESTINY-Breast03
• • Hamilton, E. et al., ASCO 2024 #1025 Poster
• DESTINY-Breast07
• • André, F. et al., ASCO 2024, #1009 Oral
• DESTINY-Lung02
• • Jänne, P. A. et al., ASCO 2024, #8543 Poster
• TROPION-Lung02
• • Levy, B. et al., ASCO 2024, #8617 Poster

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Trastuzumab deruxtecan vs physician's choice of chemotherapy in

patients with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-low or

HER2-ultralow metastatic breast cancer with prior endocrine therapy: primary results from DESTINY-Breast06

Giuseppe Curigliano

European Institute of Oncology, IRCCS, Milan, Italy;

Department of Oncology and Hematology-Oncology, University of Milan, Italy

Additional authors:

Xichun Hu, Rebecca Dent, Kan Yonemori, Carlos H Barrios, Joyce A O'Shaughnessy, Hans Wildiers, Qingyuan Zhang, Seock-Ah Im, Cristina Saura, Laura Biganzoli, Joohyuk Sohn, Christelle Lévy, William Jacot, Natasha Begbie, Jun Ke, Gargi Patel, Aditya Bardia

On behalf of the DESTINY-Breast06 investigators

ASCO 2024 #LBA1000 Oral

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DESTINY-Breast06: key takeaways

% of HR+, HER2-negative mBC

~20-25%

HER2-ultralow

~60-65%	~60-65%	Potentially
eligible for
HER2-low	HER2-low	T-DXd

DESTINY-Breast04DESTINY-Breast06

• T-DXddemonstrated efficacy in HER2-lowmBC in an earlier line of treatment to DESTINY-Breast04
• Including HER2-ultralow, the proportion of patients who could benefit from T-DXd is ~85% of HR+, HER2-negativemBC after DESTINY-Breast06

In DESTINY-Breast06,T-DXd demonstrated a statistically significant and

clinically meaningful PFS benefit vs TPC (chemotherapy) in

HR+, HER2-low mBC after ≥1 endocrine-based therapy,

with consistent results in HER2-ultralow mBC

HER2, human epidermal growth factor receptor 2; HR+, hormone receptor-positive; mBC, metastatic breast cancer; PFS, progression-free survival; T-DXd, trastuzumab deruxtecan; TPC, chemotherapy treatment of physician's choice

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Unmet treatment need in HR+, HER2-negative mBC

Current treatment landscape and outcomes: mPFS*

1L ET + CDK4/6i

ET + targeted

therapies

No prior	24.8-28.2mo1-3
CDK4/6i
Prior	5.5 mo4
CDK4/6i

2L+

ET

Prior	1.9-2.6 mo4,5

monotherapy

Single-agent

CDK4/6i

Mostly CT	6.2-7.1mo6-8

3L+

CT

naïve (mBC)

T-DXd

(HER2-low)

Prior ET	10.1 mo9
and CT

*Based on data from Phase 3 registrational studies only

CDK4/6i, cyclin-dependentkinase 4/6 inhibitor; CT, chemotherapy; ET, endocrine therapy; HER2, human epidermal growth factor receptor 2; HR+, hormone receptor -positive; mBC, metastatic breast cancer; mo, months; mPFS, median progression-free survival; T-DXd, trastuzumab deruxtecan

1. Finn RS, et al. N Engl J Med. 2016;375;1925-1936; 2. Hortobagyi GN, et al. Ann Oncol. 2018;29:1541-1547; 3. Johnston S, et al. NPJ Breast Cancer. 2019;5:5​; 4. Turner NC, et al. N Engl J Med. 2023;388:2058-2070 (Supplementary Appendix);

1. Bidard FC, et al. J Clin Oncol. 2022;40:3246-3256;6. O'Shaughnessy J, et al. JAMA Netw Open. 2021;4:e214103; 7. O'Shaughnessy J, et al. Cancer Res. 2021;81(Suppl. 4):Abstract GS4-01;8. Robert NJ, et al. J Clin Oncol. 2011;29:1252-1260;

1. Modi S, et al. N Engl J Med. 2022;387:9-20

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Targeting 'low' and 'ultralow' HER2-expressing tumors in mBC

HER2 IHC categories within HR+, HER2-negative (HER2−) mBC (per ASCO/CAP1)

DESTINY-Breast06	HER2-low	HER2-ultralow
patient population:
~60-65%2,3	~20-25%2-4
~85% of HR+, HER2− mBC

IHC 2+/ISH−	IHC 1+
Weak-to-moderate complete	Faint, incomplete
membrane staining	membrane staining
in >10% tumor cells	in >10% tumor cells

IHC 0

Faint, incomplete	Absent / no
membrane staining	observable
membrane
in ≤10% tumor cells
staining

ASCO/CAP, American Society of Clinical Oncology / College of American Pathologists; HER2, human epidermal growth factor receptor 2; HR+, hormone receptor-positive; IHC, immunohistochemistry; ISH, in situ hybridization; mBC, metastatic breast cancer; T-DXd, trastuzumab deruxtecan

Images adapted from Venetis K, et al. Front Mol Biosci. 2022;9:834651. CC BY 4.0 license available from: https://creativecommons.org/licenses/by/4.0/

1. Wolff AC, et al. J Clin Oncol. 2023;41:3867-3872; 2. Denkert C, et al. Lancet Oncol. 2021;22:1151-1161; 3. Chen Z, et al. Breast Cancer Res Treat. 2023;202:313-323; 4. Mehta S, et al. J Clin Oncol. 2024;42(Suppl. 16):Abstract e13156

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Study design

DESTINY-Breast06: a Phase 3, randomized, multicenter, open-label study (NCT04494425)

PATIENT POPULATION

• HR+ mBC
• HER2-low(IHC 1+ or IHC 2+/ISH−) or HER2-ultralow (IHC 0 with membrane staining)*
• Chemotherapy naïve in the mBC setting

Prior lines of therapy	R
• ≥2 lines of ET ± targeted therapy for mBC	1:1

OR

• 1 line for mBC AND
• • Progression ≤6 months of starting first-line ET + CDK4/6i
    OR
  • Recurrence ≤24 months of starting adjuvant ET

Stratification factors

• Prior CDK4/6i use (yes vs no)
• HER2 expression (IHC 1+ vs IHC 2+/ISH− vs IHC 0 with membrane staining)
• Prior taxane in the non-metastatic setting (yes vs no)

T-DXd

5.4 mg/kg Q3W

(n=436)

HER2-low = 713 HER2-ultralow = 153†

TPC

(n=430)

Options:

capecitabine, nab-paclitaxel, paclitaxel

ENDPOINTS

Primary

• PFS (BICR) in HER2-low

Key secondary

• PFS (BICR) in ITT (HER2-low + ultralow)
• OS in HER2-low
• OS in ITT (HER2-low + ultralow)

Other secondary

• PFS (INV) in HER2-low
• ORR (BICR/INV) and DOR (BICR/INV) in HER2-low and ITT (HER2-low + ultralow)
• Safety and tolerability
• Patient-reportedoutcomes‡

*Study enrollment was based on central HER2 testing. HER2 status was determined based on the most recent evaluable HER2 IHC sample prior to randomization. HER2-ultralow was defined as faint, partial membrane staining in ≤10% of tumor cells (also known as IHC >0<1+); † HER2-ultralow status as determined per IRT data (note: efficacy analyses in the HER2-ultralow subgroup were based on n=152 as determined per central laboratory testing data); ‡to be presented separately

BICR, blinded independent central review; CDK4/6i, cyclin-dependent kinase 4/6 inhibitor; DOR, duration of response; ET, endocrine therapy; HER2, human epidermal growth factor receptor 2; HR+, hormone receptor-positive;IHC, immunohistochemistry; INV, investigator assessed; IRT, interactive response technology; ISH, in situ hybridization; ITT, intent-to-treat;mBC, metastatic breast cancer; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-freesurvival; Q3W, every 3 weeks; R, randomization; T-DXd,trastuzumab deruxtecan; TPC, chemotherapy treatment of physician's choice

NCT04494425. Updated. April 12, 2024. Available from: https://clinicaltrials.gov/study/NCT04494425 (Accessed May 13, 2024)

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Statistical analysis

PFS primary analysis by BICR (HER2-low)

(planned after approximately 456 events)

• At DCO (March 18, 2024), there were 457 BICR-assessed PFS events in HER2-low
  - 540 events occurred in the ITT (HER2-low + -ultralow)

First interim OS analysis

(at time of primary analysis)

• At DCO, there were 282 events in the HER2-low and 335 events in the ITT (HER2-low + -ultralow)
  (maturity: ~40% of total N)
• Second interim and final OS analyses will be performed in HER2-low at ~56% and ~74% maturity, respectively

Multiple testing procedure*

5% alpha

PFS

HER2-low

1.5% alpha	Alpha	3.5% alpha
PFS	OS
recycling
ITT		HER2-low

5% alpha

OS

ITT

*Updated significance levels were determined using a Lan-DeMetsalpha-spending function with an O'Brien-Fleming boundary

BICR, blinded independent central review; DCO, data cutoff; HER2, human epidermal growth factor receptor 2; ITT, intent-to-treat; OS, overall survival; PFS, progression-free survival

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Patient disposition

Screened (N=1349)

Randomized 1:1 (N=866)

T-DXd (n=436)

Treated (99.5%)

• Discontinued study treatment (79.5%)
• • PD (57.1%)
  • Adverse event (14.1%)
  • Patient decision (4.4%)
  • Other (3.9%)
    ▪ Death (1.2%)

TPC (n=430)

Treated (97.0%)

• Discontinued study treatment (92.8%)
• • PD (70.0%)
  • Adverse event (9.4%)
  • Patient decision (8.2%)
  • Protocol non-compliance (0.2%)
  • Other (5.0%)
    ▪ Death (1.0%)

	n (%)
Capecitabine	257 (59.8)
Nab-paclitaxel	105 (24.4)
Paclitaxel	68 (15.8)

At DCO, 119 patients (14.0%) remained on treatment: 89 (20.5%) T-DXd and 30 (7.2%) TPC

Median duration of follow up: 18.2 months (ITT)

DCO, data cutoff; ITT, intent-to-treat; PD, progressive disease; T-DXd, trastuzumab deruxtecan; TPC, chemotherapy treatment of physician's choice

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Patient demographics and key baseline characteristics

*HER2-low status defined at randomization per IRT data, and HER2-ultralow status defined per central laboratory testing data. With mis-stratification, the combined sample size of these two populations may not match the ITT total; † n=14 patients had missing ECOG PS status at baseline; ‡n=2 patients in the ITT (1 per treatment group) were found to have HER2 IHC 0 with absent membrane staining per central laboratory testing; §patients with ER−/PR− status were excluded from the study; however, n=1 patient with ER-/PR- status was randomized in error; ¶defined as relapse while on the first 2 years of adjuvant endocrine therapy, or progressive disease within the first 6 months of first-line endocrine therapy for metastatic breast cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; IRT, interactive response technology;

ISH, in situ hybridization; ITT, intent-to-treat; PR, progesterone receptor; T-DXd, trastuzumab deruxtecan; TPC, chemotherapy treatment of physician's choice

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Prior therapies

*HER2-low status defined at randomization per IRT data, and HER2-ultralow status defined per central laboratory testing data; † other targeted therapies were mTORi (23.8%), PI3Ki (4.2%), or PARPi (0.9%) in the ITT; ‡approximately 30% of the patient population had de-novometastatic disease and were not included in this category

CDK4/6i, cyclin-dependent kinase 4/6 inhibitor; ET, endocrine therapy; HER2, human epidermal growth factor receptor 2; IRT, interactive response technology; ISH, in situ hybridization; ITT, intent-to-treat; mTORi, mammalian target of rapamycin inhibitor; PARPi, poly-adenosine diphosphate ribose polymerase inhibitor; PI3Ki, phosphatidylinositol-4,5-bisphosphate3-kinase catalytic subunit alpha inhibitor; T-DXd, trastuzumab deruxtecan; TPC, chemotherapy treatment of physician's choice

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