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ENHERTU® Reduced the Risk of Disease Progression or Death by 50% vs. Chemotherapy in Patients with HER2 Low Metastatic Breast Cancer with HR Positive and HR Negative Disease

2022年06月05日 PM09:00
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TOKYO & MUNICH & BASKING RIDGE, N.J.

Detailed positive results from the pivotal DESTINY-Breast04 phase 3 trial showed that ENHERTU® (trastuzumab deruxtecan) demonstrated superior and clinically meaningful progression-free survival (PFS) and overall survival (OS) in previously treated patients with HER2 low (immunohistochemistry (IHC) 1+ or IHC 2+/in-situ hybridization (ISH)-negative) unresectable and/or metastatic breast cancer with hormone receptor (HR) positive or HR negative disease versus standard of care physician’s choice of chemotherapy. Results will be presented during the Plenary Session (#LBA3) today at the American Society of Clinical Oncology (#ASCO22) Annual Meeting and have been simultaneously published in The New England Journal of Medicine.

ENHERTU is a specifically engineered HER2 directed antibody drug conjugate (ADC) being jointly developed and commercialized by Daiichi Sankyo (TSE: 4568) and AstraZeneca (LSE/STO/Nasdaq: AZN).

In the primary endpoint analysis for DESTINY-Breast04, ENHERTU demonstrated a 49% reduction in the risk of disease progression or death versus physician’s choice of chemotherapy in patients with HER2 low metastatic breast cancer with HR positive disease (hazard ratio [HR] = 0.51; 95% confidence interval [CI]: 0.40-0.64; p<0.001). A median PFS of 10.1 months (9.5-11.5) was seen in patients treated with ENHERTU compared to 5.4 months (4.4-7.1) with chemotherapy, as assessed by blinded independent central review (BICR).

Results also showed a 36% reduction in the risk of death with ENHERTU compared to chemotherapy in patients with HR positive disease (HR = 0.64; 95% CI: 0.48-0.86; p=0.003) with a median OS of 23.9 months with ENHERTU (95% CI: 20.8-24.8) versus 17.5 months with chemotherapy (95% CI: 15.2-22.4), meeting a key secondary endpoint of the trial. Confirmed objective response rate (ORR) more than tripled in the ENHERTU arm versus the chemotherapy arm (52.6% [n=175/333; 95% CI: 47.0-58.0%] versus 16.3% [n=27/166; 95% CI: 11.0-22.8%], respectively). Twelve (3.6%) complete responses (CR) and 164 (49.2%) partial responses (PR) were observed in patients with HR positive disease treated with ENHERTU compared to one (0.6%) CR and 26 (15.7%) PRs in those treated with chemotherapy. Median duration of response was 10.7 months for ENHERTU versus 6.8 months for chemotherapy.

“The results of DESTINY-Breast04 show for the first time that a HER2 directed therapy can provide a survival benefit to patients with low HER2 expression, indicating we must reconsider the way we categorize patients with metastatic breast cancer,” said Shanu Modi, MD, medical oncologist, Memorial Sloan Kettering Cancer Center and principal investigator for the trial. “The efficacy seen with ENHERTU also reinforces the potential to establish a new standard of care for more than half of all patients with breast cancer currently categorized as having HER2 negative disease, but who actually have tumors with low HER2 expression.”

Additionally, data showed consistent efficacy for ENHERTU in the overall trial population of patients with HER2 low metastatic breast cancer with HR positive or HR negative disease and across levels of HER2 expression (both IHC1+ and IHC 2+/ISH-). In the key secondary endpoint analysis of PFS by BICR in all patients, a similar 50% reduction in the risk of disease progression or death was observed between ENHERTU and chemotherapy (HR = 0.50; 95% CI:0.40-0.63; p<0.001), with a median PFS of 9.9 months (9.0-11.3) for ENHERTU versus 5.1 months (4.2-6.8) in those treated with chemotherapy. Results of the key secondary endpoint of OS in all patients also showed a median OS of 23.4 months (20.0-24.8) for ENHERTU versus 16.8 months (14.5-20.0) with chemotherapy (HR=0.64; 95% CI: 0.49-0.84; p=0.001), with confirmed ORR more than tripled in the ENHERTU arm (52.3% [n=195/373; 95% CI: 47.1-57.4%]) versus those treated with chemotherapy (16.3% [n=30/184; 95% CI: 11.3-22.5%]).

In an exploratory analysis of patients with HR negative disease, median PFS was 8.5 months (4.3-11.7) with ENHERTU versus 2.9 months (1.4-5.1) with chemotherapy (HR=0.46; 95% CI: 0.24-0.89). Median OS was 18.2 months (13.6-NE) with ENHERTU versus 8.3 months (5.6-20.6) with chemotherapy (HR=0.48; 95%CI: 0.24-0.95). Confirmed ORR was 50% with ENHERTU (n=20/40; 95% CI: 33.8-66.2%) versus 16.7% with chemotherapy (n=3/18; 95% CI: 3.6-41.4%).

The safety profile of ENHERTU was consistent with previous clinical trials with no new safety concerns identified. The most common grade 3 or higher treatment emergent adverse events were neutropenia (13.7%), anemia (8.1%), leukopenia (6.5%), fatigue (7.5%), thrombocytopenia (5.1%), nausea (4.6%), increased aminotransferase (3.2%), decreased appetite (2.4%), vomiting (1.3%) and diarrhea (1.1%). Interstitial lung disease (ILD) or pneumonitis rates were consistent with that observed in late-line HER2 positive breast cancer trials of ENHERTU with a lower rate of grade 5 ILD observed, as determined by an independent adjudication committee. Overall, 12.1% of patients had confirmed ILD or pneumonitis related to treatment as determined by an independent adjudication committee. The majority of ILD events (10%) were primarily low grade (grade 1 (3.5%) or grade 2 (6.5%)) with five grade 3 (1.3%), no grade 4 and three grade 5 (0.8%) events reported.

“As innovative research organizations, extending the survival for patients is one of our primary goals as we seek to identify potentially new treatment options for patients with metastatic breast cancer,” said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. “These potentially practice-changing data show that DESTINY-Breast04 takes us one step closer to achieving this goal, as ENHERTU is the first HER2 directed medicine to demonstrate a survival benefit in patients with HER2 low metastatic breast cancer. We are honored by the recognition these important findings are receiving at one of the world’s most prominent oncology meetings as well as in one of the leading medical journals.”

“Today’s results represent a pivotal moment demonstrating the potential for ENHERTU to redefine the treatment of HER2 targetable cancers,” said Susan Galbraith, MBBChir, PhD, Executive Vice President, Oncology R&D, AstraZeneca. “DESTINY-Breast04 validates targeting the lower end of the spectrum of HER2 expression, since ENHERTU reduced the risk of disease progression or death across all types of patients in the trial by half and reduced the risk of death by over a third. We must now evolve the way we classify and treat metastatic breast cancer to ensure these patients are effectively diagnosed and treated.”

All patients in DESTINY-Breast04 received at least one prior cancer therapy, including targeted therapy (ENHERTU = 279; chemotherapy = 140), a CDK4/6 inhibitor (ENHERTU = 239; chemotherapy = 119), endocrine therapy (ENHERTU = 347; chemotherapy = 165), chemotherapy (ENHERTU = 373; chemotherapy = 183). The median lines of prior systemic therapies in the metastatic setting were three (range 1-9). A prior CDK4/6 inhibitor was received by 70% of hormone receptor positive patients (ENHERTU = 233/331; chemotherapy = 115/163). As of data cut-off on January 11, 2022, 58 patients remained on treatment with ENHERTU and 3 patients on chemotherapy.

Summary of DESTINY-Breast04 Results

Efficacy

Measure

HR Positive (n=494)

All Patients (n=557)

HR Negative (n=58)i

 

ENHERTU

(5.4 mg/kg)

(n=331)

Chemotherapy

(n=163)

ENHERTU

(5.4 mg/kg)

(n=373)

Chemotherapy

(n=184)

ENHERTU

(5.4 mg/kg)

(n=40)

Chemotherapy

(n=18)

Median PFS

(months)

(95% CI)ii

10.1 months

(9.5-11.5)

5.4 months

(4.4-7.1)

9.9 months

(9.0-11.3)

5.1 months

(4.2-6.8)

8.5 months

(4.3-11.7)

2.9 months

(1.4-5.1)

HR=0.51 (0.40-0.64)

p<0.001

HR=0.50 (0.40-0.63)

p<0.001

HR=0.46 (0.24-0.89)

Median OS

(months)

(95% CI)

23.9 months

(20.8-24.8)

17.5 months

(15.2-22.4)

23.4 months

(20.0-24.8)

16.8 months

(14.5-20.0)

18.2 months

(13.6-NE)

8.3 months

(5.6-20.6)

HR=0.64 (0.48-0.86)

p=0.003

HR=0.64 (0.49-0.84)

p=0.001

HR=0.48 (0.24-0.95)

Confirmed

ORR (%)

(95% CI)ii,iii

52.6%

(47.0-58.0)

16.3%

(11.0-22.8)

52.3%

(47.1-57.4)

16.3%

(11.3-22.5)

50.0%

(33.8-66.2)

16.7%

(3.6-41.4)

CR (%)

3.6%

0.6%

3.5%

1.1%

2.5%

5.6%

PR (%)

49.2%

15.7%

49.1%

15.2%

47.5%

11.1%

SD (%)

35.1%

50.0%

34.6%

49.5%

30.0%

44.4%

PD (%)

(95% CI)

7.8%

21.1%

8.3%

22.3%

12.5%

33.3%

Median

DoR

(months)ii

10.7 months

6.8 months

10.7 months

6.8 months

8.6 months

4.9 months

CBR (%)ii,iv

71.2%

34.3%

70.2%

33.7%

62.5%

27.8%

DCR (%)v

88.0%

66.3%

87.1%

65.8%

80.0%

61.1%

CI, confidence interval; CBR, clinical benefit rate; CR, complete response; DCR, disease control rate; DoR, duration of response; HR, hazard ratio; NE, not evaluable; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease

i For the primary endpoint (PFS in the HR positive cohort) and key secondary endpoints (PFS among all patients and OS in the HR positive cohort and among all patients), the HR status is based on data collected with the use of the interactive Web response and voice response system at the time of randomization, which includes patients who were mis-stratified. For the other endpoints, HR status is based on data from the electronic data capture that was corrected for mis-stratification

ii As assessed by BICR 

iii ORR is (CR + PR)

iv CBR is CR + PR + SD (≥ 6 months)

v DCR is (CR + PR + SD)

About DESTINY-Breast04
DESTINY-Breast04 is a global, randomized, open-label, pivotal phase 3 trial evaluating the efficacy and safety of ENHERTU (5.4 mg/kg) versus physician’s choice of chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel or nab-paclitaxel) in patients with HR positive or HR negative, HER2 low unresectable and/or metastatic breast cancer previously treated with one or two prior lines of chemotherapy. Patients were randomized 2:1 to receive either ENHERTU or chemotherapy.

The primary endpoint of DESTINY-Breast04 is PFS in patients with HR positive disease based on blinded independent central review (BICR). Key secondary endpoints include PFS based on BICR in all randomized patients (HR positive and HR negative disease), OS in patients with HR positive disease and OS in all randomized patients (HR positive and HR negative disease). Other secondary endpoints include PFS based on investigator assessment, objective response rate based on BICR and on investigator assessment, duration of response based on BICR and safety.

DESTINY-Breast04 enrolled 557 patients at multiple sites in Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov.

About Breast Cancer and HER2 Expression
Breast cancer is the most common cancer and is one of the leading causes of cancer-related deaths worldwide.1 More than two million cases of breast cancer were diagnosed in 2020 with nearly 685,000 deaths globally.1

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors including breast, gastric, lung and colorectal cancers, and is one of many biomarkers expressed in breast cancer tumors.2

HER2 expression is currently defined as either positive or negative, and is determined by an IHC test which measures the amount of HER2 protein on a cancer cell, and/or an ISH test, which counts the copies of the HER2 gene in cancer cells.2,3 HER2 positive cancers are defined as IHC 3+, IHC 2+/ISH+.2 HER2 negative cancers are currently defined as IHC 0, IHC 1+ or IHC 2+/ISH-.2 Approximately half of all patients with breast cancer have tumors with a HER2 IHC score of 1+, or a HER2 IHC score of 2+ in combination with a negative ISH test, an expression level not currently eligible for HER2 targeted therapy.4,5,6,7 Low HER2 expression occurs in both HR positive and HR negative disease.8

HER2 testing is routinely used to determine appropriate treatment options for patients with metastatic breast cancer. Targeting the lower range of expression in the HER2 spectrum may offer another approach to delay disease progression and extend survival in patients with metastatic breast cancer.9 Currently, patients with low HER2 expression with HR positive tumors have limited treatment options following progression on endocrine (hormone) therapy.10 Few targeted options are available for those who are HR negative.11

About ENHERTU
ENHERTU® (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the U.S. only) is a HER2 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, ENHERTU is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced program in AstraZeneca’s ADC scientific platform. ENHERTU consists of a HER2 monoclonal antibody attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker.

ENHERTU (5.4 mg/kg) is approved in the U.S. and Israel for the treatment of adult patients with unresectable or metastatic HER2 positive 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 six months of completing therapy, based on results from the DESTINY-Breast03 trial. ENHERTU is also approved in approximately 40 countries for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who have received two or more prior anti-HER2-based regimens based on the results from the DESTINY-Breast01 trial.

ENHERTU (6.4 mg/kg) is approved in several countries for the treatment of adult patients with locally advanced or metastatic HER2 positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 trial.

ENHERTU is approved in the U.S. with Boxed WARNINGS for Interstitial Lung Disease and Embryo-Fetal Toxicity. For more information, please see the accompanying full Prescribing Information, including Boxed WARNINGS, and Medication Guide.

About the ENHERTU Clinical Development Program
A comprehensive global development program is underway evaluating the efficacy and safety of ENHERTU monotherapy across multiple HER2 targetable cancers including breast, gastric, lung and colorectal cancers. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

Regulatory applications for ENHERTU are currently under review in China, Europe, Japan and several other countries for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who have received a prior anti-HER2-based regimen based on the results from the DESTINY-Breast03 trial.

ENHERTU was granted Breakthrough Therapy Designation in the U.S. for the treatment of adult patients with unresectable or metastatic HER2 low (IHC 1+ or IHC 2+/ISH-negative) breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy based on the results of the DESTINY-Breast04 trial. Patients with hormone receptor (HR) positive breast cancer should additionally have received or be ineligible for endocrine therapy.

ENHERTU also is currently under review in the U.S. for the treatment of adult patients with unresectable or metastatic NSCLC whose tumors have a HER2 (ERBB2) mutation and who have received a prior systemic therapy based on the results from the DESTINY-Lung01 trial, and in Europe for the treatment of adult patients with locally advanced or metastatic HER2 positive gastric or GEJ adenocarcinoma who have received a prior anti-HER2 based regimen based on the DESTINY-Gastric01 and DESTINY-Gastric02 trials.

About the Daiichi Sankyo and AstraZeneca Collaboration
Daiichi Sankyo Company, Limited (referred to as Daiichi Sankyo) and AstraZeneca entered into a global collaboration to jointly develop and commercialize ENHERTU in March 2019 and datopotamab deruxtecan (Dato-DXd) in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is responsible for the manufacturing and supply of ENHERTU and datopotamab deruxtecan.

U.S. Important Safety Information for ENHERTU

Indications
ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with:

  • Unresectable or metastatic HER2-positive 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 six months of completing therapy
  • Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen
 
WARNING: INTERSTITIAL LUNG DISEASE and EMBRYO-FETAL TOXICITY
  • Interstitial lung disease (ILD) and pneumonitis, including fatal cases, have been reported with ENHERTU. Monitor for and promptly investigate signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Permanently discontinue ENHERTU in all patients with Grade 2 or higher ILD/pneumonitis. Advise patients of the risk and to immediately report symptoms.
  • Exposure to ENHERTU during pregnancy can cause embryo-fetal harm. Advise patients of these risks and the need for effective contraception.

Contraindications
None.

Warnings and Precautions
Interstitial Lung Disease / Pneumonitis
Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ENHERTU. Advise patients to immediately report cough, dyspnea, fever, and/or any new or worsening respiratory symptoms. Monitor patients for signs and symptoms of ILD. Promptly investigate evidence of ILD. Evaluate patients with suspected ILD by radiographic imaging. Consider consultation with a pulmonologist. For asymptomatic ILD/pneumonitis (Grade 1), interrupt ENHERTU until resolved to Grade 0, then if resolved in ≤28 days from date of onset, maintain dose. If resolved in >28 days from date of onset, reduce dose one level. Consider corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥0.5 mg/kg/day prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater), permanently discontinue ENHERTU. Promptly initiate systemic corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥1 mg/kg/day prednisolone or equivalent) and continue for at least 14 days followed by gradual taper for at least 4 weeks.

Metastatic Breast Cancer
In clinical studies, of the 491 patients with unresectable or metastatic HER2-positive breast cancer treated with ENHERTU 5.4 mg/kg, ILD occurred in 13% of patients. Fatal outcomes due to ILD and/or pneumonitis occurred in 1.4% of patients treated with ENHERTU. Median time to first onset was 5.5 months (range: 1.1 to 20.8).

Locally Advanced or Metastatic Gastric Cancer
In DESTINY-Gastric01, of the 125 patients with locally advanced or metastatic HER2‑positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, ILD occurred in 10% of patients. Median time to first onset was 2.8 months (range: 1.2 to 21.0).

Neutropenia
Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU. Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. For Grade 3 neutropenia (Absolute Neutrophil Count [ANC] <1.0 to 0.5 x 109/L) interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose. For Grade 4 neutropenia (ANC <0.5 x 109/L) interrupt ENHERTU until resolved to Grade 2 or less. Reduce dose by one level. For febrile neutropenia (ANC <1.0 x 109/L and temperature >38.3ºC or a sustained temperature of ≥38ºC for more than 1 hour), interrupt ENHERTU until resolved. Reduce dose by one level.

Metastatic Breast Cancer
In clinical studies, of the 491 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU 5.4 mg/kg, a decrease in neutrophil count was reported in 68% of patients. Eighteen percent had Grade 3 or 4 decrease in neutrophil count. Median time to first onset of decreased neutrophil count was 22 days (range: 6 to 664). Febrile neutropenia was reported in 1.2% of patients.

Locally Advanced or Metastatic Gastric Cancer
In DESTINY-Gastric01, of the 125 patients with locally advanced or metastatic HER2‑positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, a decrease in neutrophil count was reported in 72% of patients. Fifty-one percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 16 days (range: 4 to 187). Febrile neutropenia was reported in 4.8% of patients.

Left Ventricular Dysfunction
Patients treated with ENHERTU may be at increased risk of developing left ventricular dysfunction. Left ventricular ejection fraction (LVEF) decrease has been observed with anti-HER2 therapies, including ENHERTU. Assess LVEF prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated. Manage LVEF decrease through treatment interruption. When LVEF is >45% and absolute decrease from baseline is 10-20%, continue treatment with ENHERTU. When LVEF is 40-45% and absolute decrease from baseline is <10%, continue treatment with ENHERTU and repeat LVEF assessment within 3 weeks. When LVEF is 40-45% and absolute decrease from baseline is 10-20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF has not recovered to within 10% from baseline, permanently discontinue ENHERTU. If LVEF recovers to within 10% from baseline, resume treatment with ENHERTU at the same dose. When LVEF is <40% or absolute decrease from baseline is >20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF of <40% or absolute decrease from baseline of >20% is confirmed, permanently discontinue ENHERTU. Permanently discontinue ENHERTU in patients with symptomatic congestive heart failure. Treatment with ENHERTU has not been studied in patients with a history of clinically significant cardiac disease or LVEF <50% prior to initiation of treatment.

Metastatic Breast Cancer
In the 491 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU 5.4 mg/kg, 13 cases (2.6%) of asymptomatic LVEF decrease were reported.

Locally Advanced or Metastatic Gastric Cancer
In DESTINY-Gastric01, of the 125 patients with locally advanced or metastatic HER2‑positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, no clinical adverse events of heart failure were reported; however, on echocardiography, 8% were found to have asymptomatic Grade 2 decrease in LVEF.

Embryo-Fetal Toxicity
ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. Verify the pregnancy status of females of reproductive potential prior to the initiation of ENHERTU. Advise females of reproductive potential to use effective contraception during treatment and for at least 7 months following the last dose of ENHERTU. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 4 months after the last dose of ENHERTU.

Additional Dose Modifications
Thrombocytopenia
For Grade 3 thrombocytopenia (platelets <50 to 25 x 109/L) interrupt ENHERTU until resolved to Grade 1 or less, then maintain dose. For Grade 4 thrombocytopenia (platelets <25 x 109/L) interrupt ENHERTU until resolved to Grade 1 or less. Reduce dose by one level.

Adverse Reactions
Metastatic Breast Cancer
The pooled safety population for patients with metastatic breast cancer reflects exposure to ENHERTU at 5.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) in 491 patients in DESTINY-Breast03, DESTINY-Breast01, and Study DS8201-A-J101. The median duration of treatment was 13 months (range: 0.7 to 37). In this pooled safety population, the most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (78%), decreased white blood cell count (74%), decreased hemoglobin (68%), decreased neutrophil count (68%), increased aspartate aminotransferase (58%), fatigue (57%), decreased lymphocyte count (56%), vomiting (50%), decreased platelet count (49%), increased alanine aminotransferase (48%), increased blood alkaline phosphatase (45%), alopecia (41%), constipation (35%), hypokalemia (33%), decreased appetite (32%), diarrhea (31%), musculoskeletal pain (28%), increased transaminases (27%), respiratory infection (24%), headache (21%), and abdominal pain (21%).

DESTINY-Breast03
The safety of ENHERTU was evaluated in 257 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg in DESTINY-Breast03. ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 14 months (range: 0.7 to 30).

Serious adverse reactions occurred in 19% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were vomiting, interstitial lung disease, pneumonia, pyrexia, and urinary tract infection. Fatalities due to adverse reactions occurred in 0.8% of patients including COVID-19 and sudden death (one patient each).

ENHERTU was permanently discontinued in 14% of patients, of which ILD/pneumonitis accounted for 8%. Dose interruptions due to adverse reactions occurred in 44% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, leukopenia, anemia, thrombocytopenia, pneumonia, nausea, fatigue, and ILD/pneumonitis. Dose reductions occurred in 21% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were nausea, neutropenia, and fatigue.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (76%), decreased white blood cell count (74%), decreased neutrophil count (70%), increased aspartate aminotransferase (67%), decreased hemoglobin (64%), decreased lymphocyte count (55%), increased alanine aminotransferase (53%), decreased platelet count (52%), fatigue (49%), vomiting (49%), increased blood alkaline phosphatase (49%), alopecia (37%), hypokalemia (35%), constipation (34%), musculoskeletal pain (31%), diarrhea (29%), decreased appetite (29%), respiratory infection (22%), headache (22%), abdominal pain (21%), increased blood bilirubin (20%), and stomatitis (20%).

Locally Advanced or Metastatic Gastric Cancer
The safety of ENHERTU was evaluated in 187 patients with locally advanced or metastatic HER2‑positive gastric or GEJ adenocarcinoma in DESTINY‑Gastric01. Patients intravenously received at least one dose of either ENHERTU (N=125) 6.4 mg/kg once every three weeks or either irinotecan (N=55) 150 mg/m2 biweekly or paclitaxel (N=7) 80 mg/m2 weekly for 3 weeks. The median duration of treatment was 4.6 months (range: 0.7 to 22.3) in the ENHERTU group and 2.8 months (range: 0.5 to 13.1) in the irinotecan/paclitaxel group.

Serious adverse reactions occurred in 44% of patients receiving ENHERTU 6.4 mg/kg. Serious adverse reactions in >2% of patients who received ENHERTU were decreased appetite, ILD, anemia, dehydration, pneumonia, cholestatic jaundice, pyrexia, and tumor hemorrhage. Fatalities due to adverse reactions occurred in 2.4% of patients: disseminated intravascular coagulation, large intestine perforation, and pneumonia occurred in one patient each (0.8%).

ENHERTU was permanently discontinued in 15% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 62% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, decreased appetite, leukopenia, fatigue, thrombocytopenia, ILD, pneumonia, lymphopenia, upper respiratory tract infection, diarrhea, and hypokalemia. Dose reductions occurred in 32% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were neutropenia, decreased appetite, fatigue, nausea, and febrile neutropenia.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased hemoglobin (75%), decreased white blood cell count (74%), decreased neutrophil count (72%), decreased lymphocyte count (70%), decreased platelet count (68%), nausea (63%), decreased appetite (60%), increased aspartate aminotransferase (58%), fatigue (55%), increased blood alkaline phosphatase (54%), increased alanine aminotransferase (47%), diarrhea (32%), hypokalemia (30%), vomiting (26%), constipation (24%), increased blood bilirubin (24%), pyrexia (24%), and alopecia (22%).

Use in Specific Populations

  • Pregnancy: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. There are clinical considerations if ENHERTU is used in pregnant women, or if a patient becomes pregnant within 7 months following the last dose of ENHERTU.
  • Lactation: There are no data regarding the presence of ENHERTU in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with ENHERTU and for 7 months after the last dose.
  • Females and Males of Reproductive Potential: Pregnancy testing: Verify pregnancy status of females of reproductive potential prior to initiation of ENHERTU. Contraception: Females: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 7 months following the last dose. Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 4 months following the last dose. Infertility: ENHERTU may impair male reproductive function and fertility.
  • Pediatric Use: Safety and effectiveness of ENHERTU have not been established in pediatric patients.
  • Geriatric Use: Of the 491 patients with HER2-positive breast cancer treated with ENHERTU 5.4 mg/kg, 22% were ≥65 years and 4% were ≥75 years. No overall differences in efficacy within clinical studies were observed between patients ≥65 years of age compared to younger patients. There was a higher incidence of Grade 3-4 adverse reactions observed in patients aged ≥65 years (60%) as compared to younger patients (49%). Of the 125 patients with locally advanced or metastatic HER2‑positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg in DESTINY-Gastric01, 56% were ≥65 years and 14% were ≥75 years. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients.
  • Renal Impairment: A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment. Monitor patients with moderate or severe renal impairment.
  • Hepatic Impairment: In patients with moderate hepatic impairment, due to potentially increased exposure, closely monitor for increased toxicities related to the topoisomerase inhibitor.

To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or fda.gov/medwatch.

Please see accompanying full Prescribing Information, including Boxed WARNINGS, and Medication Guide.

About Daiichi Sankyo
Daiichi Sankyo is dedicated to creating new modalities and innovative medicines by leveraging our world-class science and technology for our purpose “to contribute to the enrichment of quality of life around the world.” In addition to our current portfolio of medicines for cancer and cardiovascular disease, Daiichi Sankyo is primarily focused on developing novel therapies for people with cancer as well as other diseases with high unmet medical needs. With more than 100 years of scientific expertise and a presence in more than 20 countries, Daiichi Sankyo and its 16,000 employees around the world draw upon a rich legacy of innovation to realize our 2030 Vision to become an “Innovative Global Healthcare Company Contributing to the Sustainable Development of Society.” For more information, please visit www.daiichisankyo.com.

Disclosure: Dr. Modi has financial interests related to AstraZeneca and Daiichi Sankyo.

_____________________
References
1 Sung H, et al. CA Cancer J Clin. 2021;10.3322/caac.21660.

2 Iqbal N, et al. Mol Biol Int. 2014;852748.

3 Wolff A, et al. Arch Pathol Lab Med. 2018;142(11):1364–1382.

4 Schalper K, et al. Arch Pathol Lab Med. 2014;138:213-219.

5 Ahn S, et al. J Pathol Transl Med. 2020;54(1):34–44.

6 Schettini F, et al. NPJ Breast Cancer. 2021;7:1.

7 Denkert C, et al. Lancet Oncol. 2021;22:1151-61.

8 Miglietta F, et al. NPJ Breast Cancer. 2021;7:137.

9 Eiger D, et al. Cancers. 2021;10.3390/cancers13051015.

10 Matutino A, et al. Current Oncology. 2018;25(S1):S131-S141.

11 American Cancer Society. Breast Cancer Hormone Receptor Status. Accessed April 2022.

View source version on businesswire.com: https://www.businesswire.com/news/home/20220604005034/en/

CONTACT

Media Contacts:

Global:

Victoria Amari

Daiichi Sankyo, Inc.

vamari@dsi.com

+1 908 900 3010 (mobile)

US:

Don Murphy

Daiichi Sankyo, Inc.

domurphy@dsi.com

+1 917 817 2649 (mobile)

EU:

Simone Jendsch-Dowé

Daiichi Sankyo Europe GmbH

simone.dowe@daiichi-sankyo.com

+49 (89) 7808437 (office)

+49 176 11780822 (mobile)

Japan:

Masashi Kawase

Daiichi Sankyo Co., Ltd.

kawase.masashi.a2@daiichisankyo.co.jp

+81 3 6225 1126 (office)

Investor Relations Contact:

DaiichiSankyoIR@daiichisankyo.co.jp

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