• First HER2 directed therapy to show a strong tumor response in this population
• Data from HER2 mutant cohort of pivotal DESTINY-Lung01 phase 2 trial presented at ESMO and published in The New England Journal of Medicine

TOKYO & MUNICH & BASKING RIDGE, N.J.--(BUSINESS WIRE)--Detailed primary results from the positive, pivotal DESTINY-Lung01 phase 2 trial of ENHERTU^� (trastuzumab deruxtecan), the Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) and AstraZeneca HER2 directed antibody drug conjugate (ADC), showed a robust and durable tumor response in previously-treated patients with HER2 mutant unresectable and/or metastatic non-squamous non-small cell lung cancer (NSCLC). Results presented during a late-breaking Proffered Paper session at the European Society for Medical Oncology (#ESMO21) 2021 Virtual Congress (#LBA45) and simultaneously published in The New England Journal of Medicine confirm ENHERTU as the first HER2 directed therapy to show a strong tumor response in this patient population.

Lung cancer is the leading cause of cancer-related death among both men and women, and accounts for about one-fifth of all cancer deaths globally,¹ with approximately 80% to 85% of cases classified as NSCLC.^2,3 There are currently no medicines approved specifically for the treatment of HER2 mutant NSCLC, which affects approximately 2% to 4% of patients with non-squamous NSCLC.^4,5

Primary results from the HER2 mutant cohort (cohort 2) of DESTINY-Lung01 in previously-treated HER2 mutant NSCLC demonstrated a confirmed objective response rate (ORR) of 54.9% (n=50; 95% CI: 44.2-65.4) in patients treated with ENHERTU (6.4 mg/kg) as assessed by independent central review (ICR). Out of a total of 91 patients, one (1.1%) complete response (CR) and 49 (53.8%) partial responses (PR) were observed. A confirmed disease control rate (DCR) of 92.3% (95% CI: 84.8-96.9) was seen with a reduction in tumor size observed in most patients.

After a median follow-up of 13.1 months, the median duration of response (DoR) for ENHERTU was 9.3 months (95% CI: 5.7-14.7). The median progression-free survival (PFS) was 8.2 months (95% CI: 6.0-11.9) and the median overall survival (OS) was 17.8 months (95% CI: 13.8-22.1).

Responses were observed in exploratory analyses of different HER2 mutation subtypes, as well as in patients with no detectable HER2 expression or HER2 gene amplification. Efficacy was observed in subgroups including prior treatment with platinum-based therapy, or platinum-based and anti-PD-(L)1 therapy, as well as asymptomatic brain metastases at baseline.

The overall safety profile of ENHERTU was consistent with previous NSCLC trials of ENHERTU, with no new safety signals identified. The most common grade 3 or higher drug-related treatment-emergent adverse events were neutropenia (18.7%), anemia (9.9%), nausea (8.8%), fatigue (6.6%), leukopenia (4.4%), diarrhea (3.3%) and vomiting (3.3%). Twenty-three patients (25.3%) discontinued treatment due to drug-related treatment-emergent adverse events. Rates of treatment-related interstitial lung disease (ILD) or pneumonitis were consistent with previous trials in lung cancer. There were 24 cases of ILD or pneumonitis, as determined by an independent adjudication committee, with the majority (75%) low grade (grade 1 or 2), four grade 3 and two grade 5 (ILD or pneumonitis-related death).

�Despite more than 20 years of research into HER2 mutations in non-small cell lung cancer, there are currently no approved HER2 targeted therapies for non-small cell lung cancer. Patients with HER2 mutant non-small cell lung cancer are associated with younger age, female sex, never-smoking history, and a poor prognosis with increased incidence of brain metastases, representing an unmet medical need,� said Bob Li, MD, PhD, MPH, Medical Oncologist and Principal Investigator at Memorial Sloan Kettering Cancer Center in New York. �The impressive results from DESTINY-Lung01 showed most patients experienced a reduction in tumor size with ENHERTU treatment, suggesting this medicine has the potential to become the new standard of care for these patients.�

�ENHERTU is the first HER2 targeted therapy to demonstrate a robust and durable tumor response in patients with HER2 mutant non-small cell lung cancer,� said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. �This is potentially great news for patients and we are continuing to conduct research, with the goal of bringing ENHERTU to patients with this specific form of lung cancer.�

�Lung cancer is a devastating diagnosis and for patients with HER2 mutant lung cancer, a targeted treatment for their specific disease has not been an option,� said Susan Galbraith, MBBChir, PhD, Executive Vice President, Oncology R&D, AstraZeneca. �These data reinforce the potential of ENHERTU to become the first HER2 directed therapy for these patients and reaffirm how this treatment is truly delivering on its transformative potential.�

Patients in DESTINY-Lung01 were previously-treated with a median of two lines of therapy (range, 0-7), including platinum-based chemotherapy (94.5%), immunotherapy (65.9%), platinum-based chemotherapy and immunotherapy (62.6%), docetaxel (19.8%) and HER2 tyrosine kinase inhibitors (14.3%). Of the 91 patients, 36.3% had asymptomatic brain metastases not requiring ongoing glucocorticoid or anticonvulsant therapy at baseline. As of data cut-off on May 3, 2021, 15 patients (16.5%) remain on treatment with ENHERTU.

Summary of HER2 mutant cohort of DESTINY-Lung01 Results

About DESTINY-Lung01

DESTINY-Lung01 is a global pivotal phase 2, open-label, multi-cohort trial evaluating the safety and efficacy of ENHERTU (6.4 mg/kg and 5.4 mg/kg) in previously-treated patients with HER2 mutant or HER2 overexpressing (defined as IHC3+ or IHC2+) unresectable and/or metastatic non-squamous NSCLC. The primary endpoint is confirmed ORR by ICR. Key secondary endpoints include DoR, DCR, PFS, OS and safety.

An interim analysis of ENHERTU (6.4 mg/kg) in the HER2 overexpressing cohort of DESTINY-Lung01 was presented at the 2020 World Conference on Lung Cancer (WCLC) hosted by the International Association for the Study of Lung Cancer (IASLC).

DESTINY-Lung01 enrolled approximately 180 patients at multiple sites, including Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov.

About HER2 Mutant NSCLC

Lung cancer is the leading cause of cancer death among both men and women and accounts for about one-fifth of all cancer deaths globally, with 80% to 85% classified as NSCLC.^1,2,3 For patients with metastatic disease, prognosis is particularly poor, as only approximately 6% will live beyond five years after diagnosis.²

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors, including lung, breast, gastric and colorectal cancers. HER2 gene alterations (called HER2 mutations) have been identified in NSCLC as distinct molecular targets and have been reported in approximately 2% to 4% of patients with non-squamous NSCLC.^4,5 These HER2 gene mutations are predominantly seen in younger women, with no smoking history and have been independently associated with cancer cell growth and poor prognosis,with an increased incidence of brain metastases.^4,6,7,8,9,10 Although the role of anti-HER2 treatment is well established in breast and gastric cancers, HER2 is an emerging biomarker in NSCLC with no approved HER2 directed therapies.^4,11

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 Canada, EU, Israel, Japan, UK and U.S. 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 in the metastatic setting based on the results from the DESTINY-Breast01 trial.

ENHERTU (6.4 mg/kg) is also approved in Israel, Japan and U.S. for the treatment of adult patients with locally advanced or metastatic HER2 positive gastric or gastroesophageal junction 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 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.

ENHERTU was highlighted in the Clinical Cancer Advances 2021 report as one of two significant advancements in the �ASCO Clinical Advance of the Year: Molecular Profiling Driving Progress in GI Cancers,� based on data from both the DESTINY-Gastric01 and DESTINY-CRC01 trials, as well as one of the targeted therapy advances of the year in non-small cell lung cancer (NSCLC), based on the interim results of the HER2 mutant cohort of the DESTINY-Lung01 trial.

In May 2020, ENHERTU received Breakthrough Therapy Designation in the U.S. for the treatment of patients with metastatic non-small cell lung cancer whose tumors have a HER2 mutation and with disease progression on or after platinum-based therapy.

About the Daiichi Sankyo and AstraZeneca Collaboration

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 for each ADC. Daiichi Sankyo is responsible for 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 two or more prior anti-HER2-based regimens in the metastatic setting.

  This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

• Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen.

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 234 patients with unresectable or metastatic HER2-positive breast cancer treated with ENHERTU 5.4 mg/kg, ILD occurred in 9% of patients. Fatal outcomes due to ILD and/or pneumonitis occurred in 2.6% of patients treated with ENHERTU. Median time to first onset was 4.1 months (range: 1.2 to 8.3).

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 >38.3�C or a sustained temperature of ?38�C for more than 1 hour), interrupt ENHERTU until resolved. Reduce dose by one level.

Metastatic Breast Cancer

In clinical studies, of the 234 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU 5.4 mg/kg, a decrease in neutrophil count was reported in 62% of patients. Sixteen percent had Grade 3 or 4 decrease in neutrophil count. Median time to first onset of decreased neutrophil count was 23 days (range: 6 to 547). Febrile neutropenia was reported in 1.7% 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. In the 234 patients with unresectable or metastatic HER2 positive breast cancer who received ENHERTU, two cases (0.9%) of asymptomatic LVEF decrease were reported. 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. 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.

Assess LVEF prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated. 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.

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 safety of ENHERTU was evaluated in a pooled analysis of 234 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg in DESTINY-Breast01 and Study DS8201-A-J101. ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 7 months (range: 0.7 to 31).

Serious adverse reactions occurred in 20% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were interstitial lung disease, pneumonia, vomiting, nausea, cellulitis, hypokalemia, and intestinal obstruction. Fatalities due to adverse reactions occurred in 4.3% of patients including interstitial lung disease (2.6%), and the following events occurred in one patient each (0.4%): acute hepatic failure/acute kidney injury, general physical health deterioration, pneumonia, and hemorrhagic shock.

ENHERTU was permanently discontinued in 9% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 33% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, thrombocytopenia, leukopenia, upper respiratory tract infection, fatigue, nausea, and ILD. Dose reductions occurred in 18% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, and neutropenia.

The most common (?20%) adverse reactions, including laboratory abnormalities, were nausea (79%), white blood cell count decreased (70%), hemoglobin decreased (70%), neutrophil count decreased (62%), fatigue (59%), vomiting (47%), alopecia (46%), aspartate aminotransferase increased (41%), alanine aminotransferase increased (38%), platelet count decreased (37%), constipation (35%), decreased appetite (32%), anemia (31%), diarrhea (29%), hypokalemia (26%), and cough (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 3 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 hemoglobin decreased (75%), white blood cell count decreased (74%), neutrophil count decreased (72%), lymphocyte count decreased (70%), platelet count decreased (68%), nausea (63%), decreased appetite (60%), anemia (58%), aspartate aminotransferase increased (58%), fatigue (55%), blood alkaline phosphatase increased (54%), alanine aminotransferase increased (47%), diarrhea (32%), hypokalemia (30%), vomiting (26%), constipation (24%), blood bilirubin increased (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.

Contacts

Media:

Global:
Victoria Amari

Daiichi Sankyo, Inc.

[email protected]
+1 908 900 3010 (mobile)

US:
Don Murphy

Daiichi Sankyo, Inc.

[email protected]
+1 917 817 2649 (mobile)

EU:
Lydia Worms

Daiichi Sankyo Europe GmbH

[email protected]
+49 (89) 7808751 (office)

+49 176 11780861 (mobile)

Japan:
Masashi Kawase

Daiichi Sankyo Co., Ltd.

[email protected]
+81 3 6225 1126 (office)

Investor Relations Contact:
[email protected]

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