ENHERTU® Demonstrated Strong and Durable Tumor Responses in Previously Treated HER2 Mutant Advanced Lung Cancer in DESTINY-Lung02 Phase 2 Trial
- Strong and durable tumor responses
- Objective response rates of 49% and 56%
- None.
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Daiichi Sankyo and AstraZeneca’s ENHERTU showed objective response rates of
49% and56% with 5.4 mg/kg and 6.4 mg/kg doses, respectively, in primary analysis - ENHERTU provided a median progression free survival of 9.9 months at 5.4 mg/kg dose and 15.4 months at 6.4 mg/kg dose with a median duration of response of 16.8 months seen at the 5.4 mg/kg dose and not reached at the 6.4 mg/kg dose
- Favorable safety profile confirms 5.4 mg/kg as optimal dose in this tumor type and reinforces role of ENHERTU in this setting
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).
At the primary analysis, a confirmed objective response rate (ORR) of
Median PFS as assessed by BICR was 9.9 months (
“The primary results from DESTINY-Lung02 demonstrate that ENHERTU continues to show strong and durable tumor responses for patients treated at either dose,” said Pasi A. Jänne, MD, PhD, Director, Lowe Center for Thoracic Oncology and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute. “The favorable safety profile seen at the 5.4 mg/kg dose continues to support the use of ENHERTU in the treatment of patients with HER2 mutant non-small cell lung cancer, a particularly aggressive form of the disease where patients face a poor prognosis and have historically had few options.”
In DESTINY-Lung02, a favorable safety profile was observed in patients treated with ENHERTU 5.4 mg/kg with no new safety signals identified at either dose. Grade 3 or higher treatment-related treatment emergent adverse events (TEAEs) were lower with ENHERTU 5.4 mg/kg versus 6.4 mg/kg. Grade 3 or higher treatment-related TEAEs occurred in
“The disease control achieved by more than
“These results from DESTINY-Lung02 highlight that HER2 is an actionable target in lung cancer and reinforce the importance of testing for predictive biomarkers, including HER2 alterations in lung cancer, at the time of diagnosis to accurately identify patients who may be able to benefit from a targeted treatment,” said Susan Galbraith, MBBChir, PhD, Executive Vice President, Oncology R&D, AstraZeneca. “The data also reaffirm our belief in ENHERTU as a potential new targeted treatment option for patients who have historically had limited options.”
Patients in the DESTINY-Lung02 trial received a median of two prior cancer therapies in each ENHERTU arm (5.4 mg/kg: range 1-12; 6.4 mg/kg: range 1-7). HER2 mutations were primarily in the kinase domain (5.4 mg/kg:
Summary of DESTINY-Lung02 Primary Analysis Results
Efficacy Measure |
ENHERTU (5.4 mg/kg) n=102i |
ENHERTU (6.4 mg/kg) n=50i |
Confirmed ORR (%) ( |
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CR (%) |
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PR (%) |
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SD (%) |
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PD (%) |
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NE (%)iv |
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DCR ( |
|
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Median DoR (months) ( |
16.8 months (6.4-NE) |
NE (8.3-NE) |
Median TTIR (months)vi |
1.8 months (1.2-7.0) |
1.6 months (1.2-11.2) |
Median PFS (months) ( |
9.9 months (7.4-NE) |
15.4 months (8.3-NE) |
Median OS (months) ( |
19.5 months (13.6-NE) |
NE (12.1-NE) |
CI, confidence interval; CR, complete response; DCR, disease control rate; DoR, duration of response; NE, not estimable; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; TTIR, time to initial response
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About DESTINY-Lung02
DESTINY-Lung02 is a global, randomized phase 2 trial evaluating the safety and efficacy of ENHERTU in patients with HER2 mutant unresectable and/or metastatic NSCLC with disease recurrence or progression during or after at least one regimen of prior anticancer therapy that must have contained a platinum-based chemotherapy. Patients were randomized 2:1 to receive ENHERTU 5.4 mg/kg (n=102) or ENHERTU 6.4 mg/kg (n=50).
The primary endpoint of the trial is confirmed ORR as assessed by BICR. Secondary endpoints include DCR, DoR and PFS assessed by investigator and BICR, OS and safety. DESTINY-Lung02 enrolled 152 patients at multiple sites, including
About HER2 Mutant NSCLC
Lung cancer is the second most common form of cancer globally, with more than two million cases diagnosed in 2020.1 Prognosis is particularly poor for patients with metastatic NSCLC as only approximately
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. Certain HER2 (ERBB2) gene alterations (called HER2 mutations) have been identified in patients with non-squamous NSCLC as a distinct molecular target and occur in approximately
Although the role of anti-HER2 treatment is well established in breast and gastric cancers, there were no approved HER2 directed therapies in NSCLC prior to the approvals of ENHERTU by the Israel Ministry of Health (MOH) Pharmaceutical Division, the Japan Ministry of Health, Labour and Welfare and the accelerated
About ENHERTU
ENHERTU (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the
ENHERTU (5.4 mg/kg) is approved in more than 50 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who have received a (or one or more) 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 the results from the DESTINY-Breast03 trial.
ENHERTU (5.4 mg/kg) is approved in more than 40 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2 low (IHC 1+ or IHC 2+/in-situ hybridization (ISH)-) 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 from the DESTINY-Breast04 trial.
ENHERTU (5.4 mg/kg) is approved in
ENHERTU (6.4 mg/kg) is approved in more than 30 countries worldwide 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 and/or DESTINY-Gastric02 trials.
About the ENHERTU Clinical Development Program
A comprehensive global clinical development program is underway evaluating the efficacy and safety of ENHERTU monotherapy across multiple HER2 targetable cancers. Trials in combination with other anticancer treatments, such as immunotherapy, also are underway.
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
About the DXd ADC Portfolio of Daiichi Sankyo
The DXd ADC portfolio of Daiichi Sankyo currently consists of six ADCs in clinical development across multiple types of cancer. ENHERTU, a HER2 directed ADC, and datopotamab deruxtecan (Dato-DXd), a TROP2 directed ADC, are being jointly developed and commercialized globally with AstraZeneca. Four additional Daiichi Sankyo DXd ADCs include patritumab deruxtecan (HER3-DXd), a HER3 directed ADC, ifinatamab deruxtecan (I-DXd; DS-7300), a B7-H3 directed ADC, raludotatug deruxtecan (R-DXd; DS-6000), a CDH6 directed ADC, and DS-3939, a TA-MUC1 directed ADC.
Designed using Daiichi Sankyo’s proprietary DXd ADC technology to target and deliver a cytotoxic payload inside cancer cells that express a specific cell surface antigen, each ADC consists of a monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.
Datopotamab deruxtecan, ifinatamab deruxtecan, patritumab deruxtecan, raludotatug deruxtecan and DS-3939 are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established.
ENHERTU
Indications
ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with:
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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
- Unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer, as determined by an FDA-approved test, who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy
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Unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy
This indication is approved under accelerated approval based on objective 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
WARNING: INTERSTITIAL LUNG DISEASE and EMBRYO-FETAL TOXICITY
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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. A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment. 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 and HER2-Mutant NSCLC (5.4 mg/kg)
In patients with metastatic breast cancer and HER2-mutant NSCLC treated with ENHERTU 5.4 mg/kg, ILD occurred in
Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)
In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, ILD occurred in
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, then reduce dose by one level. For febrile neutropenia (ANC <1.0 x 109/L and temperature >38.3º C or a sustained temperature of ≥38º C for more than 1 hour), interrupt ENHERTU until resolved, then reduce dose by one level.
Metastatic Breast Cancer and HER2-Mutant NSCLC (5.4 mg/kg)
In patients with metastatic breast cancer and HER2-mutant NSCLC treated with ENHERTU 5.4 mg/kg, a decrease in neutrophil count was reported in
Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)
In 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
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 >
Metastatic Breast Cancer and HER2-Mutant NSCLC (5.4 mg/kg)
In patients with metastatic breast cancer and HER2-mutant NSCLC treated with ENHERTU 5.4 mg/kg, LVEF decrease was reported in
Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)
In 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,
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 7 months after the last dose of ENHERTU. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for 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, then reduce dose by one level.
Adverse Reactions
Metastatic Breast Cancer and HER2-Mutant NSCLC (5.4 mg/kg)
The pooled safety population reflects exposure to ENHERTU 5.4 mg/kg intravenously every 3 weeks in 984 patients in Study DS8201-A-J101 (NCT02564900), DESTINY-Breast01, DESTINY-Breast03, DESTINY-Breast04, and DESTINY-Lung02. Among these patients
HER2-Positive Metastatic Breast Cancer
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 intravenously every three weeks in DESTINY-Breast03. The median duration of treatment was 14 months (range: 0.7 to 30).
Serious adverse reactions occurred in
ENHERTU was permanently discontinued in
The most common (≥
HER2-Low Metastatic Breast Cancer
DESTINY-Breast04
The safety of ENHERTU was evaluated in 371 patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who received ENHERTU 5.4 mg/kg intravenously every 3 weeks in DESTINY-Breast04. The median duration of treatment was 8 months (range: 0.2 to 33) for patients who received ENHERTU.
Serious adverse reactions occurred in
ENHERTU was permanently discontinued in
The most common (≥
Unresectable or Metastatic HER2-Mutant NSCLC (5.4 mg/kg)
DESTINY-Lung02 evaluated two dose levels (5.4 mg/kg [n=101] and 6.4 mg/kg [n=50]); however, only the results for the recommended dose of 5.4 mg/kg intravenously every 3 weeks are described below due to increased toxicity observed with the higher dose in patients with NSCLC, including ILD/pneumonitis.
The safety of ENHERTU was evaluated in 101 patients with unresectable or metastatic HER2-mutant NSCLC who received ENHERTU 5.4 mg/kg intravenously every three weeks in DESTINY‑Lung02. Nineteen percent of patients were exposed for >6 months.
Serious adverse reactions occurred in
ENHERTU was permanently discontinued in
The most common (≥
Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)
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 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) for patients who received ENHERTU.
Serious adverse reactions occurred in
ENHERTU was permanently discontinued in
The most common (≥
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 after 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 7 months after the last dose. Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for 4 months after 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.
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Geriatric Use: Of the 883 patients with breast cancer treated with ENHERTU 5.4 mg/kg,
22% were ≥65 years and3.6% 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 (48% ). Of the 101 patients with unresectable or metastatic HER2-mutant NSCLC treated with ENHERTU 5.4 mg/kg,40% were ≥65 years and8% were ≥75 years. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients. 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 and14% 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 renal impairment more frequently. The recommended dosage of ENHERTU has not been established for patients with severe renal impairment (CLcr <30 mL/min).
- Hepatic Impairment: In patients with moderate hepatic impairment, due to potentially increased exposure, closely monitor for increased toxicities related to the topoisomerase inhibitor. The recommended dosage of ENHERTU has not been established for patients with severe hepatic impairment (total bilirubin >3 times ULN and any AST).
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 an innovative global healthcare company contributing to the sustainable development of society that discovers, develops and delivers new standards of care to enrich the quality of life around the world. With more than 120 years of experience, Daiichi Sankyo leverages its world-class science and technology to create new modalities and innovative medicines for people with cancer, cardiovascular and other diseases with high unmet medical need. For more information, please visit www.daiichisankyo.com.
References
1 WHO. Cancer Today. 2020. Accessed August 2023.
2 American Cancer Society. Lung Cancer Survival Rates. Accessed August 2023.
3 Liu S, et al. Clin Cancer Res. 2018;24(11):2594-2604.
4 Riudavets M, et al. ESMO Open. 2021; 6(5): 100260.
5 Pillai RN, et al. Cancer. 2017;123:4099-105.
6 Offin M, et al. Cancer. 2019;125:4380-7.
7 Hechtman J, et al. Cancer Cyto. 2019; 127(7): 428-431.
8 Gulilat, M, et al, BMC Med.Gen 2019. 12:81.
9 Zhou J, et al. Ther Adv Med Oncol. 2020;12.
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Jennifer Brennan
Daiichi Sankyo, Inc.
jbrennan2@dsi.com
+1 908 900 3183 (mobile)
Koji Ogiwara
Daiichi Sankyo Co., Ltd.
ogiwara.koji.ay@daiichisankyo.co.jp
+81 3 6225 1126 (office)
Investor Relations Contact:
DaiichiSankyoIR@daiichisankyo.co.jp
Source: Daiichi Sankyo