Enhertu by AstraZeneca and Daiichi Sankyo Approved in China as First HER2-Directed Therapy for Metastatic Lung Cancer

Enhertu by AstraZeneca and Daiichi Sankyo Approved in China as First HER2-Directed Therapy for Metastatic Lung Cancer

(IN BRIEF) AstraZeneca and Daiichi Sankyo’s Enhertu (trastuzumab deruxtecan) has received conditional approval in China for the treatment of patients with unresectable, locally advanced, or metastatic non-small cell lung cancer (NSCLC) with HER2 (ERBB2) mutations who have previously undergone systemic therapy. This approval is based on successful results from the DESTINY-Lung02 and DESTINY-Lung05 Phase II trials, demonstrating clinically meaningful responses. Enhertu becomes the first HER2-directed therapy approved in China for this type of lung cancer, providing a crucial new option for patients with HER2-mutant NSCLC. Full approval will depend on the clinical outcomes of a confirmatory trial.

(PRESS RELEASE) CAMBRIDGE, 14-Oct-2024 — /EuropaWire/ — AstraZeneca and Daiichi Sankyo’s Enhertu (trastuzumab deruxtecan) has received conditional approval in China for treating adult patients with unresectable, locally advanced, or metastatic non-small cell lung cancer (NSCLC) with HER2 (ERBB2) mutations, who have previously undergone systemic therapy. This marks the first time a HER2-directed therapy has been approved in China for NSCLC patients. The approval is based on positive results from the DESTINY-Lung02 and DESTINY-Lung05 Phase II trials, showcasing Enhertu’s efficacy in treating this aggressive cancer type. Full approval depends on the outcome of a confirmatory trial.

Lung cancer remains a significant health challenge in China, with more than a million new cases diagnosed annually, representing over 40% of the global lung cancer burden. Of these, 2% to 4% are patients with HER2 mutations. Until now, treatment options for this specific subset of patients have been limited.

Ying Cheng, MD, PhD, Director of the Jilin Lung Cancer Centre and principal investigator for DESTINY-Lung05, highlighted the importance of this development, stating that Enhertu provides a much-needed treatment for patients with HER2-mutant NSCLC. AstraZeneca’s Dave Fredrickson, Executive Vice President of Oncology Business Unit, emphasized the significance of biomarker testing to ensure appropriate treatment strategies for patients.

Daiichi Sankyo’s Head of Asia, South & Central America Business Unit, Kiminori Nagao, stressed that this milestone reinforces the drug’s utility across various HER2-targetable cancers, following its approval for HER2-positive breast and gastric cancers in China.

In the trials, Enhertu demonstrated promising results, with a 49.0% confirmed objective response rate (ORR) in the DESTINY-Lung02 trial, and a 58.3% ORR in DESTINY-Lung05, both indicating clinically meaningful responses in patients. The safety profile of Enhertu remained consistent with previous studies, without new safety concerns.

Enhertu, jointly developed by AstraZeneca and Daiichi Sankyo, is already approved for HER2-mutant NSCLC treatment in over 45 countries, including the US, Japan, and across Europe.

Notes

HER2-mutant NSCLC
Lung cancer is the most common form of cancer globally in both men and women.2 Each year there are approximately 2.5 million people diagnosed with lung cancer globally, with 80-85% diagnosed with NSCLC.2,6 Prognosis is poor for patients with metastatic NSCLC as only approximately 9% will live beyond five years after diagnosis.7

In China, lung cancer is the most commonly diagnosed cancer with more than one million cases diagnosed in 2022.1 It is also the leading cause of cancer-related deaths in China, with more than 733,000 deaths reported in 2022.1

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of multiple tumour types. 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 2% to 4% of patients with this type of lung cancer.4,5 While HER2 gene mutations can occur in a range of patients, they are more commonly found in patients with NSCLC who are younger, female and have never smoked.8 HER2 gene mutations have been independently associated with cancer cell growth and poor prognosis, with an increased incidence of brain metastases.9 Next-generation sequencing has been utilised in the identification of HER2 (ERBB2) mutations.10

DESTINY-Lung02
DESTINY-Lung02 is a global, randomised Phase II 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 randomised 2:1 to receive Enhertu 5.4mg/kg (n=102) or Enhertu 6.4mg/kg (n=50).

The primary endpoint of the trial is confirmed ORR as assessed by BICR. Secondary endpoints include disease control rate (DCR), DoR and PFS assessed by investigator and BICR, OS and safety.

DESTINY-Lung02 enrolled 152 patients at multiple sites, including Asia, Europe, Oceania and North America. For more information about the trial, visit clinicaltrials.gov.

DESTINY-Lung05
DESTINY-Lung05 is an open-label, single-arm Phase II trial evaluating the safety and efficacy of Enhertu (5.4mg/kg) in patients with HER2-mutant metastatic NSCLC with disease progression on or after at least one prior anticancer therapy.

The primary endpoint of the trial is confirmed ORR as assessed by ICR. Secondary endpoints include investigator-assessed confirmed ORR, as well as ICR and investigator-assessed DoR, DCR, PFS and safety.

DESTINY-Lung05 enrolled 72 patients at multiple sites in China. For more information about the trial, visit clinicaltrials.gov.

Enhertu
Enhertu 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 programme in AstraZeneca’s ADC scientific platform. Enhertu consists of a HER2 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

Enhertu (5.4mg/kg) is approved in more than 65 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2-positive (immunohistochemistry [IHC 3+ or in-situ hybridisation [ISH]+) 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 (5.4mg/kg) is approved in more than 65 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ 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 (5.4mg/kg) is approved in more than 45 countries worldwide for the treatment of adult patients with unresectable or metastatic NSCLC whose tumours have activating HER2 (ERBB2) mutations, as detected by a locally or regionally approved test, and who have received a prior systemic therapy based on the results from the DESTINY-Lung02 and/or DESTINY-Lung05 trials. Continued approval in China and the US for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Enhertu (6.4mg/kg) is approved in more than 45 countries worldwide for the treatment of adult patients with locally advanced or metastatic HER2-positive (IHC 3+ or 2+/ISH+) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01, DESTINY-Gastric02 and/or DESTINY-Gastric06 trials. Continued approval in China for this indication will depend on whether a randomised controlled confirmatory clinical trial can demonstrate clinical benefit in this population.

Enhertu (5.4mg/kg) is approved in the US for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumours who have received prior systemic treatment and have no satisfactory alternative treatment options based on efficacy results from the DESTINY-PanTumor02, DESTINY-Lung01 and DESTINY-CRC02 trials. Continued approval for this indication in the US may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Enhertu development programme
A comprehensive global clinical development programme is underway evaluating the efficacy and safety of Enhertu monotherapy across multiple HER2-targetable cancers. Trials in combination with other anti-cancer treatments, such as immunotherapy, also are underway.

Daiichi Sankyo collaboration
AstraZeneca and Daiichi Sankyo entered into a global collaboration to jointly develop and commercialise Enhertu in March 2019 and datopotamab deruxtecan in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights for each ADC. Daiichi Sankyo is responsible for the manufacturing and supply of Enhertu and datopotamab deruxtecan.

AstraZeneca in oncology
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The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

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References

1. WHO. International Agency of Cancer Research. Cancer Today. China. 2022. Available at: https://gco.iarc.who.int/media/globocan/factsheets/populations/160-china-fact-sheet.pdf. Accessed October 2024.

2. WHO. International Agency of Cancer Research. Cancer Today. Lung. 2022. Available at: https://gco.iarc.who.int/media/globocan/factsheets/cancers/15-trachea-bronchus-and-lung-fact-sheet.pdf. Accessed October 2024.

3. Fan H, et al. Incidence and survival of non-small cell lung cancer in Shanghai: a population-based cohort study. BMJ Open. 2015;5:e009419.

4. Liu S, et al. Targeting HER2 Aberrations in Non–Small Cell Lung Cancer with Osimertinib. Clinical Cancer Research. 2018;24(11):2594-2604.

5. Riudavets M, et al. Targeting HER2 in non-small-cell lung cancer (NSCLC): a glimpse of hope? An updated review on therapeutic strategies in NSCLC harbouring HER2 alterations. ESMO Open. 2021;6(5):100260.

6. American Cancer Society. Key Statistics for Lung Cancer. Available at: https://www.cancer.org/cancer/types/lung-cancer/about/key-statistics.html. Accessed October 2024.

7. American Cancer Society. Lung Cancer Survival Rates. Available at: https://www.cancer.org/cancer/types/lung-cancer/detection-diagnosis-staging/survival-rates.html. Accessed October 2024.

8. Pillai RN, et al. HER2 mutations in lung adenocarcinomas: A report from the Lung Cancer Mutation Consortium. Cancer. 2017;123:4099-105.

9. Offin M, et al. Frequency and outcomes of brain metastases in patients with HER2-mutant lung cancers. Cancer. 2019;125:4380-7.

10, Hechtman J, et al. The Past, Present, and Future of HER2 (ERBB2) in Cancer: Approaches to Molecular Testing and an Evolving Role in Targeted Therapy. Cancer Cytopathology. 2019;127(7): 428-431

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