AstraZeneca and Daiichi Sankyo’s HER2-Targeted ADC Enhertu Receives Conditional Approval in China for Heavily Pretreated HER2-Positive Gastric Cancer

HER2-positive advanced gastric cancer is highly aggressive, difficult to treat, and often associated with a poor prognosis once patients progress after first-line treatment and subsequent chemotherapy. The ADC drug trastuzumab deruxtecan can provide clinically meaningful benefits for patients following disease progression after prior treatments. Its approval will bring an important new targeted therapy option for HER2-positive metastatic gastric cancer patients in China.

After more than 30 years in China, AstraZeneca, as a leader in the field of oncology treatment, adheres to the concept of 'patient-centeredness,' focusing on high-incidence cancers in China and continuously providing patients with more and better treatment options. China bears a heavy disease burden as a major country afflicted by gastric cancer, particularly for patients with advanced HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma who have urgent unmet clinical needs. It is exciting to see that the new-generation ADC drug trastuzumab deruxtecan has successfully gained approval for its third significant indication within less than two years of being introduced in China, becoming the second product from AstraZeneca to enter the gastrointestinal cancer field after durvalumab. In the future, AstraZeneca will continue to focus on the field of gastrointestinal tumors, hoping to provide life-changing drugs to patients through a rich pipeline of products, improve their five-year survival rate, fully support the enhancement of China’s full-course management capabilities in cancer ‘screening, diagnosis, treatment, and follow-up,’ improve the treatment landscape for cancer patients, and contribute to the early realization of the ‘Healthy China 2030’ goals.

AstraZeneca is continuously committed to the research and development of life-changing medicines, with our R&D pipeline designed and constructed from various perspectives. Previously, Trastuzumab Deruxtecan was approved for HER2-positive metastatic breast cancer and HER2-low metastatic breast cancer. This recent approval in China, based on the results of the DESTINY-Gastric06 trial, further demonstrates the global impact of this innovative antibody-drug conjugate. Moving forward, we will continue to leverage the dual advantages of internal innovation and external collaboration, reinforcing Trastuzumab Deruxtecan’s position as a transformative treatment option for patients with HER2-expressing cancers through our clinical development programs, aiming to benefit more patients.

Gastric cancer is the fifth most common cancer globally and the fourth leading cause of cancer mortality, with a five-year survival rate of 5% to 10% for advanced or metastatic disease.^6,7In 2022, there were approximately 1 million new cases of gastric cancer reported globally, with about 660,000 deaths.⁸。

The incidence of gastric cancer is significantly higher in East Asia, especially in China, where more than one-third of the global cases occur.^8,9Gastric cancer is the fifth most common cancer in China, with approximately 359,000 new cases reported in 2022.⁸In addition, stomach cancer is the third leading cause of cancer-related deaths in China, with approximately 260,000 people dying from the disease in 2022.⁸Moreover, approximately 65% of patients in China are already at the middle or late stage upon diagnosis.²。

Approximately one-fifth of gastric cancers worldwide are HER2-positive.^{7, 10}HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of various tumors, including gastric cancer.¹¹。

In China, the recommended first-line treatment for HER2-positive advanced or metastatic gastric cancer is combination chemotherapy plus trastuzumab, an anti-HER2 drug, with or without pembrolizumab.¹²For patients with metastatic gastric cancer whose condition worsens after initial treatment with trastuzumab, subsequent anti-HER2 treatment options are limited.¹²。

DESTINY-Gastric06 is an open-label, single-arm Phase II trial conducted in China to evaluate the safety and efficacy of trastuzumab deruxtecan (6.4mg/kg) in HER2-positive patients with locally advanced or metastatic gastric cancer or gastroesophageal adenocarcinoma who have previously received two or more treatment regimens, including fluoropyrimidines and platinum-based drugs.

The primary endpoint of DESTINY-Gastric06 is the objective response rate (ORR) confirmed by independent central review (ICR). Secondary endpoints include ORR confirmed by investigator assessment (INV), progression-free survival (PFS), duration of response (DoR), disease control rate (DCR), overall survival (OS), and safety.

DESTINY-Gastric06 enrolled 95 patients at multiple sites in China. For more information about this trial, please visit clinicaltrials.gov.

DESTINY-Gastric01 is a Phase II, open-label, multicenter, randomized controlled trial that compared the safety and efficacy of trastuzumab deruxtecan (6.4 mg/kg) with investigator-selected chemotherapy regimens in HER2-positive treatment-naïve patients from Japan and Korea. The main cohort enrolled HER2-positive patients with locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma from Japan and Korea who had previously received at least two prior treatment regimens, including trastuzumab plus a fluoropyrimidine and platinum-based chemotherapy combination, but had experienced disease progression.

The primary endpoint of the study was the ORR assessed by independent central review, the key secondary endpoint was OS, and other secondary endpoints included PFS, DoR, and DCR, etc.

Trastuzumab Deruxtecan is a HER2-targeted ADC designed using Daiichi Sankyo's proprietary DXd ADC technology. It is the leading ADC in Daiichi Sankyo’s oncology portfolio and the most advanced project in AstraZeneca’s ADC scientific platform. Trastuzumab Deruxtecan is composed of a humanized anti-HER2 monoclonal antibody linked to a topoisomerase-I inhibitor (a camptothecin derivative, DXd) via a stable, cleavable tetrapeptide linker.

Based on the results of the DESTINY-Breast03 trial, trastuzumab deruxtecan (5.4mg/kg) has been approved in more than 65 countries and regions for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+ or in situ hybridization [ISH]+) breast cancer who have previously received anti-HER2-based treatment either in the metastatic setting or during neoadjuvant or adjuvant therapy (with disease recurrence during or within six months after completing treatment).

Based on the results of the DESTINY-Breast04 trial, trastuzumab deruxtecan (5.4mg/kg) has been approved in more than 65 countries and regions for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who have previously received one systemic therapy in the metastatic setting or developed disease recurrence during or within six months after adjuvant chemotherapy.

Based on the results of the DESTINY-Lung02 trial, trastuzumab deruxtecan (5.4mg/kg) has been approved in more than 35 countries for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer whose tumors are identified by locally or regionally approved tests to have activating HER2 (ERBB2) mutations and who have received prior systemic therapy. Continued approval for this indication in the United States may be contingent upon verification and description of clinical benefit in confirmatory trials.

Based on the results of the DESTINY-Gastric01 and/or DESTINY-Gastric02 trials, trastuzumab deruxtecan (6.4mg/kg) has been approved in more than 45 countries for the treatment of adult patients with locally advanced or metastatic HER2-positive (IHC 3+ or IHC 2+/ISH+) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have previously received a trastuzumab-based regimen. Based on the results of the DESTINY-Gastric06 trial, trastuzumab deruxtecan has also been approved in China for this indication.

Based on the trial results of DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02, trastuzumab deruxtecan (5.4 mg/kg) has been approved in the United States for the treatment of adult patients with HER2-positive (IHC 3+) unresectable or metastatic solid tumors who have previously received systemic therapy and have no satisfactory alternative subsequent treatment options. Continued approval for this indication in the United States may be contingent upon verification and description of clinical benefit in confirmatory trials.