Trastuzumab Deruxtecan (Enhertu®) Receives Conditional Approval in China for Heavily Pretreated HER2-Positive Advanced or Metastatic Gastric Cancer

Based on the clinical results of DESTINY-Gastric06, Trastuzumab Deruxtecan can bring clinically meaningful benefits to patients.

On August 5, 2024, Enhertu, jointly developed and commercialized by AstraZeneca and Daiichi Sankyo.^®(English trade name: Enhertu^® , Generic Name: Trastuzumab Deruxtecan for Injection) has been granted conditional approval by the China National Medical Products Administration (NMPA). This product is indicated as monotherapy for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received two or more prior treatment regimens.

Trastuzumab Deruxtecan, an antibody-drug conjugate (ADC) uniquely designed to target HER2, was jointly developed and commercialized by AstraZeneca and Daiichi Sankyo. On February 21, 2023, Trastuzumab Deruxtecan was officially approved for marketing by the National Medical Products Administration in China. Less than two years after its introduction into China, it had already been successively approved as a monotherapy for adult patients with unresectable or metastatic HER2-positive breast cancer who have previously received one or more anti-HER2 therapies; or for adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received at least one systemic therapy during the metastatic disease stage, or who relapsed within six months of adjuvant chemotherapy or after completing adjuvant chemotherapy. This time, the approval of this therapy's third significant indication in China will bring better survival benefits to Chinese patients with HER2-positive advanced gastric cancer.

This conditional approval is based on the positive results of the DESTINY-Gastric06 Phase II clinical trial. In the DESTINY-Gastric06 trial, the confirmed objective response rate (ORR) for patients treated with trastuzumab deruxtecan (6.4 mg/kg), as assessed by independent central review, was 28.8%. The median progression-free survival (PFS) was 5.7 months. These patients had previously received two or more prior treatment regimens, including a fluoropyrimidine and a platinum-based drug. Full approval for this indication will depend on the results of ongoing randomized controlled confirmatory clinical trials demonstrating clinical benefit in this population.

The safety profile of Trastuzumab Deruxtecan in the DESTINY-Gastric06 trial was consistent with previous clinical trials of Trastuzumab Deruxtecan in gastric cancer, with no new safety issues identified.

In addition, the positive results of the DESTINY-Gastric01 Phase II clinical trial, which included patients from Japan and South Korea, also supported this conditional approval. In the trial, confirmed objective response rate (ORR) (40.5% in the trastuzumab deruxtecan group vs 11.3% in the chemotherapy group; p<0.0001) and median overall survival (OS) (12.5 months in the trastuzumab deruxtecan group vs 8.4 months in the chemotherapy group; hazard ratio [HR] 0.59; 95% confidence interval [CI] 0.39-0.88; p=0.0097) showed statistically significant improvements in HER2-positive metastatic gastric cancer patients treated with trastuzumab deruxtecan. Previously, based on the results of the DESTINY-Gastric01/02 studies, trastuzumab deruxtecan has been approved in more than 45 countries and regions, including the United States, Japan, and the European Union. Based on these results, trastuzumab deruxtecan has been recommended as a treatment option in authoritative guidelines both in China and internationally. The "2024 CSCO Gastric Cancer Diagnosis and Treatment Guidelines" include it in third-line and above treatments; the 2023 NCCN (National Comprehensive Cancer Network), ASCO (American Society of Clinical Oncology), and ESMO (European Society for Medical Oncology) guidelines all recommend its use for later-line treatment of HER2-positive advanced gastric cancer patients.

China is a country with high incidence and mortality of gastric cancer. According to statistics, more than one-third of the world's gastric cancer cases occur in China.¹, about 65% of Chinese patients are already at the middle or late stage at the time of diagnosis.²The 5-year survival rate is 9.4%.³, the prognosis of patients is poor. In China, HER2 positive gastric cancer accounts for about 13%-18% of all gastric cancers.^4,5HER2 protein is not only a poor prognostic indicator for gastric cancer but also a classic target for effective treatment. Anti-HER2 therapy plays an indispensable role in the treatment history of gastric cancer.

Professor Lin Shen, Director of the Department of Gastrointestinal Oncology, Peking University Cancer Hospital"HER2-positive advanced gastric cancer is highly aggressive and difficult to treat. Patients who progress after receiving first-line treatment and subsequent chemotherapy often have a poor prognosis. The ADC drug trastuzumab deruxtecan can provide clinically meaningful benefits to patients after prior treatment failure. Its approval will bring an important new targeted treatment option for HER2-positive metastatic gastric cancer patients in China."

Ming-Lung Lai, Global Senior Vice President of AstraZeneca, General Manager of AstraZeneca China, and General Manager of AstraZeneca China Oncology BusinessStated: "After entering China for more than 30 years, AstraZeneca, as a leader in the field of cancer treatment, adheres to the concept of 'patient-centered' and focuses on high-incidence cancer areas in China, continuously providing patients with more and better treatment options. China is a major country for gastric cancer, with a heavy disease burden, especially for patients with advanced HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma who have urgent unmet clinical needs. We are very pleased to see that the new generation ADC drug Trastuzumab Deruxtecan has successfully been approved for its third significant indication within less than two years of being introduced to China, becoming the second product from AstraZeneca to enter the gastrointestinal cancer field after Durvalumab. In the future, AstraZeneca will continue to deepen its focus on gastrointestinal cancers, and we look forward to providing life-changing drugs to patients through a rich product pipeline, improving their five-year survival rate while fully supporting the enhancement of China’s full-process management capabilities in cancer ‘screening, diagnosis, treatment, and follow-up’, improving the diagnosis and treatment landscape for cancer patients, and contributing to the early realization of the 'Healthy China 2030' goals."

Dr. He Jing, Senior Vice President of AstraZeneca Global and President of AstraZeneca Global R&D China CenterSaid: "AstraZeneca is continuously committed to the research and development of life-changing medicines, and our R&D pipeline is also designed and constructed from different perspectives. Previously, Trastuzumab Deruxtecan was approved for HER2-positive metastatic breast cancer and HER2-low metastatic breast cancer. This approval in China, based on the results of the DESTINY-Gastric06 trial, further demonstrates the global impact of this innovative antibody-drug conjugate. In the future, we will continue to leverage the dual advantages of independent research and external collaboration to further strengthen Trastuzumab Deruxtecan's position as a transformative treatment option for patients with HER2-expressing cancers through our clinical development programs, with the aim of benefiting more patients."

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About HER2-Positive Gastric Cancer

Gastric cancer is the fifth most common cancer globally and the fourth leading cause of cancer-related 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 stomach cancer in 2022.⁸Moreover, about 65% of patients in China are already at the middle or late stage when diagnosed.²。

Approximately one-fifth of gastric cancers worldwide are HER2-positive.^7,10HER2 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 metastatic gastric cancer patients whose condition worsens after initial treatment with trastuzumab, subsequent anti-HER2 treatment options are limited.¹²。

About DESTINY-Gastric06

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

About DESTINY-Gastric01

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's choice of chemotherapy regimen 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 in combination with fluoropyrimidine and platinum-based chemotherapy, 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, among others.

About Trastuzumab Deruxtecan

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 (DXd, a camptothecin derivative) via a stable, cleavable tetrapeptide linker.

Based onDESTINY-Breast03The trial results indicate that 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. These patients have previously received anti-HER2-based treatment either during the metastatic stage or during neoadjuvant or adjuvant therapy (with disease recurrence occurring during treatment or within six months after completing treatment).

Based onDESTINY-Breast04Trial results: 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 received prior systemic therapy in the metastatic setting or developed disease recurrence during or within six months after adjuvant chemotherapy.

Based onDESTINY-Lung02 The trial results indicate that 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 have activating HER2 (ERBB2) mutations as detected by locally or regionally approved tests 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 onDESTINY-Gastric01Trial and/orDESTINY-Gastric02The trial results indicate that 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.DESTINY-Gastric06Trial results: China also approves trastuzumab deruxtecan for this indication.

Based onDESTINY-PanTumor02、DESTINY-Lung01AndDESTINY-CRC02The trial results led to the approval of trastuzumab deruxtecan (5.4mg/kg) 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 treatment options. Continued approval for this indication in the U.S. may depend on the verification and description of clinical benefit in confirmatory trials.

About the Clinical Development Plan for Trastuzumab Deruxtecan

A comprehensive development program evaluating the efficacy and safety of trastuzumab deruxtecan monotherapy in multiple HER2-targeted cancers is underway globally. Trials in combination with other anti-cancer treatments, such as immunotherapy, are also being conducted.

Regarding the Collaboration with Daiichi-Sankyo

In March 2019, Daiichi Sankyo and AstraZeneca entered into a global collaboration to co-develop and commercialize DS8201 (HER2-targeted ADC) in markets outside of Japan (where Daiichi Sankyo holds exclusive rights in Japan). In July 2020, the two parties again reached an agreement for the co-development and commercialization of datopotamab deruxtecan (DS-1062; TROP2-targeted ADC). Daiichi Sankyo is responsible for the manufacturing and supply of DS8201 and datopotamab deruxtecan.

Research on AstraZeneca's Oncology Field

AstraZeneca is leading a revolution in the field of oncology, committed to providing diversified cancer treatment solutions. Through scientific exploration of the complexities in oncology, AstraZeneca discovers, develops, and delivers life-changing drugs to patients.

AstraZeneca's oncology business focuses on the most challenging cancer diseases. Through continuous innovation, AstraZeneca has built a leading, diversified portfolio and pipeline across the industry, constantly driving changes in medical practice and transforming the patient experience.

AstraZeneca's vision aims to redefine cancer treatment with the hope of ending cancer as a cause of death in the future.

Disclaimer: This article involves products or indications not approved in China. AstraZeneca does not recommend the use of any unapproved drugs/indications.

Source: Press Release (Internal Approval Number: CN-141461)

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