Enhertu Shows 38% Objective Response Rate and Durable Responses in Western Patients with HER2-Positive Gastric Cancer in Phase II DESTINY-Gastric02 Trial

September 18, 2021 /BioonBIOON/ --AstraZeneca(AstraZeneca) and Daiichi Sankyo recently announced positive Phase 2 DESTINY-Gastric02 at the 2021 European Society for Medical Oncology (ESMO) Virtual CongressClinical TrialDetailed results of (NCT04014075). Data show,In patients with HER2-positive metastatic and/or unresectable gastric or gastroesophageal junction (GEJ) adenocarcinoma who had previously received one trastuzumab-based regimen, treatment with the HER2-targeted antibody-drug conjugate (ADC) Enhertu (fam-trastuzumab deruxtecan) provided clinically meaningful and durableTumorRemission.

Although the benefits of HER2-targeted therapy in the first-line treatment of metastatic gastric cancer are well established, the disease will eventually progress.DESTINY-Gastric02 is the first trial specifically evaluating Enhertu for the treatment of gastric cancer in Western patients.. In the preliminary analysis, as assessed by independent central review (ICR), the confirmed overall response rate (ORR) for Enhertu (6.4 mg/kg) treatment was 38%. Among patients treated with Enhertu, complete response (CR) was observed in 3 patients (3.8%) and partial response (PR) in 27 patients (34.2%). After a median follow-up of 5.7 months,The median duration of response (DoR) was 8.1 months.（95%CI:4.1-NE）。Median progression-free survival (PFS) was 5.5 months.（95%CI:4.2-7.3）。The confirmed disease control rate (DCR) was 81%.（95%CI:70.6-89.0）。

These results are consistent with the Phase 2 DESTINY-Gastric01 trial previously published in *The New England Journal of Medicine*Clinical Trialconsistent with the results of.In the DESTINY-Gastric02 trial, the overall safety profile of Enhertu was consistent with that in the DESTINY-Gastric01 trial. The most common Grade ≥3 drug-related treatment-emergent adverse events (TEAEs) wereAnemia(7.6%), neutropenia (7.6%), nausea (3.8%), fatigue (3.8%).As determined by the independent review committee, 6 cases (7.6%) of treatment-related interstitial lung disease (ILD) or pneumonitis were reported. The majority (83%) were low-grade (Grade 1 or 2), and 1 case was Grade 5 (death related to ILD or pneumonitis).

AstraZenecaTumorSusan Galbraith, Executive Vice President, Head of Research and Development, said: "Data from the DESTINY-Gastric02 trial reaffirm the clinical significance of the potential benefits of Enhertu for patients with advanced gastric cancer. Patients typically experience disease progression after initial treatment and are then faced with limited treatment options, so today's results bring hope to patients and treating physicians."

Gastric cancer carries a poor prognosis, particularly in advanced stages, with a 5-year survival rate of only 5%–10%. Approximately one-fifth of gastric cancers are considered HER2-positive. However, loss of HER2 expression is observed in 29%–69% of gastric cancer patients treated with trastuzumab, suggesting that downregulation of HER2 expression may lead to disease progression on trastuzumab therapy and may be associated with a poor prognosis. For patients who experience disease progression following first-line HER2-targeted systemic therapy, second-line treatment options are limited, underscoring an urgent need for novel HER2-targeted therapies.

Enhertu is the first antibody-drug conjugate (ADC) approved for the treatment of HER2-positive gastric cancer. The drug was approved in Japan in September 2020 and in the United States in January 2021, respectively, for the treatment of patients with HER2-positive metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.It is worth noting that,Enhertu is the first HER2-targeted therapy to demonstrate a significant prolongation in overall survival compared with chemotherapy (median OS: 12.5 months vs. 8.4 months) in patients with HER2-positive metastatic gastric cancer who have previously received chemotherapy and anti-HER2 therapy. According toClinical TrialWith its compelling and robust efficacy, Enhertu will become the new standard of care for this patient population.

The approval is based on the results of the open-label, randomized phase 2 DESTINY-Gastric01 trial. The trial enrolled 187 patients (including 149 from Japan) with HER2-positive advanced gastric or gastroesophageal junction adenocarcinoma (defined as IHC 3+ or IHC 2+/ISH+), who had disease progression after receiving two or more prior regimens (including 5-FU, platinum-based chemotherapy, and trastuzumab). In the study, patients were randomized in a 2:1 ratio to receive Enhertu (6.4 mg/kg) or investigator's choice of chemotherapy (paclitaxel or irinotecan monotherapy) every 3 weeks.

The results demonstrated that the study met its primary and key secondary endpoints: compared with the chemotherapy group, the Enhertu group achieved statistically and clinically significant improvements in objective response rate (ORR) and overall survival (OS). Specifically, among 175 evaluable patients (including 140 Japanese patients), as assessed by independent central review (ICR), the ORR was 51.3% (95% CI: 41.9–60.5%) in the Enhertu group versus 14.3% (95% CI: 6.4–26.2%) in the chemotherapy group. In a prespecified interim analysis, Enhertu reduced the risk of death by 41% compared with chemotherapy (HR=0.59; 95% CI: 0.39–0.88; p=0.0097). The median OS was 12.5 months in the Enhertu group and 8.4 months in the chemotherapy group.

Gastric cancer is the fifth most common cancer worldwide and the fourth leading cause of cancer death. The 5-year survival rate for patients with advanced or metastatic disease is only 5%–10%. In 2020, there were approximately 1 million new cases of gastric cancer globally and 768,000 deaths. The incidence of gastric cancer is significantly higher in East Asia, accounting for approximately half of all cases. Gastric cancer is typically diagnosed at an advanced stage, but even when diagnosed at an early stage, survival rates remain low.

Approximately one-fifth of gastric cancers are HER2-positive.HER2 is a growth-promoting receptor tyrosine kinase, expressed in many types ofTumorCell surface, includingBreast cancer, gastric cancer, lung cancer, and colorectal cancer. HER2 overexpression may be associated with specific HER2 gene alterations known as HER2 amplification.

For HER2-positive advanced or metastatic gastric cancer, the recommended first-line treatment regimen is a combination of chemotherapy and trastuzumab. Trastuzumab is an anti-HER2 agent that has been demonstrated to improve patient survival when used in combination with chemotherapy. However, loss of HER2 expression has been observed in 29%–69% of gastric cancer patients following trastuzumab treatment. This suggests that reduced HER2 expression may lead to disease progression during trastuzumab therapy and may be associated with a poor prognosis in gastric cancer. For patients with metastatic gastric cancer who experience disease progression after initial treatment with a trastuzumab-based regimen, treatment options remain limited, and no other HER2-targeted therapies are available in many regions worldwide.

2026 ADC Drug Sales Forecast (Image sourced from PMID 33762691)

Enhertu is a next-generation antibody-drug conjugate (ADC) that links a HER2-targeted humanized monoclonal antibody, trastuzumab, to a novel topoisomerase I inhibitor exatecan derivative (DX-8951 derivative, DXd) via a tetrapeptide linker. It enables targeted delivery of the cytotoxic payload into cancer cells, thereby reducing systemic exposure to the cytotoxic agent compared with conventional chemotherapy.

In March 2019, AstraZeneca and Daiichi Sankyo reached an immuno-TumorScientific collaboration to co-develop Enhertu for the treatment of patients with cancers exhibiting various HER2 expression levels or HER2 mutations, including gastric cancer, colorectal cancer, lung cancer, and HER2-low breast cancer. Under the agreement, both parties will co-develop and commercialize Enhertu globally, with Daiichi Sankyo retaining exclusive rights in the Japanese market while assuming full responsibility for manufacturing and supply.

To date,Enhertu has been approved for two indications: (1) for the treatment of adult patients with HER2-positive metastatic breast cancer who have previously received two or more anti-HER2 therapies in the metastatic setting; (2) for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.

The industry is highly optimistic about the commercial prospects of Enhertu. In March this year, the journal *Nature Reviews Drug Discovery* published an article ("The oncology market for antibody-drug conjugates") noting that,The market size of globally approved antibody-drug conjugates (ADCs) is expected to exceed USD 16.4 billion by 2026, with Enhertu ranking first with sales of USD 6.2 billion.(Bioon.com)

Original Source:Enhertu demonstrated clinically meaningful and durable response in patients with HER2-positive advanced gastric cancer in DESTINY-Gastric02 Phase II trial