2021-01-22| Trials & Approvals

AstraZeneca, Daiichi Sankyo’s Potential Blockbuster Bags Second US Approval, This Time for Gastric Cancer

by Eduardo Longoria
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ENHERTU (fam-trastuzumab deruxtecan-nxki), a product of a joint endeavor between AstraZeneca and Daiichi Sankyo, has bagged FDA approval for treating adults with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen.

The approval is based on a successful Phase 2 trial conducted in Japan and South Korea, the results of which were published in The New England Journal of Medicine last June. The trial demonstrated a statistically significant improvement in overall survival (OS) and objective response rate (ORR) versus chemotherapy (irinotecan or paclitaxel) in patients with advanced gastric cancer or GEJ adenocarcinoma who had progressed on at least two or more prior chemotherapy regimens.



Gastric cancer is a relatively rare disease, affecting fewer than 200,000 Americans, primarily the ones over the age of 70. The DESTINY-Gastric01 Phase 2 trial showed that patients treated with ENHERTU had a 41% reduction in the risk of death versus patients treated with chemotherapy (based on a hazard ratio [HR] of 0.59; 95% confidence interval [CI] 0.39-0.88; p=0.0097) with a median OS of 12.5 months versus 8.4 months.

Results showed a confirmed ORR of 40.5% in patients treated with ENHERTU (n=126) compared to 11.3% in patients treated with chemotherapy (n=62). Patients treated with ENHERTU had a 7.9% complete response rate and a 32.5% partial response rate compared to 0% and 11.3% for patients treated with chemotherapy. ENHERTU demonstrated a median progression-free survival (PFS) of 5.6 months and a median duration of response (DoR) of 11.3 months as compared to 3.5 months and 3.9 months in the chemotherapy arm.


First HER2- Directed Therapy for Gastric Cancer

An antibody-drug conjugate, made from humanized anti-HER2 IgG1, ENHERTU is the first HER2-directed therapy approved in gastric cancer in nearly ten years. DXd is a topoisomerase I inhibitor that causes DNA damage and apoptotic cell death and is attached to the antibody by a cleavable linker. Following binding to HER2 on tumor cells, fam-trastuzumab deruxtecan-nxki undergoes internalization and intracellular linker cleavage by lysosomal enzymes.

The approval of ENHERTU comes as excellent news since nearly 20% of gastric cancers is HER2 positive. Yet, the drug is not without any side effects. Some adverse events include anemia, leukopenia, neutropenia, lymphocytopenia, and thrombocytopenia to name a few. Besides, Interstitial lung disease (ILD) or pneumonitis occurred in 10% of patients.

Moreover, the drug is not advised for pregnant women as it could pose additional risks for their unborn children. Along with gastric cancer, ENHERTU has been approved for the treatment of HER2 positive metastatic breast cancer in both the EU and US. The recent EU approval was the result of the DESTINY-Breast01 Phase 2 trial that demonstrated clinically meaningful responses in patients.

“Enhertu is the first antibody drug conjugate to receive approval in the US for the treatment of patients with metastatic gastric cancer, and represents a major advance in managing this difficult-to-treat disease. This second indication in the US represents an important step forward in our ambitious plan to accelerate the development of Enhertu across a broad range of HER2-targetable cancers,” said Antoine Yver, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo.

Thanks to the FDA approval, Daiichi Sankyo is now due an amount of $115 million from AstraZeneca as a combined 2nd-line and 3rd-line milestone payment.

Related Article: Enhertu, AstraZeneca’s Drug against Gastric Cancer Gets Breakthrough Therapy Designation



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