Enhertu Becomes First ADC Approved by FDA for HER2-Positive Gastric Cancer, Redefining Treatment Paradigm

January 15, 2021 News /BioonBIOON/ --AstraZenecaEnhertu (fam-trastuzumab deruxtecan, DS-8201), a HER2-targeted antibody-drug conjugate (ADC) co-developed by AstraZeneca and Daiichi Sankyo, was recently approved by the U.S. Food and Drug Administration (FDA) approval of a new indication for the treatment of patients with HER2-positive metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.

It is worth mentioning that,Enhertu is the first antibody-drug conjugate (ADC) approved for the treatment of HER2-positive gastric cancer, bringing meaningful therapeutic advances to this type of cancer.This indication was approved through the priority review program. Previously,FDAEnhertu Granted Breakthrough Therapy Designation (BTD) for HER2-Positive Gastric Cancer. In the United States, there are more than 27,000 new cases of gastric cancer annually, with approximately one-fifth of patients being HER2-positive. Prior to the approval of Enhertu, there were no other approved HER2-targeted therapies available for patients with metastatic gastric cancer whose disease had progressed after initial treatment with an anti-HER2 agent.

Enhertu is the first and only HER2-targeted therapy demonstrated to significantly prolong overall survival (median OS: 12.5 months vs. 8.4 months) compared with chemotherapy in patients with HER2-positive metastatic gastric cancer who had previously received chemotherapy and anti-HER2 therapy.According toClinical Trialscompelling and robust efficacy inEnhertu will become the new standard of care in the clinical treatment of this patient population.

Enhertu is being developed globally by Daiichi Sankyo and AstraZeneca, with Daiichi Sankyo retaining rights in Japan. In September 2020, Enhertu was approved in Japan for the treatment of patients with HER2-positive unresectable advanced or recurrent gastric cancer. Previously, Enhertu had been granted SAKIGAKE (innovative drug) designation by the MHLW for the treatment of HER2-positive gastric cancer.

The approvals of Enhertu for gastric cancer indications in the United States and Japan were both based on the results of the open-label, randomized Phase 2 DESTINY-Gastric01 trial. This trial enrolled 187 patients (including 149 from Japan) with HER2-positive advanced gastric cancer or gastroesophageal junction adenocarcinoma (defined as IHC 3+ or IHC 2+/ISH+), who had previously progressed after treatment with two or more regimens (including 5-FU, platinum-based chemotherapy, and trastuzumab). In the study, patients were randomized in a 2:1 ratio to receive either Enhertu (6.4 mg/kg) or investigator’s choice of chemotherapy (monotherapy with paclitaxel or irinotecan), administered once every three weeks.

The results demonstrated that the study met its primary and key secondary endpoints: compared with the chemotherapy group, the Enhertu treatment group achieved statistically significant and clinically meaningful 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 and 14.3% (95% CI: 6.4–26.2%) in the chemotherapy group.In a prespecified interim analysis,The Enhertu group demonstrated a 41% reduction in the risk of death compared with the chemotherapy group (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.

In this trial, the safety and tolerability of Enhertu were consistent with those reported in previous Enhertu trials. Among the 125 patients treated with Enhertu (including 99 Japanese patients), 122 (97.6%) experienced drug-related adverse reactions. The most commonAdverse Reactionsneutropenia (78 cases, 62.4%), nausea (72 cases, 57.6%), decreased appetite (66 cases, 52.8%),Anemia(51 cases, 40.8%), thrombocytopenia (48 cases, 38.4%), leukopenia (47 cases, 37.6%), fatigue (43 cases, 34.4%), diarrhea (31 cases, 24.8%), alopecia (28 cases, 22.4%), decreased lymphocyte count (27 cases, 21.6%), vomiting (26 cases, 20.8%), and others.

Enhertu (trastuzumab deruxtecan, DS-8201) is a next-generation antibody-drug conjugate (ADC) that links trastuzumab, a humanized monoclonal antibody targeting HER2, to a novel topoisomerase I inhibitor, an exatecan derivative (DX-8951 derivative, DXd), via a tetrapeptide linker. This enables targeted delivery of the cytotoxic agent into cancer cells, thereby reducing systemic exposure to the cytotoxic agent compared with conventional chemotherapy.

In March 2019, AstraZeneca and Daiichi Sankyo reached an agreement worth up to $6.9 billion for immuneTumorcollaborated to jointly develop Enhertu for the treatment of patients with various cancers characterized by HER2 expression or HER2 mutations, including gastric cancer, colorectal cancer, and lung cancer, as well as those with low HER2 expressionBreast Cancer. Under the agreement, the two parties will jointly develop and commercialize Enhertu globally, with Daiichi Sankyo retaining exclusive rights for the Japanese market and assuming full responsibility for manufacturing and supply.

In December 2019, Enhertu received its first global approval in the United States: the FDA granted accelerated approval to Enhertu for adult patients with HER2-positive metastatic breast cancer who had previously received two or more anti-HER2 therapies in the metastatic setting. Enhertu received its first global approval in the United States in December 2019:FDAAccelerated approval for adult patients with HER2-positive metastatic breast cancer who have received two or more prior anti-HER2 therapies in the metastatic setting.

Previously,FDAEnhertu has been granted three Breakthrough Therapy Designations (BTD): (1) for the treatment of disease progression during or after platinum-based chemotherapy,Tumor(1) patients with metastatic non-small cell lung cancer (NSCLC) harboring HER2 mutations; (2) for the treatment of patients with HER2-positive, unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma who have previously received at least two regimens (including trastuzumab); (3) for the treatment of patients with HER2-positive metastatic breast cancer, an indication approved in December 2019.

The industry holds a highly optimistic view of Enhertu's commercial prospects. Previously, the pharmaceutical market research firm EvaluatePharma predicted that Enhertu's sales would reach $2 billion in 2024. (Bioon.com)

Original Source: AstraZeneca's Antibody-Drug Conjugate Enhertu Wins Expandedapproval from the FDA