Daiichi Sankyo Submits sNDA in Japan for Enhertu (Trastuzumab Deruxtecan) as Treatment for HER2-Positive Metastatic Gastric Cancer

Compiled by S. Li

Recently, Daiichi Sankyo announced that it has submitted a supplemental new drug application (sNDA) for Enhertu (trastuzumab deruxtecan, DS-8201) to the Japanese Ministry of Health, Labour and Welfare (MHLW), seeking approval for the treatment of patients with HER2-positive metastatic gastric cancer.

This submission of the new indication application is based on data from the pivotal Phase 2 clinical DESTINY-Gastric01 study published in The Lancet Oncology, as well as data from Phase 1 clinical trials.

DESTINY-Gastric01 is an open-label, multicenter, pivotal Phase 2 clinical trial that evaluated the safety and efficacy of Enhertu in 189 patients from Japan and South Korea with advanced gastric cancer or gastroesophageal junction adenocarcinoma. These patients had HER2-positive tumors and experienced disease progression after treatment with two or more prior regimens, including fluoropyrimidine (5-FU), platinum-based chemotherapy, and trastuzumab. Patients were randomized in a 2:1 ratio to receive either Enhertu or chemotherapy (paclitaxel or irinotecan monotherapy). The primary endpoint was objective response rate (ORR), and secondary endpoints included overall survival (OS), progression-free survival (PFS), duration of response, disease control rate, and time to treatment failure.

Results from the DESTINY-Gastric01 trial demonstrated that Enhertu provided statistically significant and clinically meaningful improvements in both ORR and OS compared with chemotherapy (irinotecan or paclitaxel monotherapy). The full results of this trial will be presented at the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting.

Furthermore, the overall safety and tolerability profile in DESTINY-Gastric01 was consistent with the results from Phase 1 trials. The most common adverse events were hematologic and gastrointestinal toxicities, including neutropenia, anemia, nausea, and decreased appetite. There were some cases of drug-related interstitial lung disease (ILD) and pneumonitis, with the majority of these events being Grade 1 or Grade 2 in severity. No ILD-related deaths (Grade 5) occurred in either trial.

Currently, there are no approved HER2-directed therapeutic options for patients with HER2-positive metastatic gastric cancer who experience disease progression following trastuzumab treatment. HER2 is a tyrosine kinase receptor protein that promotes cell growth and is expressed on the surface of cancer cells in many types of tumors, including gastric, breast, and lung cancers. HER2 overexpression is associated with specific HER2 genetic alterations, known as HER2 amplification, and typically indicates aggressive disease and a poor prognosis.

Enhertu leverages Daiichi Sankyo’s proprietary antibody-drug conjugate (ADC) technology to link trastuzumab, a humanized HER2 antibody, to a novel topoisomerase I inhibitor via a tetrapeptide linker, thereby targeting cancer cells and delivering the drug intracellularly. In March 2019, AstraZeneca and Daiichi Sankyo entered into a collaboration valued at up to $6.9 billion to jointly develop Enhertu for the treatment of patients with various cancers characterized by differing levels of HER2 expression or HER2 mutations, including gastric cancer, colorectal cancer, lung cancer, and HER2-low breast cancer. Enhertu received accelerated approval from the U.S. Food and Drug Administration (FDA) late last year for adult patients with HER2-positive metastatic breast cancer who have previously received two or more prior anti-HER2-based regimens in the metastatic setting. Additionally, it was approved in Japan this March for patients with HER2-positive, unresectable or metastatic breast cancer that has recurred following prior chemotherapy (limited to patients who are refractory to or intolerant of standard therapy).

Dr. Wataru Takasaki, Executive Officer of Daiichi Sankyo’s Research Division in Japan, stated, “The application submitted by Daiichi Sankyo further bridges the gap between trastuzumab deruxtecan and patient populations in Japan with unmet medical needs. If approved, trastuzumab deruxtecan, as the first antibody-drug conjugate (ADC) approved for the treatment of this type of cancer, has the potential to significantly improve outcomes for patients with HER2-positive metastatic gastric cancer.”

Reference Source: Daiichi Sankyo Submits Supplemental New Drug Application for Trastuzumab Deruxtecan in Japan for Treatment of Patients with HER2-Positive Metastatic Gastric Cancer