Trastuzumab Deruxtecan Shows Efficacy in HER2+ Gastric Cancer

John Marshall, MD, discusses the DESTINY-Gastric01 study of fam-trastuzumab deruxtecan-nxki in patients with locally advanced or metastatic HER2-positive gastric cancer.

John Marshall, MD, clinical director of oncology and chief of the division of hematology-oncology for Georgetown University Hospital, and associate director for clinical care of the Lombardi Comprehensive Cancer Center, discusses the DESTINY-Gastric01 study (NCT03329690) of fam-trastuzumab deruxtecan-nxki (Enhertu) in patients with locally advanced or metastatic HER2-positive gastric cancer.

HER2-targeted agents have been investigated in breast, gastric, and colon cancer, and are being tested in other solid tumors currently. According to Marshall, HER2-targeted therapies are likely to be effective across disease types.

Trastuzumab deruxtecan is an antibody-drug conjugate that combines the monoclonal antibody trastuzumab with a topoisomerase inhibitor that binds to the cancer and delivers a chemotherapeutic agent. It was used successfully in patients with HER2-positive metastatic breast cancer in the DESTINY-Breast01 trial (NCT03248492), Marshall says.

In the phase 2 DESTINY-Gastric01 trial, 188 patients with advanced HER2-positive upper gastrointestinal [GI] cancers who had received at least 2 prior therapies, including trastuzumab, were randomized 2:1 to receive trastuzumab deruxtecan or physician’s choice of irinotecan or paclitaxel chemotherapy. Patients receiving trastuzumab deruxtecan had an objective response rate (ORR) of 51% versus 14% with chemotherapy. Median overall survival (OS) was 12.5 months versus 8.4 months, while progression-free survival was 5.6 months versus 3.5 months.

Based on the efficacy results, trastuzumab was approved as second-line and later therapy for patients with HER2-positive locally advanced or metastatic gastric cancer.


0:08 | We have been targeting HER2 for a long time, really led by the breast cancer teams, gastric cancer, now colon cancer has come behind. But we are now testing lots of cancers for HER2 positivity because the therapies do seem to work one disease to the next. In breast cancer, they had already figured out novel ways to target the HER2 pathway and receptor in through lines of therapy.

One of those is a novel therapy, a sort of loaded antibody, if you will, trastuzumab deruxtecan. This is essentially trastuzumab with a topoisomerase inhibitor attached to it. So the principle here is the antibody comes and binds to the receptor, probably has a pathway targeting piece to it as well, but brings along a very potent chemotherapeutic agent to the cancer cell and delivers that successfully. And we'd already seen this compound work in metastatic breast cancer.

1:14 | And the [DESTINY-Gastric01] study, it's a clinical trial looking in second- and third-line HER2-positive upper GI cancers where half the patients were randomized to receive chemotherapy of choice. The other half were given the single-agent trastuzumab deruxtecan, and the results were quite positive. They had a higher ORR, a higher PFS, [and] a higher OS in this space, which subsequently led to the approval of this drug, also known as Enhertu, in second- and subsequent-line therapy, [in] gastric cancer that is HER2-positive.

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