Current treatment options are highly limited for patients with advanced human epidermal growth factor receptor 2 (HER2)-positive gastric or gastro-esophageal junction cancer, particularly after trastuzumab. A potential new treatment has emerged in a phase 1 clinical trial, which reports that [fam-] trastuzumab deruxtecan shows preliminary activity in patients with heavily pretreated HER2-positive gastric or gastro-esophageal junction cancer. In this interview with i3 Health, Kohei Shitara, MD, lead author of the study, discusses the importance of the trial's results.
Can you comment on the significance of the trial's findings regarding [fam-] trastuzumab deruxtecan as post-trastuzumab treatment for patients with advanced HER2-positive gastric or gastro-esophageal junction cancer?
Kohei Shitara, MD: There are no other anti-HER2 therapies approved for gastric cancer after trastuzumab. Previous phase 3 trials failed to show the survival benefit of other anti-HER2 therapies such as lapatinib, ado-trastuzumab emtansine, and pertuzumab, although all of these agents have become standard treatments for HER2-positive breast cancer. Therefore, efficacy findings in our study with [fam-] trastuzumab deruxtecan for HER2-positive gastric or gastro-esophageal junction cancer are encouraging in terms of high response rate and durable response. The most important hurdle to developing anti-HER2 therapy for gastric cancer is intratumor heterogeneity of HER2 expression, which might result in lower efficacy of ado-trastuzumab emtansine in gastric cancer compared with breast cancer. In contrast to ado-trastuzumab emtansine, [fam-] trastuzumab deruxtecan showed activity in HER2-low expressed tumor models in a preclinical study based on better permeability of payload, which may result in high activity of [fam-] trastuzumab deruxtecan for gastric cancer.
How does [fam-] trastuzumab deruxtecan compare with existing later-line treatments for HER2-positive gastric or gastro-esophageal junction cancer, both in its safety and its efficacy?
Dr. Shitara: For patients with HER2-positive gastric cancer who have sufficient general status, chemotherapy/trastuzumab in the first line and paclitaxel/ramucirumab as second-line therapy are the most recommended treatments. Other treatment options in the third line or later include irinotecan, immune checkpoint inhibitors such as pembrolizumab or nivolumab, and trifluridine/tipiracil where available. Usually response rates of these agents ranged around 10%; thus, the observed response rate of [fam-] trastuzumab deruxtecan in our study for similar patient populations is higher, although indirect comparison should be cautiously interpreted.
[Fam-] trastuzumab deruxtecan was well tolerated in our study, with the most frequent toxicities being a mild degree of gastrointestinal toxicities or myelosuppression. Pulmonary toxicity is one of the concerns, although we did not observe fatal cases among patients with gastric cancer.
What other new treatments are on the horizon for heavily pretreated gastric and gastro-esophageal junction cancers?
Dr. Shitara: Other promising agents for HER2-positive gastric cancer include ZW25 as a novel bispecific antibody for HER2 or margetuximab as an Fc-modified antibody for HER2 in combination with pembrolizumab. These agents are showing promising activity in early clinical trials.
About Dr. Shitara
Kohei Shitara, MD, is Chief of the Department of Experimental Therapeutics and Gastrointestinal Oncology at the National Cancer Center Hospital East in Kashiwa, Japan. Dr. Shitara's primary research interests include the development of new cancer treatments, the optimization of chemotherapy regimens for gastrointestinal cancer, and translational research through the development of molecular targeted agents. Dr. Shitara has published more than 140 peer-reviewed articles in these fields.
For More Information
Clinicaltrials.gov (2019). Study of DS-8201a in subjects with advanced solid malignant tumors. NLM identifier: NCT02564900.
Shitara K, Iwata H, Takahashi S, et al (2019). Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive gastric cancer: a dose-expansion, phase 1 study. Lancet Oncol. [Epub ahead of print] DOI:10.1016/S1470-2045(19)30088-9
Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily represent the views of i3 Health.