Fam-trastuzumab deruxtecan-nxki (Enhertu®, Daiichi Sankyo) has recently been FDA approved for the treatment of adult patients with locally advanced or metastatic human epidermal growth factor receptor 2 (HER2)-positive gastric or gastroesophageal adenocarcinoma previously treated with a trastuzumab-based regimen. In this interview with i3 Health, Kohei Shitara, MD, Chief of the Department of Gastrointestinal Oncology at the National Cancer Center Hospital East in Kashiwa, Japan, and lead investigator of the phase 3 DESTINY-Gastric01 trial, on which the approval was based, shares his insights on this approval, on the challenges of treating this patient population, and on the future of treatment for patients with gastric or gastroesophageal adenocarcinoma.
What are the most challenging aspects of treating patients with HER2-positive gastric adenocarcinoma?
Kohei Shitara, MD: Approximately 10% to 15% of patients with gastric cancer have overexpression or gene amplification of HER2. Chemotherapy plus trastuzumab is the standard treatment for HER2-positive gastric cancer. However, following several randomized studies with other HER2-targeted agents, including lapatinib, ado-trastuzumab (T-DM1), and pertuzumab, this treatment failed to show survival benefit. Therefore, there has been an unmet need for patients with HER2-positive gastric cancer, especially after trastuzumab.
Can you comment on the significance of the FDA approval of fam-trastuzumab deruxtecan-nxki for HER2-positive gastric adenocarcinoma?
Dr. Shitara: Trastuzumab deruxtecan (T-DXd) is a new HER2-targeted antibody drug conjugate with a DNA topoisomerase inhibitor payload. The DESTINY-Gastric 01 study showed a significantly higher objective response rate with T-DXd compared with standard chemotherapy with irinotecan or paclitaxel. Overall survival was also significantly longer with T-DXd by 4.1 months, which is clinically meaningful in this treatment setting. Now the FDA approved T-DXd for trastuzumab-treated gastric cancer based on the DESTINY-Gastric 01 study. This is great news for us and our patients. I believe T-DXd has become the most preferred third-line treatment option for HER2-positive gastric cancer after trastuzumab.
What are the unmet needs that still exist in this patient population?Dr. Shitara: Trastuzumab deruxtecan warrants further evaluation in earlier treatment settings, as monotherapy or in combination with other agents. In my experience, T-DXd didn't always result in dramatic anti-tumor response, and more than half of the patients eventually showed disease progression. Therefore, predictive factors or resistance mechanisms to T-DXd should be further explored. Also, other available agents such as irinotecan, taxane agents, trifluridine/tipiracil (FTP/TPI), ramucirumab, and immune checkpoint inhibitors have limited efficacies. So we need further treatment options for gastric cancer.
How do you see the treatment landscape evolving in the coming years?
Dr. Shitara: I hope further precision therapy can be achieved for gastric cancer in the coming years. HER2 is one of the most important targets for gastric cancer, for which we have trastuzumab and T-DXd. Other promising treatments are also under investigation, which include combinations of anti-HER2 and immunotherapy treatments, a newer bispecific monoclonal antibody (ZW25), an Fc-modified monoclonal antibody (margetuximab), and a newer tyrosine kinase inhibitor (tucatinib). Also, recent randomized phase 2 studies showed promising activity of claudin 18.2 monoclonal antibody (zolbetuximab) and an FGFR2b monoclonal antibody (bemarituzumab), which are also candidates for one of the potential components of precision therapy for gastric cancer.
Do you have any advice for community oncologists who treat this patient population?
Dr. Shitara: Interstitial lung disease (ILD) or pneumonitis are notable toxicities of T-DXd, occurring in around 10% of patients. Early diagnosis of these toxicities and adequate management is essential. In clinical trials, computed tomography (CT) scans have been performed every six weeks, which are useful to detect ILD/pneumonitis at an early phase. Education for patients regarding possible symptoms, such as cough, fever and dyspnea, is also important. Of note, excluding other etiology, such as infection, is particularly important, especially during this era of COVID-19. Early administration of corticosteroid is also recommended for pneumonitis and ILD. Adequate anti-emetics are also needed for prevention of nausea and other gastrointestinal toxicities. With this management, I believe many patients can achieve maximum benefit with T-DXd.
About Dr. Shitara
Kohei Shitara, MD, is the Chief of the Department of Gastrointestinal Oncology at the National Cancer Center Hospital East in Kashiwa, Japan. Dr. Shitara is an active member of American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), the Japanese Society of Internal Medicine, the Japanese Society of Medical Oncology, the Japanese Society of Clinical Onclogy, and the Japanese Gastric Cancer Association. His main research interests include the development of new anti-cancer agents, optimal chemotherapy regimen for gastrointestinal cancer, and translational research. He has published extensively on these topics.
For More Information
United States Food & Drug Administration (2020). FDA approves fam-trastuzumab deruxtecan-nxki for HER2-positive gastric adenocarcinomas. Available at: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-fam-trastuzumab-deruxtecan-nxki-her2-positive-gastric-adenocarcinomas
Transcript edited for clarity. Any views expressed above the speaker's own and do not necessarily reflect those of i3 Health.