Trastuzumab deruxtecan (fam-trastuzumab deruxtecan-nxki; DS-1062; Enhertu®; Daiichi Sankyo and AstraZeneca), has been granted Priority Review by the U.S. Food and Drug Administration for the treatment of patients with HER2 positive metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, a rare type of cancer of the esophagus.
Gastric or stomach cancer is the fifth most common cancer worldwide and the third leading cause of cancer mortality with a five-year survival rate of 5% for metastatic disease.
In the U.S., it is estimated that 27,600 new cases of gastric cancer will be diagnosed in 2020 and more than 11,000 people will die from the disease.  Globally, there were approximately one million new cases reported in 2018 and 783,000 deaths 
Over the last few decades, the incidence of gastroesophageal junction adenocarcinomas has been rising, creating a need for the development of novel, effective therapeutic strategies.
Especially the treatment of locally advanced GEJ tumors presents a unique challenge. One reason is that these tumors have generally been diagnosed as either esophageal or gastric cancers. As a result, optimal preoperative management remains uncertain. Both neoadjuvant chemoradiation and perioperative chemotherapy have been widely adopted in standard practice 
Approximately 15 to 20% of advanced gastric and gastroesophageal junction cancers, which are especially prevalent in East Asia, is human epidermal growth factor receptor 2 (HER2) positive.
HER2 is a tyrosine kinase receptor growthpromoting protein expressed on the surface of many types of tumors including breast, gastric, lung and colorectal cancers. Gastric cancer is usually diagnosed in the advanced stage, but even when diagnosed in earlier stages of the disease the survival rate remains modest.
Recommended first-line treatment for HER2 positive metastatic gastric cancer is combination chemotherapy plus trastuzumab, an anti-HER2 medicine, which has been shown to improve survival outcomes when added to chemotherapy. For metastatic gastric cancer that progresses on first-line treatment, there are no other approved HER2 targeting medicines.
For patients with metastatic gastric cancer who progress on initial treatment with an anti-HER2 regimen, there are no other approved HER2 directed medicines.
The antibody-drug conjugate or ADC, which includes a HER2 monoclonal antibody attached to a topoisomerase I inhibitor payload by a tetrapeptide-based linker, is the only HER2 directed drug to demonstrate significant improvement in overall survival compared to chemotherapy for previously treated patients iwith HER2+ metastatic gastric cancer.
The developers have also received acceptance for the supplemental Biologics License Application (sBLA) for trastuzumab deruxtecan.
The PDUFA date* has been set for the first quarter of the 2021 calendar year.
The FDA grants Priority Review to applications for medicines that offer significant advances over available options by demonstrating safety or efficacy improvements, preventing serious conditions, or enhancing patient compliance.
The sBLA is based on results from the randomized phase II DESTINY-Gastric01 trial, which demonstrated a statistically significant and clinically meaningful improvement in objective response rate (ORR), the primary endpoint, and overall survival (OS), a key secondary endpoint, for patients treated with trastuzumab deruxtecan versus chemotherapy (paclitaxel or irinotecan monotherapy).
The results from the trial were presented during the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program and simultaneously published online in The New England Journal of Medicine.
Breakthrough Therapy Designation
Trastuzumab deruxtecan received Breakthrough Therapy Designation (BTD) from the FDA in May 2020 for patients with unresectable or metastatic HER2 positive gastric or GEJ adenocarcinoma who have received two or more prior regimens including trastuzumab – one of three BTDs that have been granted to trastuzumab deruxtecan in the U.S.– and Orphan Drug Designation (ODD) for patients with gastric cancer, including GEJ adenocarcinoma.
The safety and tolerability profiles of trastuzumab deruxtecan in DESTINY-Gastric01 were consistent with that observed in the gastric cancer cohort of the phase 1 trial and previously reported trastuzumab deruxtecan trials in other tumors.
DESTINY-Gastric01 is an open-label, multi-center, randomized, pivotal phase II trial evaluating the safety and efficacy of trastuzumab deruxtecan versus investigator’s choice of chemotherapy in a primary cohort of 188 patients from Japan and South Korea with HER2 positive (defined as IHC3+ or IHC2+/ISH+), advanced gastric cancer or GEJ adenocarcinoma who had progressed on two or more prior treatment regimens including fluoropyrimidine (5-FU), platinum chemotherapy and trastuzumab. Patients were randomized 2:1 to receive trastuzumab deruxtecan or investigator’s choice of chemotherapy (paclitaxel or irinotecan monotherapy).
Patients were treated with trastuzumab deruxtecan 6.4 mg/kg once every three weeks or chemotherapy.
The primary endpoint of the trial is ORR, as assessed by independent central review. OS, a key secondary endpoint, was to be evaluated hierarchically at a prespecified interim analysis if the primary endpoint was statistically significant. Additional efficacy endpoints include progression-free survival, duration of response, disease control rate and confirmed ORR assessed in those responses confirmed by a follow-up scan of at least four weeks after initial independent central review.
Two additional phase II trials DESTINY-Gastric02 and DESTINY-Gastric03 are underway further evaluating the use of ENHERTU in patients with HER2 positive metastatic gastric cancer.
The most common grade 3 or higher treatment-emergent adverse events were decreased neutrophil count, anemia, decreased white blood cell count and decreased appetite. There were 12 cases (9.6%) of confirmed treatmentrelated interstitial lung disease (ILD) or pneumonitis in 125 patients treated with trastuzumab deruxtecan as determined by an independent adjudication committee.
The majority of cases were grade 1 or 2 with two grade 3, one grade 4 and no grade 5 (no ILD-related deaths).
“The results of the DESTINY-Gastric01 trial are unprecedented as they represent the first time a HER2 directed medicine has demonstrated an improvement in survival following chemotherapy and HER2 treatment in the metastatic setting,” noted Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo.
“Building on the recent Breakthrough Therapy Designation, the filing of the application and Priority Review by the FDA for this potential new indication for trastuzumab deruxtecan reflects the importance of the data and the significant unmet need for patients with previously treated HER2 positive metastatic gastric cancer.”
“Once patients with HER2 positive metastatic gastric cancer progress following initial treatment with an anti-HER2 regimen, there are no approved HER2 directed medicines,” said José Baselga, MD, PhD, Executive Vice President, Oncology R&D, AstraZeneca.
“The prognosis for these patients is poor as available treatment options offer only limited clinical benefit. This milestone brings us one step closer to delivering this potentially practice-changing medicine to patients with gastric cancer in the U.S.,” Baselga concluded.
Trastuzumab deruxtecan (5.4 mg/kg) is approved in the U.S. and Japan for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who have received two or more prior anti-HER2 based regimens in the metastatic setting based on the DESTINY-Breast01 trial, and is under accelerated assessment in the European Union for HER2 positive metastatic breast cancer.
Recently, in September 2020, trastuzumab deruxtecan (6.4. mg/kg) was approved in Japan for patients with HER2 positive unresectable advanced or recurrent gastric cancer that has progressed after chemotherapy.
Trastuzumab deruxtecan is an investigational agent for various indications and has not been approved in the European Union, or countries outside of Japan and the U.S. In July 2020, the European Medicines Agency’s Committee for Medicinal Products for Human Use granted trastuzumab deruxtecan accelerated assessment for the treatment of adults with unresectable or metastatic HER2 positive breast cancer who have received two or more prior anti-HER2 based regimens.
* Prescription Drug User Fee Act
DS-8201a in Human Epidermal Growth Factor Receptor 2 (HER2)-Expressing Gastric Cancer [DESTINY-Gastric01] – NCT03329690
DS-8201a in HER2-positive Gastric Cancer That Cannot Be Surgically Removed or Has Spread (DESTINY-Gastric02) – NCT04014075
Ph1b/2 Study of the Safety and Efficacy of T-DXd Combinations in Advanced HER2+ Gastric Cancer (DESTINY-Gastric03) (DG-03) – NCT04379596
Highlights of Prescribing Information
Trastuzumab deruxtecan (fam-trastuzumab deruxtecan-nxki;Enhertu®; Daiichi Sankyo/AstraZeneca) [Prescribing information]
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