FDA Grants Priority Review to Trastuzumab Deruxtecan for HER2+ Metastatic Gastric, GEJ Cancer


The FDA granted priority review to the supplemental biologics license application for trastuzumab deruxtecan (Enhertu) for the treatment of patients with HER2-positive metastatic gastric or gastroesophageal junction adenocarcinoma.

The FDA has granted priority review to the supplemental biologics license application (sBLA) for trastuzumab deruxtecan (Enhertu) for the treatment of patients with HER2-positive metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, according to AstraZeneca and Daiichi Sankyo Company, the co-developers of the agent.1

The FDA has set a prescription drug user fee act (PDUFA) date for their regulatory decision during the first quarter of 2021.

The sBLA was accepted by the FDA based on results from the open-label, multicenter, randomized, controlled, phase 2 DESTINY-Gastric01 trial, which demonstrated a statistically significant and clinically meaningful improvement in the primary end point of objective response rate (ORR), as well as overall survival (OS), a secondary end point, for patients treated with trastuzumab deruxtecan versus chemotherapy with paclitaxel or irinotecan monotherapy.

The results from the trial were presented during the American Society of Clinical Oncology (ASCO) 2020 Virtual Scientific Program and simultaneously published in The New England Journal of Medicine.2

“Once patients with HER2-positive metastatic gastric cancer progress following initial treatment with an anti-HER2 regimen, there are no approved HER2-directed medicines. The prognosis for these patients is poor, as available treatment options offer only limited clinical benefit,” José Baselga, MD, PhD, executive vice president of Oncology R&D, said in a press release. “This milestone brings us one step closer to delivering a potentially practice-changing medicine to patients with gastric cancer in the US.”

The trial consisted of a primary cohort of 187 patients from Japan and South Korea with HER2-positive, advanced gastric or GEJ adenocarcinoma who had progressed on 2 or more prior treatment regimens including fluoropyrimidine and platinum chemotherapy and trastuzumab. Patients enrolled in the trial were randomized 2:1 to receive either 6.4 mg/kg of trastuzumab deruxtecan once every 3 weeks or investigator’s choice of chemotherapy with paclitaxel or irinotecan monotherapy.

The primary end point of the trial is ORR, as assessed by independent central review. OS was to be assessed hierarchically at a prespecified interim analysis if the primary end point was found to be statistically significant.

Additional secondary end points include progression-free survival, duration of response, disease control rate, and confirmed ORR assessed in responses confirmed by a follow-up scan of at least 4 weeks after the initial independent central review.

Of the total cohort of patients, 125 received trastuzumab deruxtecan and 62 chemotherapy, including 55 who received irinotecan and 7 paclitaxel. An objective response was reported in 51% of the patients in the trastuzumab deruxtecan group versus 14% of those in the physician’s choice group (P < .001). Moreover, OS was longer with trastuzumab deruxtecan than with chemotherapy (median, 12.5 vs. 8.4 months; HR, 0.59; 95% CI, 0.39-0.88; P = .01, which crossed the prespecified O’Brien–Fleming boundary [0.0202 on the basis of number of deaths]).

The safety and tolerability profiles of trastuzumab deruxtecan in DESTINY-Gastric01 were found to be consistent with that observed in the gastric cancer cohort of the phase I trial and previously reported trastuzumab deruxtecan trials in other tumors. The most common grade 3 or higher treatment-emergent adverse events in the trastuzumab deruxtecan and physician’s choice groups were decreased neutrophil count (51% vs 24%, respectively), anemia (38% vs 23%), and decreased white blood cell count (21% vs 11%).

Further, there were 12 (9.6%) cases of confirmed treatment-related interstitial lung disease (ILD) or pneumonitis in 125 patients treated with the agent as determined by an independent review committee. However, the majority of cases were grade 1 or 2, with 2 grade 3, 1 grade 4, and no grade 5. One drug-related death due to pneumonia was noted in the trastuzumab deruxtecan group; no drug-related deaths occurred in the physician’s choice group.

“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,” Antoine Yver, MD, executive vice president and global head of Oncology Research and Development at Daiichi Sankyo, said in the release. “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.”

Of note, trastuzumab deruxtecan received breakthrough therapy designation from the FDA in May 2020 for patients with unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma who have received 2 or more prior regimens including trastuzumab. In addition, the agent was granted orphan drug designation for patients with gastric cancer, including GEJ adenocarcinoma.

Importantly though, trastuzumab deruxtecan has not been approved in the US for gastric or GEJ adenocarcinoma.


1. Enhertu granted Priority Review in the US for the treatment of HER2-positive metastatic gastric cancer [news release]. Published October 28, 2020. Accessed October 28, 2020. https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2020/enhertu-us-priority-review-in-gastric-cancer.html

2. Shitara K, Bang Y, Iwasa S, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. The New England Journal of Medicine. doi: 10.1056/NEJMoa2004413

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