FDA Approves Fam-Trastuzumab Deruxtecan-nxki for HER2+ Gastric or GEJ Adenocarcinoma

The approval was based on results from the phase 2 DESTINY-Gastric01 trial which evaluated patients with HER2-positive locally advanced or metastatic gastric or GEJ adenocarcinoma who had progressed on at least 2 prior regimens.

The FDA has approved fam-trastuzumab deruxtecan-nxki (Enhertu) for adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen.1

The recommended dose of fam-trastuzumab deruxtecan-nxki for gastric cancer is 6.4 mg/kg administered as an intravenous infusion once every 3 weeks during a 21-day cycle, until disease progression or unacceptable toxicity.

“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 previously issued announcing the FDA’s priority review issuance to the drug.2 In the release, he added that fam-trastuzumab deruxtecan-nxki treatment could be practice-changing for those with gastric cancer in the US.

The approval was based on results from the open-label, multicenter, randomized, controlled, phase 2 DESTINY-Gastric01 trial (NCT03329690) – designed to evaluate the agent in patients with HER2-positive locally advanced or metastatic gastric or GEJ adenocarcinoma who had progressed on at least 2 prior regimens, including trastuzumab, a fluoropyrimidine-, or a platinum-containing chemotherapy.

The investigators randomized 188 patients 2:1 to receive either fam-trastuzumab deruxtecan-nxki at a dose of 6.4 mg/kg intravenously every 3 weeks, or physician’s choice of either irinotecan or paclitaxel monotherapy.

The study’s dual primary end points were overall survival (OS) and objective response rate (ORR) assessed by independent central review (RECIST 1.1) in the intent-to-treat population. Key secondary end points were progression-free survival (PFS) and duration of response (DOR).

OS was 12.5 months (95% CI, 9.6-14.3) in the fam-trastuzumab deruxtecan-nxki arm versus 8.4 months (95% CI, 6.9-10.7) in the irinotecan or paclitaxel arm (HR, 0.59; 95% CI, 0.39-0.88; P = .0097). Confirmed ORR was 40.5% (95% CI, 31.8-49.6) in the fam-trastuzumab deruxtecan-nxki cohort compared with 11.3% (95% CI, 4.7-21.9) for patients receiving irinotecan or paclitaxel.

Moreover, median PFS was 5.6 months (95% CI, 4.3-6.9) in the fam-trastuzumab deruxtecan-nxki arm compared to 3.5 months (95% CI, 2.0-4.3) in the irinotecan or paclitaxel arm. Median DOR was 11.3 months (95% CI, 5.6-not reached [NR]) versus 3.9 months (95% CI, 3.0-4.9), respectively.

Regarding safety, the most common adverse events observed in patients receiving fam-trastuzumab deruxtecan-nxki, including laboratory abnormalities, were anemia, leukopenia, neutropenia, lymphocytopenia, thrombocytopenia, nausea, decreased appetite, increased aspartate aminotransferase, fatigue, increased blood alkaline phosphatase, increased alanine aminotransferase, diarrhea, hypokalemia, vomiting, constipation, increased blood bilirubin, pyrexia, and alopecia.

Notably, a boxed warning is also included on the prescribing information advising health professionals of the risks of interstitial lung disease and embryo-fetal toxicity.

Results from the DESTINY-Gastric01 trial were also presented during the American Society of Clinical Oncology (ASCO) 2020 Virtual Scientific Program and simultaneously published in The New England Journal of Medicine.3

The results 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.

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 (< .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; = .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.


1. FDA. FDA approves fam-trastuzumab deruxtecan-nxki for HER2-positive gastric adenocarcinomas. FDA website. Published January 15, 2021. Accessed January 15, 2021. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-fam-trastuzumab-deruxtecan-nxki-her2-positive-gastric-adenocarcinomas

2. Enhertu granted Priority Review in the US for the treatment of HER2-positive metastatic gastric cancer [news release]. Published October 28, 2020. Accessed January 15, 2021. https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2020/enhertu-us-priority-review-in-gastric-cancer.html

3. Shitara K, Bang Y, Iwasa S, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. N Engl J Med. 2020; 382:2419-2430. doi:10.1056/NEJMoa2004413

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