FDA Approves Trastuzumab Deruxtecan for HER2+ Gastric/GEJ Cancer

The FDA has approved fam-trastuzumab deruxtecan-nxki for the treatment of adult patients with HER2-positive locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen.

The FDA has approved fam-trastuzumab deruxtecan-nxki (DS-8201a; Enhertu) for the treatment of adult patients with HER2-positive locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab (Herceptin)-based regimen.1

“The impact of this approval is great for our patients to be able to offer our patients HER2-directed therapy in the third-line setting is really game-changing, and to the patients, to their families, it offers hope that you can target HER2 and something important about tumor biology that is driving their tumor. And I think a more long-term impact is on the research field to be able to validate and for the first time say, targeting HER2 in later lines of therapy is important and has promise,” Yelena Y. Janjigian, MD, chief of the Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center, told Targeted Oncology in an interview.

Trastuzumab deruxtecan is a HER2-targeted antibody-drug conjugate (ADC) with a humanized anti-HER2 antibody, a cleavable peptide-based linker, and a topoisomerase I inhibitor payload.

The approval is based on findings from the phase 2 DESTINY-Gastric01 trial (NCT03329690).

DESTINY-Gastric01 was an open-label randomized study that explored the use of trastuzumab deruxtecan versus chemotherapy in patients with HER2-positive advanced gastric cancer GEJ adenocarcinoma that had progressed on at least 2 prior therapies, including trastuzumab. Patients in the study (n = 188) were randomized 2:1 to the investigational or control arm.2

In the trastuzumab deruxtecan arm, patients received intravenous treatment at 6.4 mg/kg every 3 weeks and in the control arm patients received physician’s choice of irinotecan at 150 mg/m2 every 2 weeks or paclitaxel at 80 mg/m2 on days 1, 8, and 15 of every 28-day cycle. Treatment continued until disease progression, withdraw of consent, or unacceptable toxicity.

The primary end point was objective response rate (ORR) by RECIST criteria as assessed by independent central review. Secondary end points included overall survival (OS), duration of response (DOR), progression-free survival (PFS), disease control rate (DCR), and safety.

Baseline characteristics were balanced between the 2 arms. The median age of patients was 65 (range, 34-82) in the trastuzumab deruxtecan arm and 66 (range, 28-82) in the chemotherapy arm. The majority of patients across both arms were male (76%), from Japan (80%), had intestinal histologic subtype (68%), and had immunohistochemistry (IHC) 3+ HER2 expression (77%). The primary site of disease was in the stomach in 87% and GEJ in 13%.

A majority of patients had received 2 prior systemic therapies for advanced or metastatic disease (56%) and 17% had received 4 or more prior regimens. These treatments included trastuzumab for all patients, taxane for 86%, ramucirumab (Cyramza) for 72%, immune checkpoint inhibition for 33%, and irinotecan or another topoisomerase I inhibitor for 7%.

The median duration of treatment was 4.6 months (range, 0.7-22.3) in the trastuzumab deruxtecan arm and 2.8 months (range, 0.5-13.1) in the control arm.

The ORR was 51% (95% CI, 42%-61%) with trastuzumab deruxtecan versus 14% (95% CI, 6%-26%) with physician’s choice of chemotherapy (P <.001). In the investigational arm, responses consisted of complete responses in 9% and partial responses in 42%, another 35% had stable disease. The confirmed ORR was 43% versus 12% in the ADC and chemotherapy arms, respectively. The confirmed DCR was 86% with trastuzumab deruxtecan and 62% with chemotherapy.

Median DOR was 11.3 months (95% CI, 5.6-not estimable [NE]) with trastuzumab deruxtecan versus 3.9 months (95% CI, 3.0-4.9) with chemotherapy. The median time to response was 1.5 and 1.6 months in the trastuzumab deruxtecan and chemotherapy arms, respectively.

OS was significantly longer with the ADC with a median of 12.5 months (95% CI, 9.6-14.3) versus 8.4 months (95% CI, 6.9-10.7) with chemotherapy (HR, 0.59; 95% CI, 0.39-0.88; P = .01). At 6 months, the OS rate was 80% with trastuzumab deruxtecan versus 66% with chemotherapy; the 1-year rates were 52% and 29%, respectively.

Median PFS was 5.6 months (95% CI, 4.3-6.9) with trastuzumab deruxtecan and 3.5 months (95% CI, 2.0-4.3) with chemotherapy (HR, 0.47; 95% CI, 0.31-0.71). The 6-month PFS rate was 43% in the investigational arm and 21% in the control arm, and the rates at 1 year were 30% versus 0%, respectively.

Adverse events (AEs) were reported in all of patients in the ADC arm versus in 98% of the chemotherapy arm. The most common grade ≥3 AEs were decreased neutrophil count (51% with trastuzumab deruxtecan vs 24% with chemotherapy), anemia (38% vs 23%), decreased white cell count (21% vs 11%), and decreased appetite (17% vs 13%). Febrile neutropenia was reported in 6 patients in the investigational arm (all of grade 3) versus in 2 in the control arm (1 grade 3, 1 grade 4).

Drug-related interstitial lung disease or pneumonitis was reported in 10% of the trastuzumab deruxtecan group, most of these were grade 1 or 2 in severity, but 2 were of grade 3 and 1 of grade 4. The median time to first onset was 84.5 days (range, 36-638) and the majority of cases resolved or were in the process of resolving at data cutoff.

Treatment discontinuation due to AEs were reported in 15% of the trastuzumab deruxtecan arm and 6% of the chemotherapy arm. Treatment interruption was reported in 62% and 37% of the ADC and chemotherapy arms, respectively, and dose reduction was needed in 32% and 34%. One death due to pneumonia was reported in the trastuzumab deruxtecan arm that was considered to be treatment related.

In a prior phase 1 dose-escalation study (NCT02564900) of patients with advanced solid tumors, patients received either 5.4 mg/kg or 6.4 mg/kg of trastuzumab deruxtecan every 3 weeks. In patients with gastric cancer, the dose of 6.4 mg/kg was selected for dose expansion.3

Among the 44 patients with HER2-positive gastric or GEJ cancer from the phase 1 study, preliminary activity and a manageable safety profile was demonstrated. The ORR in these patients was 43.2% (95% CI, 28.3%-59.0%). Serious treatment-emergent AEs were observed in one-fourth of the patients and pneumonitis was reported in 4 patients, including 1 grade 3 case, but no drug-related deaths due to AEs were reported in this subgroup.


1. FDA approves fam-trastuzumab deruxtecan-nxki for HER2-positive gastric adenocarcinomas. FDA. January 15, 2021. Accessed January 15, 2021. https://bit.ly/3sxawRJ

2. Shitara K, Bang YJ, Iwasa S, et al; DESTINY-Gastric01 Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. N Engl J Med. 2020;382:2419-2430. doi:10.1056/NEJMoa2004413

3. Shitara K, Iwata H, Takahashi S, et al; DESTINY-Gastric01 Investigators. Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive gastric cancer: a dose-expansion, phase 1 study. Lancet Oncol. 2019;20(6):827-836. doi:10.1016/S1470-2045(19)30088-9

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