Based on findings from the DESTINY-Gastric01 and -02 trials, the European Commission has approved fam-trastuzumab deruxtecan-nxki monotherapy for patients with advanced HER2-positive gastric or gastroesophageal junction adenocarcinoma.
The European Commission has approved monotherapy treatment with fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for patients with advanced HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab (Herceptin)-based regimen.1
Approval for T-DXd in Europes come over a year after FDA approval was granted to trastuzumab deruxtecan for the indication in the United States. The EU approval follows the positive opinion of the Committee for Medicinal Products for Human Use issued in November 2022 and basis of the approval comes from results of the phase 2 DESTINY-Gastric02 (NCT04014075) and DESTINY-Gastric01 (NCT03329690) trials.
In the DESTINY-Gastric02 study, European and North American patients treated with 6.4 mg/kg of T-DXd had a confirmed objective response rate (ORR) of 41.8% (95% CI, 30.8%-53.4%) as assessed by independent central review (ICR). Then, the median duration of response (DOR) was 8.1 months (95% CI, 5.9-not evaluable).
For patients treated in the DESTINY-Gastric01 trial, an ORR of 40.5% was observed with the antibody drug conjugate (ADC) vs 11.3% with irinotecan or paclitaxel in Japanese and South Korean patients as assessed by ICR. Further, the median DOR was 11.3 months with trastuzumab deruxtecan and 3.9 months with chemotherapy, the median overall survival (OS) was 12.5 months (95% CI, 9.6-14.3) vs 8.4 months (95% CI, 6.9-10.7) with T-DXd and chemotherapy, respectively (HR, 0.59; 95% CI, 0.39-0.88; P =.0097).
This approval of T-DXd marks the first HER2-directed therapy to be approved in the European Union for patients with metastatic gastric cancer with disease progression following first-line therapy with a trastuzumab-based regimen.
“Today’s news is a welcome advance for patients with HER2 positive advanced gastric cancer,” said Eric Van Cutsem, MD, PhD, head of the Department of Oncology at the University of Leuven in Belgium, in the press release. “Patients with this disease face poor outcomes following progression on initial treatment with a HER2-directed medicine as many do not respond to further treatment, and even those that do respond often do not have durable responses. Data from the DESTINY-Gastric02 and DESTINY-Gastric01 trials support Enhertu becoming a new standard of care for patients in this setting.”
DESTINY-Gastric02 is an open-label, single-arm phase 2 trial which evaluated T-DXd administered at a dose of 6.4 mg/kg in patients with HER2-positive metastatic and/or unresectable gastric or GEJ adenocarcinoma. Patients must have had disease progression on or after receiving a trastuzumab-containing regimen.
Investigators evaluated the primary end point of confirmed ORR based on ICR along with the secondary end points of progression-free survival (PFS), OS, DOR, and safety.
Updated findings from the phase 2 DESTINY-Gastric02 study (NCT04014075) were presented at the 2022 ESMO Congress and confirmed that treatment with the ADC had a clinical benefit and tolerable safety profile in this patient population.
Then in the randomized, open-label, phase 2 DESTINY-Gastric01 trial, 187 patients with HER2-positive advanced gastric cancer or GEJ adenocarcinoma with disease progression following at least 2 prior treatment regimens including fluoropyrimidine (5-FU), platinum chemotherapy, and trastuzumab were enrolled. Patients also must have had HER2-positive disease, defined as immunohistochemistry (IHC) 3+ or IHC 2+/in-situ hybridization positive. Those enrolled were treated with trastuzumab deruxtecan at 6.4 mg/kg.
The DESTINY-Gastric01 trial evaluated the primary end point of ORR and secondary end points of OS, PFS, DOR, disease control rate, time to treatment failure, pharmacokinetics, and safety.
Within both the DESTINY-Gastric01 and -02 trials, treatment with trastuzumab deruxtecan elicited similar safety profiles compared with those previously reported in trials. Further, no new signals were identified.
“Enhertu is the first [ADC] to be approved in Europe for advanced gastric cancer, representing a major advance in treating this difficult-to-treat cancer,” said Ken Keller, global head of Oncology Business and president and chief executive officer of Daiichi Sankyo, Inc, in the press release. “With this approval, we can now offer patients with previously treated HER2-positive gastric cancer a treatment with clinically meaningful efficacy.”