T-DXd Wins Conditional Approval in China for Pretreated HER2+ Gastric/GEJ Cancer

Fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) has been granted conditional approval by China’s National Medical Products Administration (NMPA) for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma following at least 2 prior lines of therapy.^1,2

The regulatory decision was supported by findings from the phase 2 DESTINY-Gastric06 trial (NCT04989816), which evaluated the safety and efficacy of T-DXd in patients with HER2-expressing advanced gastric or GEJ adenocarcinoma who received at least 2 prior regimens, including a fluoropyrimidine agent and a platinum agent. Patients who received T-DXd at a dose of 6.4 mg/kg (n = 95) experienced a confirmed objective response rate (ORR) of 28.8% (95% CI, 18.8%-40.6%) per independent central review (ICR) assessment, including 1 complete response. The median progression-free survival (PFS) was 5.7 months (95% CI, 4.0-6.8).^2,3

Data from the phase 2 DESTINY-Gastric01 study (NCT03329690) also supported the approval. Findings from DESTINY-Gastric01 demonstrated that patients from Japan and South Korea with HER2-positive metastatic gastric cancer who received T-DXd achieved an ORR of 40.5% vs 11.3% among those treated with chemotherapy (P < .0001). The median overall survival (OS) was 12.5 months compared with 8.4 months, respectively (HR, 0.59; 95% CI, 0.39-0.88; P = .0097).¹

“HER2-positive metastatic gastric cancer can be particularly aggressive and difficult to treat,” Lin Shen, MD, director of the Department of Gastrointestinal Oncology at Peking University Cancer Hospital in China, stated in a news release.¹ “Patients often face poor outcomes following disease progression on first-line treatment and subsequent chemotherapy. With the approval of T-DXd, patients in China with HER2-positive metastatic gastric cancer will now have an important anti-HER2 treatment option that has demonstrated clinically meaningful efficacy following progression on previous therapies.”

DESTINY-Gastric06 was an open-label, single-arm, multicenter study in China that enrolled adult patients with pathologically documented gastric or GEJ adenocarcinoma who experienced disease progression after at least 2 prior lines of therapy. Patients needed to have an ECOG performance status of 1 or less and a minimum left ventricular ejection fraction of 50%.³ 

All enrolled patients received T-DXd at 6.4mg/kg once every 3 weeks. The primary end point was confirmed ORR by RECIST 1.1 criteria per ICR assessment; secondary end points included PFS, disease control rate (DCR), duration of response (DOR), and OS.³

DESTINY-Gastric01 was a multicenter, open-label trial that enrolled patients with HER2-expressing advanced gastric or GEJ adenocarcinoma who experienced disease progression following treatment with at least 2 prior regimens, including a fluoropyrimidine agent, platinum agent, and trastuzumab (Herceptin).⁴

Patients (n = 188) were randomly assigned 2:1 to receive T-DXd in the investigational arm or physician’s choice of irinotecan or paclitaxel monotherapy in the comparator arm. The coprimary end points were ORR and best overall response, both per ICR assessment; secondary end points included OS, PFS, DOR, DCR, and pharmacokinetics.

Additional data from DESTINY-Gastric06 showed that the safety profile of T-DXd was consistent with previous findings for the agent reported in patients with gastric cancer with no new safety signals. Results from a pooled safety analysis revealed that patients with varying tumor types who received T-DXd at a dose of 6.4 mg/kg experienced grade 3 or 4 treatment-related adverse effects (AEs) including neutropenia (27.9%), anemia (23.1%), leukopenia (12.9%), thrombocytopenia (9.0%), fatigue (8.2%), decreased appetite (8.1%), lymphopenia (7.4%), nausea (5.8%), increased transaminases (4.7%), hypokalemia (4.2%), pneumonia (2.9%), febrile neutropenia (2.9%), vomiting (2.4%), diarrhea (2.1%), decreased weight (2.1%), increased blood alkaline phosphatase (1.8%), interstitial lung disease (ILD; 1.6%), dyspnea (1.3%), and decreased ejection fraction (1.1%). Grade 5 AEs were reported at a rate of 2.6%, including ILD at a rate of 1.9%. Patients were forced to discontinue treatment due to an AE at a rate of 17.0%, with the most frequent AE associated with permanent discontinuation being ILD (12.4%).²

“This milestone marks the third approval in China for T-DXd in less than 2 years, following approvals for HER2-positive metastatic breast cancer and HER2-low metastatic breast cancer,” Kiminori Nagao, head of the Asia, South & Central America Business Unit at Daiichi Sankyo, added in the news release.¹ “Our DESTINY clinical trial program continues to reinforce T-DXd as a practice-changing treatment option for patients with HER2-expressing cancers and this latest approval in China further illustrates the global impact of this innovative antibody-drug conjugate.”

References

1. Enhertu approved in China for patients with previously treated HER2-positive advanced or metastatic gastric cancer. News release. AstraZeneca. August 13, 2024. Accessed August 13, 2024. https://www.astrazeneca.com/media-centre/press-releases/2024/enhertu-approved-in-china-for-patients-with-previously-treated-her2-positive-advanced-or-metastatic-gastric-cancer.html
2. Enhertu approved in China for patients with previously treated HER2 positive advanced or metastatic gastric cancer. News release. Daiichi Sankyo. August 13, 2024. Accessed August 13, 2024. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202408/20240813_E.pdf
3. Study of T-DXd monotherapy in patients with HER2-expressing locally advanced or metastatic gastric or GEJ adenocarcinoma who have received 2 or more prior regimens (DG-06). ClinicalTrials.gov. Updated May 7, 2024. Accessed August 13, 2024. https://clinicaltrials.gov/study/NCT04989816
4. DS-8201a in human epidermal growth factor receptor 2 (HER2)-expressing gastric cancer [DESTINY-Gastric01]. ClinicalTrials.gov. Updated March 18, 2022. https://clinicaltrials.gov/study/NCT03329690