Trastuzumab Deruxtecan Demonstrates Durable Tumor Responses in Previously Treated HER2-Mutant Metastatic Non-Small Cell Lung Cancer

On September 11, the primary analysis results of the Phase II clinical study DESTINY-Lung02 showed that Enhertu® (trastuzumab deruxtecan for injection) continued to demonstrate clinically meaningful and durable tumor responses in patients with previously treated HER2-mutated unresectable and/or metastatic non-squamous non-small cell lung cancer (NSCLC). The data will be presented in a mini-oral presentation (#MA13.10) at the International Association for the Study of Lung Cancer (IASLC) 2023 World Conference on Lung Cancer (#WCLC23), where progression-free survival (PFS) and overall survival (OS) will be reported for the first time. The findings will also be simultaneously published in the Journal of Clinical Oncology.

Enhertu® is a HER2-targeted antibody-drug conjugate (ADC) designed with proprietary technology, jointly developed and commercialized by Daiichi Sankyo and AstraZeneca.

According to the assessment results of the blinded independent central review (BICR), the confirmed objective response rates (ORR) for the 5.4mg/kg treatment group and the 6.4mg/kg treatment group were 49.0% (95% confidence interval [CI]: 39.0–59.1) and 56.0% (95% CI: 41.3–70.0), respectively. In the 5.4mg/kg treatment group, one case (1.0%) of complete response (CR) and 49 cases (48.0%) of partial response (PR) were observed, while in the 6.4mg/kg treatment group, two cases (4.0%) of complete response and 26 patients (52.0%) with partial response were observed. The disease control rate (DCR) in the 5.4mg/kg dose group reached 93.1% (86.4–97.2), and in the 6.4mg/kg dose group, it was 92.0% (80.8–97.8). The median duration of response (DoR) in the 5.4mg/kg treatment group was 16.8 months (95% CI: 6.4–not estimable [NE]), while the median DoR was not reached in the 6.4mg/kg treatment group (95% CI: 8.3–NE).

According to BICR assessment, the median PFS for the 5.4mg/kg group was 9.9 months (95% CI: 7.4–NE), and 15.4 months (95% CI: 8.3–NE) for the 6.4mg/kg group. The median OS for the 5.4mg/kg group was 19.5 months (95% CI: 13.6–NE), while it was not reached for the 6.4mg/kg treatment group (95% CI: 12.1–NE). As of the data cutoff date of December 23, 2022, the median follow-up time for the 5.4mg/kg treatment group (n=102) was 11.5 months, and 11.8 months for the 6.4mg/kg treatment group (n=50).

In DESTINY-Lung02, the safety profile of the Enhertu® 5.4mg/kg treatment group was better, and no new safety signals were identified at either dose. The incidence of Grade 3 treatment-emergent adverse events (TEAEs) was higher in the Enhertu® 6.4mg/kg group compared to the 5.4mg/kg group. Among all patients treated in the Enhertu® 5.4mg/kg or 6.4mg/kg groups, 38.6% and 58.0%, respectively, experienced Grade 3 or higher treatment-related TEAEs. The most common Grade 3 or higher treatment-related TEAEs were neutropenia (18.8% [5.4mg/kg]; 36.0% [6.4mg/kg]) and anemia (10.9% [5.4mg/kg]; 16.0% [6.4mg/kg]). A total of 27 cases of treatment-related interstitial lung disease (ILD) or non-infectious pneumonia were reported as determined by the independent adjudication committee (incidence rate: 12.9% in the 5.4mg/kg treatment group; 28.0% in the 6.4mg/kg treatment group). In the 5.4mg/kg treatment group, most events were lower grade (Grade 1 or 2 events: 10.9%, including four Grade 1 events and seven Grade 2 events), with one Grade 3 event, zero Grade 4 events, and one Grade 5 event reported. In the 6.4mg/kg treatment group, most events were also lower grade (Grade 1 or 2 events: 26%, including four Grade 1 events and nine Grade 2 events), with zero Grade 3 events, zero Grade 4 events, and one Grade 5 event reported.

In the DESTINY-Lung02 study, the median number of prior systemic treatments received by patients in each Enhertu® treatment group was two (5.4mg/kg group: range 1–12; 6.4mg/kg group: range 1–7). HER2 mutations were mainly located in the kinase domain (5.4mg/kg group: 97.1%; 6.4mg/kg group: 100%). Baseline central nervous system (CNS) metastases were present in 34.3% and 44.0% of patients in the 5.4mg/kg and 6.4mg/kg treatment groups, respectively. The median follow-up time was 11.5 months (1.1–20.6) in the 5.4mg/kg treatment group and 11.8 months (0.6–21.0) in the 6.4mg/kg treatment group.

About Enhertu®

Enhertu® (Trastuzumab Deruxtecan for Injection; known as fam-trastuzumab deruxtecan-nxki in the United States) is a HER2-targeted antibody-drug conjugate (ADC). Enhertu® utilizes Daiichi Sankyo's proprietary DXd-ADC technology and is the leading ADC product in Daiichi Sankyo’s oncology portfolio, as well as the most advanced project on AstraZeneca’s ADC scientific platform. Enhertu® consists of a HER2 monoclonal antibody linked to a topoisomerase I inhibitor payload (a derivative of exatecan) via a stable, cleavable tetrapeptide linker.

Based on the results obtained from the DESTINY-Breast03 study, Enhertu® (5.4mg/kg) has been approved in more than 50 countries and regions worldwide for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received (one or more) anti-HER2 treatment regimens during the metastatic stage, neoadjuvant therapy, or adjuvant therapy, and experienced disease recurrence during or within 6 months after completing treatment.

Based on the results obtained from the DESTINY-Breast04 study, Enhertu® (5.4mg/kg) has been approved in more than 40 countries/regions worldwide for the treatment of adult patients with unresectable or metastatic HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization [ISH]-) breast cancer who have received prior systemic therapy in the metastatic setting or developed disease recurrence during or within six months after completing adjuvant chemotherapy.

Based on the results obtained from the DESTINY-Lung02 study, Enhertu® (5.4mg/kg) has been approved in Israel and Japan, and has received accelerated approval in the United States for the treatment of adult patients with unresectable or metastatic NSCLC whose tumors have HER2 (ERBB2) activating mutations (detected by locally or regionally approved testing methods) and who have previously received one systemic therapy. Continued approval for this indication in the United States is contingent upon verification and description of clinical benefit in confirmatory validation studies.

Based on the results obtained from the DESTINY-Gastric01 and/or DESTINY-Gastric02 studies, Enhertu® (6.4mg/kg) has been approved in more than 30 countries/regions worldwide for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have previously received a trastuzumab-based treatment regimen.

Editor: Mu Mian

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