Interim results from the Phase II DESTINY-Lung02 trial of trastuzumab deruxtecan supporting the recent accelerated approval revealed

Globally, lung cancer is the second most common form of cancer. Non–small-cell lung cancer (NSCLC), accounts for ~85% of all lung cancer cases. Patients with metastatic NSCLC have a poor prognosis. Targeted therapies for molecular alterations such as EGFR, ALK, and others have had remarkable success in improving patients' prognosis and quality of life. As a result, targeted treatments are routinely recommended for all patients with NSCLC who have certain genetic abnormalities. HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors. HER2 is an important gene that, in addition to breast cancer, is present in a variety of solid cancers. HER2, for example, is involved in NSCLC. Apart from NSCLC and Breast Cancer, HER2 biomarkers are seen in gastric and colorectal cancers as well. Certain HER2 gene alterations (called HER2 mutations) have been identified in patients with non-squamous NSCLC as a distinct molecular target. 

DESTINY-Lung02 was a global Phase II trial evaluating the safety and efficacy of two doses (5.4mg/kg or 6.4mg/kg) of Enhertu (trastuzumab deruxtecan) in patients with HER2m metastatic NSCLC with disease recurrence or progression during or after at least one regimen of prior anticancer therapy that must have contained platinum-based chemotherapy. 

Based on the results from the DESTINY-Lung02 Phase II trial, in August 2022, AstraZeneca and Daiichi Sankyo’s Enhertu received accelerated approval by the US FDA for adult patients with previously treated HER2-mutant metastatic NSCLC, as detected by an FDA-approved test, and who have received prior systemic therapy. This is the first drug approved for HER2-mutant NSCLC.

The interim results for DESTINY-Lung02 demonstrated clinically meaningful activity with trastuzumab deruxtecan (T-DXd) 5.4 mg/kg and 6.4 mg/kg in patients with previously treated HER2m NSCLC in the prespecified early cohort (PEC), with a more favorable safety profile with T-DXd 5.4 mg/kg. In the PEC, the confirmed objective response rate (cORR) was 53.8% and 42.9%, respectively, in patients receiving T-DXd 5.4 or 6.4 mg/kg, as assessed by blinded independent central review (BICR). 

At the prespecified interim analysis, the 5.4mg/kg arm did not achieve a median duration of response (DoR), whereas the 6.4mg/kg arm achieved a DoR of 5.9 months (95% CI 2.8-NE). Because the median DoR in the 5.4mg/kg arm was not reached, a further 90-day follow-up response analysis was performed. Enhertu demonstrated a verified ORR of 57.7% (95% CI 43.2-71.3) and a median DoR of 8.7 months (95% CI 7.1-NE), with Complete Response observed in 1.9% of patients and Partial Response in 55.8%.

Grade 3 treatment-emergent adverse events (TEAEs) were higher with Enhertu 6.4mg/kg versus 5.4mg/kg, with Grade 3 or higher treatment-related TEAEs occurring in 31.7% and 58.0% of all patients receiving Enhertu 5.4mg/kg or 6.4mg/kg, respectively.

Apart from this, updated results from the DESTINY-Lung01 Phase II trial, which evaluated Enhertu in HER2m (cohort 2) or HER2-overexpressing (cohort 1 and cohort 1a) NSCLC, were also presented at ESMO, demonstrating that Enhertu continues to demonstrate consistent efficacy, safety, and survival with longer follow-up.

For patients and the oncology community, the approval of Enhertu in NSCLC is a significant accomplishment. The approval of the first HER2-directed treatment option has established HER2 as an actionable target in lung cancer. The outcomes of DESTINY-Lung02 are in line with the results previously seen with Enhertu in NSCLC. Furthermore, the clinically relevant activity, together with the excellent safety profile shown in the DESTINY-Lung02 study, aids in determining the appropriate dosage of Enhertu, which is 5.4mg/kg in previously treated HER2-mutant NSCLC. In conclusion, the efficacy demonstrated in this interim analysis of the DESTINY-Lung02 trial reinforces the potential for this therapy to be established as a treatment option for HER2 Lung Cancer patients. 

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