Phase 2 Trial Results Suggest Enhertu May Fill Treatment Gap for HER2-Overexpressing Non-Small Cell Lung Cancer

Results from a new phase 2 trial suggest that Enhertu (trastuzumab deruxtecan), a HER2-directed antibody-drug conjugate, produces antitumor activity in a certain type of non-small-cell lung cancer (NSCLC). The results of the trial were published online last month in The Lancet Oncology.

NSCLC represents the most common type of lung cancer. Prognosis and treatment options for NSCLC are influenced by several factors including the stage of the cancer (size and spread) and whether the cancer has mutations or abnormalities in certain genes. In recent years, new medications have been developed that target the mutated receptors, proteins, or signals in the cell that result from these gene mutations.

Mutations of the human epidermal growth factor receptor 2 (HER2) represent a notable alteration in NSCLC. Cancer cells that have too many HER2 receptors on their surface (overexpression) may grow more quickly. HER2-overexpressing lung cancer is rare, occurring in approximately 8–23% of NSCLC patients. Current treatment options for such patients are limited, and no targeted therapies have been specifically approved for HER2-overexpressing NSLC. Prognosis is generally poor, especially for those with advanced, metastatic disease.

Given the lack of effective treatments for metastatic, HER2-overexpressing NSCLC, a team of researchers led by Egbert Smit, M.D. sought to assess the potential benefit of Enhertu in this cancer type. The trial recruited adults with metastatic, HER2-overexpressing NSCLC who had relapsed or were refractory to standard treatments. The investigators assigned the participants to cohorts sequentially; participants first received a dose of 6.4 mg/kg (Cohort 1) then 5.4 mg/kg (Cohort 1A) once every 3 weeks. An independent board reviewed each participant’s response to the medication to measure antitumor activity, including assessments of disease and tumor control, duration of response, and progression-free survival. Additionally, side effects and safety data were collected.

At both doses, Enhertu demonstrated antitumor activity against HER2-overexpressing metastatic NSCLC. Of the participants in Cohort 1, 13 of 49 (26.5%) responded to treatment and 14 of 41 (34.1%) participants in Cohort 1A responded to treatment. Notably, while all 13 responses in Cohort 1 were deemed partial by the independent review board, 2 of the 14 responders in Cohort 1A experienced complete responses, with the other 12 having partial responses.

From a safety perspective, the observed side effects were similar to those identified during studies of Enhertu for its existing indications. The most common side effects were neutropenia, pneumonia, and fatigue. As expected, the side effects were dose-dependent, with higher doses associated with more frequent and severe side effects than lower doses.

Enhertu has received previous FDA-approval for adults with advanced or metastatic HER2-positive and HER2-mutated cancers in other areas of the body. The drug has also received accelerated approval for previously-treated unresectable or metastatic NSCLC in adults whose tumors have HER2-activating mutations (also known as ERBB2 mutations). Full approval will depend on the results of additional studies.

The results of this study highlight the potential of Enhertu in the management of metastatic, HER2-overexpressing NSCLC. This medication may fulfill a significant therapeutic gap in lung cancer care. However, the study authors underline the realistic place for the medication in management of NSCLC; in other studies, adding Enhertu to typical first-line treatments for NSCLC added no further benefit. Additional studies of Enhertu for NSCLC are ongoing to investigate optimal patient selection and dosing.

“Results of the current trial support further exploration and development of trastuzumab deruxtecan as a potential treatment option for patients with HER2-overexpressing NSCLC,” the authors concluded in their paper.

The study was designed and funded by Daiichi Sankyo in collaboration with AstraZeneca.