Phase 3 Multicenter Randomized Open-label Trial of Trastuzumab Deruxtecan and Pembrolizumab vs. Pembrolizumab with Platinum-based Chemotherapy in HER2+ NSCLC

The primary objective of this study is to compare the efficacy of trastuzumab deruxtecan in combination with pembrolizumab versus platinum-based chemotherapy in combination with pembrolizumab in terms of progression-free survival, as assessed by a blinded independent review committee. This evaluation is conducted in participants with locally advanced unresectable or metastatic non-small cell lung cancer that is HER2-overexpressing and has a PD-L1 tumor proportion score of less than 50%. Secondary objectives include:

• Comparison of efficacy regarding overall survival and other clinical endpoints.
• Assessment of safety and tolerability.
• Evaluation of patient-reported symptoms, functioning, and general health status.

This study involves a total of 527 participants diagnosed with non-squamous non-small cell lung cancer. The study population includes both male and female patients, including vulnerable groups, within specific age ranges. Eligible participants must have histologically documented unresectable or metastatic disease characterized by HER2 overexpression and a PD-L1 tumor proportion score (TPS) of less than 50%. Inclusion requires the presence of Stage IV or Stage IIIB/IIIC disease where patients are not candidates for surgical resection or definitive chemoradiation. Participants must not have received prior systemic anticancer therapy for advanced or metastatic non-squamous disease, with specific allowances for certain adjuvant or neoadjuvant regimens provided they meet established washout periods. Additionally, patients must have adequate, non-irradiated tumor tissue available for the assessment of protein expression. Individuals with known HER2 mutations or available therapies targeting actionable genomic alterations are excluded.

This Phase 3, multicenter, randomized, open-label trial is designed to compare the efficacy of trastuzumab deruxtecan in combination with pembrolizumab against a combination of platinum-based chemotherapy and pembrolizumab. The study targets individuals with non-small cell lung cancer that is non-squamous, locally advanced unresectable or metastatic, HER2-overexpressing, and has a PD-L1 tumor proportion score less than 50%. The primary endpoint is progression-free survival, which is evaluated by a blinded independent review committee using RECIST v1.1 criteria. Secondary endpoints include overall survival. The research process begins with a screening period to assess HER2 and PD-L1 expression through tumor tissue analysis. Following randomization, participants receive their assigned intravenous infusion regimen. The trial is estimated to continue until June 2032.

The experimental treatment consists of trastuzumab deruxtecan (DS-8201a) administered as a solution for infusion via intravenous infusion at a dosage of 5.4 mg/kg.

The comparator regimens include pembrolizumab administered via intravenous infusion at a dose of 200 mg, in combination with either carboplatin at 75 mg via intravenous infusion, cisplatin at 75 mg/m² via intravenous infusion, or pemetrexed at 500 mg/m² via intravenous infusion.

The efficacy of the investigated treatment regimens will be evaluated using progression-free survival as the primary endpoint. This parameter is defined as the time interval from the date of randomization to the occurrence of radiographic disease progression or death from any cause. Assessment of tumor response will be conducted by a blinded independent review committee utilizing RECIST v1.1 to evaluate tumor scans.

Secondary efficacy assessment includes overall survival, which is defined as the time interval from the date of randomization to death from any cause.