For patients with advanced/metastatic non-small-cell lung cancer (NSCLC) without actionable genomic alterations and low (<50%) PD-L1 expression, pembrolizumab plus pemetrexed and platinum chemotherapy is a preferred first-line treatment. These patients have comparatively worse outcomes than those with higher PD-L1 expression, underscoring the need for new combination strategies. Datopotamab deruxtecan (Dato-DXd), a TROP2-directed antibody-drug conjugate, has demonstrated encouraging antitumor activity and safety in this patient population. We describe the rationale and design of TROPION-Lung07, a randomized, open-label Phase III study assessing Dato-DXd in combination with pembrolizumab with/without platinum-based chemotherapy versus pembrolizumab plus pemetrexed and platinum-based chemotherapy in patients with advanced/metastatic non-squamous NSCLC without actionable genomic alterations and <50% PD-L1 expression. Primary study objectives are progression-free survival and overall survival.Clinical Trial Registration: NCT05555732 (ClinicalTrials.gov).
Keywords: Dato-DXd; TROPION; antibody–drug conjugate; datopotamab deruxtecan; non-small-cell lung cancer.
Most patients discover they have non-small-cell lung cancer (NSCLC) after it has already spread beyond the lungs (metastasized) making it more challenging to treat. If patients with NSCLC also lack specific genetic changes, called “actionable genomic alterations”, or have low levels of a protein called PD-L1 (which cancer cells use to avoid attack from the immune system and continue to grow), current treatments may not fully help, or only help for a while. However, newer approaches are being investigated that may benefit these patients with fewer side effects than traditional chemotherapy. Datopotamab deruxtecan (Dato-DXd) is an investigational drug which combines an antibody with a chemotherapy agent to specifically target and kill cancer cells. The antibody in Dato-DXd attaches to a protein called TROP2, which is widely expressed in NSCLC tumors, and delivers chemotherapy directly into cancer cells to kill them. The TROPION-Lung07 study will assess the potential benefits and side effects of adding Dato-DXd to other drugs, including pembrolizumab (an immunotherapy which attaches to PD-1 on immune cells and triggers the death of cancer cells) and chemotherapy. Three treatment groups will be compared: pembrolizumab with chemotherapy; Dato-DXd with pembrolizumab; and Dato-DXd with pembrolizumab and chemotherapy. The study will help us to understand if adding Dato-DXd to other anticancer drugs allow patients to live longer without their disease getting worse.