TROPION-Lung07: Phase III study of Dato-DXd + pembrolizumab ± platinum-based chemotherapy as 1L therapy for advanced non-small-cell lung cancer

Abstract

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.

Figure 1.

Mechanism of action of Dato-DXd, pembrolizumab, pemetrexed and cisplatin/carboplatin on a tumor cell. (A) Dato-DXd binds to TROP2 on the tumor cell surface. (B) This binding internalizes Dato-DXd into the tumor cell and releases the cytotoxic payload which damages intracellular DNA and can directly kill the tumor cell via apoptosis; the payload can also be released into the tumor microenvironment and penetrate neighboring tumor cells. (C) Dato-DXd-induced damage results in the release of antigens and DAMPs from the tumor cell; tumor antigens are captured and presented by dendritic cells while DAMPs activate dendritic cells, subsequently activating T cells. Dato-DXd-induced DNA damage also results in increased MHC class I expression and PD-L1/2 expression (potentially inhibitory of T-cell stimulation) on the tumor cell. Increased MHC class I expression enhances CD8⁺ T-cell stimulation. (D) The addition of pembrolizumab blocks interaction of PD-1 with PD-L1/2 which leads to enhanced T-cell proliferation and activation. (E) Pemetrexed synergizes with cisplatin/carboplatin, which damages DNA and inhibits DNA synthesis. (F) T cells recognize, infiltrate and kill tumor cells. ADC: Antibody-drug conjugate; Dato-DXd: Datopotamab deruxtecan; DNA: Deoxyribonucleic acid.

Figure 2.

TROPION-Lung07 study design. Protocol deviations that are deemed to pose significant safety risk by the investigator and/or sponsor may lead to permanent study drug discontinuation. Participants who discontinue study treatment without radiographic disease progression will continue to undergo tumor assessments every 6 weeks (±7 days) for the first four cycles from randomization, followed by every 9 weeks (±7 days) up to 2 years and then every 12 weeks (±7 days) thereafter, during follow-up until radiographic disease progression as determined by BICR review, death, loss to follow-up or withdrawal of consent. AUC: Area under the curve; BICR: Blinded independent central review; Dato-DXd: Datopotamab deruxtecan; ECOG PS: Eastern Cooperative Oncology Group Performance Status; NSCLC: Non-small-cell lung cancer; OS: Overall survival; PFS: Progression-free survival; q3w: Every 3 weeks; R: Randomization; ROW: Rest of world; TPS: Tumor proportion score.