Open-label, randomized, multicenter, phase 3 study evaluating trastuzumab deruxtecan (T-DXd) as first-line treatment in patients with unresectable, locally advanced, or metastatic non–small cell lung cancer (NSCLC) harboring HER2 exon 19 or 20 mutations (DESTINY-Lung04).

Bob T. Li Memorial Sloan Kettering Cancer Center, New York, NY info_outline Bob T. Li, Myung-Ju Ahn, Koichi Goto, Julien Mazieres, Sukhmani Kaur Padda, William Nassib William, Yi-Long Wu, Simon Dearden, Alejandra Ragone, Natasha Viglianti, Amaya Gasco

Authors Bob T. Li Memorial Sloan Kettering Cancer Center, New York, NY info_outline Bob T. Li, Myung-Ju Ahn, Koichi Goto, Julien Mazieres, Sukhmani Kaur Padda, William Nassib William, Yi-Long Wu, Simon Dearden, Alejandra Ragone, Natasha Viglianti, Amaya Gasco Organizations Memorial Sloan Kettering Cancer Center, New York, NY, Department of Hematology & Oncology, Samsung Medical Center, Seoul, South Korea, Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan, Hôpital LARREY-Service de Pneumologie, Toulouse, France, Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, Rua Maestro Cardim, 769 – Bela Vista, São Paulo, TX, Brazil, Department of Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China, AstraZeneca Pharmaceuticals, Cambridge, United Kingdom, AstraZeneca Pharmaceuticals, Mississauga, ON, Canada, AstraZeneca Pharmaceuticals, Gaithersburg, MD Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Background: The standard of care (SOC) for patients with oncogene driver subsets of metastatic NSCLC is guided by specific molecular characterization and includes immunotherapy, chemoimmunotherapy, and matched targeted therapies. Although targeting HER2 has transformed the care of patients with breast and gastric cancers, there is currently no approved HER2-targeted therapy for NSCLC. T-DXd is an antibody-drug conjugate consisting of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a topoisomerase I inhibitor payload. In a cohort of pretreated patients (median, 2 prior lines) with unresectable or metastatic HER2-mutant NSCLC, T-DXd demonstrated durable and robust anticancer activity, with a confirmed objective response rate (ORR) of 55% and median duration of response (DOR), progression-free survival (PFS), and overall survival (OS) of 9.3, 8.2, and 17.8 months, respectively (Li et al. N Engl J Med. 2022). Given the efficacy observed in later-line settings and the unmet need for targeted therapies in patients with HER2-mutant NSCLC, evaluating the efficacy of T-DXd in the first-line setting vs SOC is important to determine the optimal treatment. Here we describe the phase 3 DESTINY-Lung04 trial (NCT05048797) evaluating T-DXd as a first-line treatment in patients with NSCLC harboring HER2 mutations. Methods: DESTINY-Lung04 is an open-label, randomized, multicenter, phase 3 study evaluating the efficacy and safety of first-line T-DXd vs SOC in patients with unresectable, locally advanced (not amenable to curative therapy), or metastatic nonsquamous NSCLC with HER2 exon 19 or 20 mutations (detected in tissue or circulating tumor DNA). Patients must be naive to systemic therapy with palliative intent in the locally advanced or metastatic disease setting and must not have tumors with EGFR or other targetable oncogenic alterations. Patients with brain metastases must have previously completed local therapy. Patients will be randomized to receive T-DXd or SOC (platinum [investigator’s choice of cisplatin or carboplatin], pemetrexed, and pembrolizumab). The primary endpoint is PFS defined by RECIST version 1.1 per blinded independent central review (BICR). Secondary endpoints include OS, ORR, and DOR (by RECIST 1.1 per BICR and investigator), investigator-assessed PFS (by RECIST 1.1) and time to second progression or death (per local standard clinical practice), central nervous system PFS (by RECIST 1.1 per BICR), landmark PFS at 12 months (by RECIST 1.1 per BICR and investigator), and landmark OS at 24 months. Safety and tolerability, pharmacokinetics, immunogenicity, and patient-reported outcomes, including pulmonary symptoms and tolerability, will be assessed. Clinical trial information: NCT05048797.