Patients with metastatic lung cancer and low PD-L1 expression face limited targeted treatment options in the first-line setting, with current standard care relying on immunotherapy combined with traditional chemotherapy. Daiichi Sankyo and AstraZeneca have initiated the DESTINY-Lung06 phase 3 trial, dosing the first patient in a study evaluating whether their antibody drug conjugate ENHERTU could replace chemotherapy when combined with standard immunotherapy for this patient population.
Key Points
- The trial compares ENHERTU (trastuzumab deruxtecan) at 5.4 mg/kg plus pembrolizumab against the current standard of care—pembrolizumab combined with platinum-based chemotherapy and pemetrexed—in patients with HER2 overexpressing, PD-L1 TPS <50% non-squamous non-small cell lung cancer.
- ENHERTU is a HER2-directed antibody drug conjugate consisting of a HER2 monoclonal antibody attached to topoisomerase I inhibitor payloads through cleavable linkers. The drug carries a boxed warning for interstitial lung disease and embryo-fetal toxicity.
- The multicenter, randomized, open-label trial will enroll approximately 686 patients across Asia, Europe, North America, and South America, with the primary endpoint being progression-free survival assessed by blinded independent central review.
- HER2 overexpressing non-small cell lung cancer occurs in up to approximately 20% of NSCLC patients and is associated with poor treatment response and worse clinical outcomes. There are currently no HER2-directed medicines approved in the first-line setting for this indication.
- ENHERTU is already approved in more than 60 countries for HER2 mutant NSCLC after prior systemic therapy based on earlier trial results, though continued approval may be contingent upon verification in confirmatory trials.
The trial aims to determine whether replacing traditional chemotherapy with a targeted antibody drug conjugate could improve outcomes for lung cancer patients with HER2 overexpression who have lower PD-L1 expression levels.
The Data
- Non-small cell lung cancer accounts for approximately 85% of lung cancer cases, with 2.48 million lung cancer cases diagnosed globally in 2022 and 1.8 million deaths.
- Only approximately 10% of patients with metastatic NSCLC survive beyond five years after diagnosis. HER2 overexpressing NSCLC occurs in up to approximately 20% of patients with NSCLC.
- The trial’s key secondary endpoint is overall survival, with additional secondary endpoints including investigator-assessed progression-free survival, objective response rate, duration of response, and safety.
- In previous trials of ENHERTU at 5.4 mg/kg for metastatic breast cancer, HER2-mutant NSCLC, and other solid tumors, interstitial lung disease occurred in 12% of patients, with fatal outcomes in 0.9% of cases.
Industry Context
In the trial, we are evaluating whether replacing traditional chemotherapy with ENHERTU and combining it with standard of care immunotherapy could potentially improve outcomes for patients in the first-line metastatic setting.
Abderrahmane Laadem, MD, Head, Late-Stage Oncology Clinical Development, Daiichi Sankyo
The trial addresses a specific gap in lung cancer treatment. While pembrolizumab combined with platinum-based chemotherapy and pemetrexed is one of the current recommended first-line treatments for patients with HER2 overexpressing metastatic non-squamous NSCLC, improved outcomes for immunotherapy-based treatments correlate with higher PD-L1 levels. This creates a need for alternative approaches for patients with PD-L1 tumor proportion scores below 50%.
HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of multiple tumor types. In NSCLC, HER2 overexpression is associated with poor treatment response and worse clinical outcomes. ENHERTU uses Daiichi Sankyo’s proprietary DXd antibody drug conjugate technology, which links a HER2 monoclonal antibody to topoisomerase I inhibitor payloads via tetrapeptide-based cleavable linkers.
The drug is being jointly developed and commercialized globally by Daiichi Sankyo and AstraZeneca, except in Japan where Daiichi Sankyo maintains exclusive rights. Whether ENHERTU combined with immunotherapy will demonstrate meaningful advantages over current chemotherapy-based regimens remains to be determined through this trial’s progression-free survival and overall survival endpoints.
DESTINY-Lung06 addresses a distinct population from other ENHERTU lung cancer trials. While DESTINY-Lung04, initiated in 2022, evaluates ENHERTU monotherapy in first-line HER2-mutant NSCLC (representing 2-4% of cases), DESTINY-Lung06 targets HER2 overexpression (affecting up to 20% of cases)—a different molecular alteration. According to a 2023 Cancer Treatment Reviews analysis, HER2-directed therapies that succeeded in breast and gastric cancers have not replicated those results in NSCLC, possibly due to the heterogeneity of HER2 alterations across different tumor types. The lack of standardized HER2 immunohistochemistry scoring methods in NSCLC, with current approaches extrapolated from breast and gastrointestinal cancers, further complicates patient selection for HER2-targeted trials.
