Trastuzumab Deruxtecan Superior to Chemoimmunotherapy in HER2-Mutant Advanced NSCLC

Trastuzumab deruxtecan-nxki (T-DXd, Enhertu; AstraZeneca/Daiichi Sankyo) demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with platinum-pemetrexed chemotherapy plus pembrolizumab (Keytruda; Merck) as first-line treatment for unresectable, locally advanced or metastatic HER2-mutant nonsquamous non–small cell lung cancer (NSCLC), according to topline findings from the phase 3 DESTINY-Lung04 trial (NCT05048797).¹

These results make trastuzumab deruxtecan the first HER2-directed therapy to improve PFS over the global first-line standard of care in a phase 3 trial involving this population. The findings could support moving the antibody-drug conjugate (ADC) from previously treated disease into the first-line setting.¹

However, AstraZeneca and Daiichi Sankyo did not release numerical PFS results, including the median values or hazard ratio, in the August 17, 2026, announcement. Overall survival (OS) data remain immature, and the trial will continue as planned to evaluate OS and other secondary end points.¹

DESTINY-Lung04 Compares T-DXd With First-Line Standard of Care

DESTINY-Lung04 is a global, randomized, open-label phase 3 trial that enrolled 454 adults with unresectable, locally advanced or metastatic nonsquamous NSCLC harboring a HER2 exon 19 or 20 mutation. Eligible patients had not received systemic therapy with palliative intent for locally advanced or metastatic disease.¹,²

Patients were randomly assigned 1:1 to receive T-DXd at 5.4 mg/kg or the investigator’s choice of cisplatin or carboplatin administered with pemetrexed and pembrolizumab. Randomization was stratified according to smoking history and the presence or history of brain metastases.¹

The primary end point was PFS assessed by blinded independent central review. Secondary end points included OS, investigator-assessed PFS, objective response rate, duration of response, pharmacokinetics, safety, and patient-reported outcomes.¹,²

The safety profile of T-DXd was generally consistent with its established profile, with no new safety concerns reported. Complete safety findings, including rates of treatment discontinuation, dose modification, and interstitial lung disease (ILD) or pneumonitis, have not yet been disclosed.¹ Investigators plan to present the complete DESTINY-Lung04 results at an upcoming medical meeting and share them with global regulatory authorities.

Findings Could Move HER2-Directed Treatment Into the First Line

HER2 mutations occur in approximately 2% to 4% of patients with nonsquamous NSCLC and represent a distinct molecular driver rather than the same condition as HER2 protein overexpression or gene amplification.¹^,³ These mutations are reported more frequently among younger patients, women, and individuals without a smoking history. They are also associated with a higher incidence of brain metastases and poor prognosis.¹

First-line treatment has generally consisted of platinum-based chemotherapy combined with immunotherapy because HER2-directed agents have been reserved for previously treated disease. T-DXd is currently approved for adults with unresectable or metastatic NSCLC harboring an activating HER2 mutation who have received prior systemic therapy.¹

T-DXd combines a HER2-targeting monoclonal antibody with a topoisomerase I inhibitor payload through a cleavable linker. This structure is designed to deliver the cytotoxic payload directly to HER2-expressing cancer cells while also producing a bystander antitumor effect in nearby cells.¹

Evidence supporting its use in previously treated disease came from the phase 2 DESTINY-Lung02 trial. At the approved 5.4 mg/kg dose, T-DXd produced a confirmed objective response rate of 49%, with a median response duration of 16.8 months and median PFS of 9.9 months.⁴

Pharmacists Should Remain Alert for ILD and Other ADC Toxicities

ILD and pneumonitis remain among the most important risks associated with T-DXd. In DESTINY-Lung02, adjudicated drug-related ILD occurred in 12.9% of patients receiving 5.4 mg/kg, including grade 3 and fatal events in 1% each. Other common toxicities included nausea, neutropenia, fatigue, decreased appetite, and anemia.⁴

Oncology pharmacists can support early recognition of ILD by counseling patients to immediately report new cough, dyspnea, fever, or worsening respiratory symptoms. Current safety guidance recommends interrupting T-DXd when ILD is suspected and permanently discontinuing treatment for symptomatic grade 2 or higher disease.⁵ Complete blood cell counts and left ventricular function also require monitoring during treatment.

Although the magnitude of the PFS advantage and the effect on OS are not yet known, DESTINY-Lung04 provides the first phase 3 evidence that a HER2-directed therapy can outperform chemoimmunotherapy in the first-line treatment of HER2-mutant advanced NSCLC.

References

1. AstraZeneca. Enhertu demonstrated statistically significant and clinically meaningful improvement in progression-free survival as 1st-line treatment of patients with HER2-mutant advanced non-small cell lung cancer in DESTINY-Lung04 phase III trial. Published August 17, 2026. Accessed August 17, 2026. https://www.astrazeneca.com/media-centre/press-releases/2026/enhertu-improved-pfs-in-1l-her2m-lung-cancer.html

2. AstraZeneca. A study to investigate the efficacy and safety of trastuzumab deruxtecan as the first treatment option for unresectable, locally advanced/metastatic non-small cell lung cancer with HER2 mutations. NCT05048797. Accessed August 17, 2026. https://www.astrazenecaclinicaltrials.com/study/D967SC00001/

3. Arcila ME, Chaft JE, Nafa K, et al. Prevalence, clinicopathologic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas. Clin Cancer Res. 2012;18(18):4910-4918. doi:10.1158/1078-0432.CCR-12-0912

4. Goto K, Goto Y, Kubo T, et al. Trastuzumab Deruxtecan in Patients With HER2-Mutant Metastatic Non-Small-Cell Lung Cancer: Primary Results From the Randomized, Phase II DESTINY-Lung02 Trial. J Clin Oncol. 2023;41(31):4852-4863. doi:10.1200/JCO.23.01361

5. Goto K, Goto Y, Kubo T, et al. Trastuzumab Deruxtecan in Patients With HER2-Mutant Metastatic Non-Small-Cell Lung Cancer: Primary Results From the Randomized, Phase II DESTINY-Lung02 Trial. J Clin Oncol. 2023;41(31):4852-4863. doi:10.1200/JCO.23.01361