Real-World Data Show T-DXd Activity in HER2-Mutant NSCLC

Trastuzumab deruxtecan (T-DXd; Enhertu) produced an objective response rate (ORR) of 54.8% and a median overall survival (OS) of 18.3 months in the largest real-world cohort of patients with HER2-mutant non–small cell lung cancer (NSCLC) reported to date, according to results from the multinational TRACER/HERTras study published in the Journal of Thoracic Oncology.¹ The retrospective analysis, which included 168 patients treated at 68 centers across Europe and Israel, also found that T-DXd produced meaningful intracranial responses in patients with active brain metastases and in those receiving the agent as first-line therapy—2 populations largely excluded from the pivotal DESTINY-Lung trials.

Among all patients, the disease control rate (DCR) was 88.7% (95% CI, 82.9%-93.1%), and median progression-free survival (PFS) was 7.2 months (95% CI, 6.2-9.7). In the 18 treatment-naive patients, ORR reached 72.2% (95% CI, 46.5%-90.3%) and median OS was 22.1 months, numerically higher than the 52.7% ORR and 18.2-month OS observed in the 150 previously treated patients. Among 27 patients with measurable, active brain metastases, the intracranial ORR was 74.1% (95% CI, 53.7%-88.9%), including complete intracranial responses in 25.9% of patients; responses occurred even among the 18 patients who received no local central nervous system therapy.

Patients were treated between August 2021 and January 2025, before and after regulatory approval, largely through managed-access programs and off-label use. Median age at treatment initiation was 62 years, 59% of patients were women, and 56% were never-smokers. Nearly all tumors (99%) were adenocarcinomas, and 89.3% of HER2 mutations were located in exon 20. Most patients (89%) were pretreated, having received a median of one prior line of therapy, most commonly platinum-based chemotherapy (86%) and anti–PD-1/PD-L1 immunotherapy (76%).

Safety findings were largely consistent with prior clinical trial data. Treatment-related adverse events (TRAEs) of any grade occurred in 92% of patients, most frequently nausea (43%), anemia (37%), and fatigue (33%). Grade 3 or higher TRAEs occurred in 32% of patients. Interstitial lung disease (ILD) or pneumonitis, the toxicity of greatest concern with antibody-drug conjugates of this class, occurred in 14% of patients, including four fatal cases; no consistent clinical predictors of ILD/pneumonitis were identified. Overall, 7% of patients died from events considered related to treatment. Exploratory analyses suggested that a starting dose of 5.4 mg/kg was associated with fewer grade 3 or higher TRAEs and numerically longer OS and PFS than the 6.4 mg/kg starting dose, consistent with the dosing strategy adopted in the phase 2 DESTINY-Lung02 trial (NCT04644237).²

The study authors noted that efficacy outcomes in this real-world cohort were broadly comparable to those reported in the phase 2 DESTINY-Lung01 (NCT03505710)³ and DESTINY-Lung02 trials, despite the inclusion of patients with poorer performance status and active brain metastases who were excluded from those studies. The authors also referenced findings from the China-based DESTINY-Lung05 trial (NCT05246514),⁴ which reported a higher overall incidence of TRAEs but no fatal treatment-related events, a difference the authors attributed to differences in trial monitoring compared with real-world practice.

Exploratory subgroup analyses further suggested that HER2 insertions were associated with a higher likelihood of response than substitutions, and that mutations affecting the tyrosine kinase domain (TKD), particularly exon 20, were associated with longer duration of response than non–TKD alterations. The authors cautioned that these findings, along with a numerically higher ORR observed in tumors with high PD-L1 expression, are hypothesis-generating given small subgroup sizes and should be validated in larger, prospectively characterized cohorts.

The authors acknowledged several limitations inherent to the retrospective design, including investigator-assessed responses without centralized radiologic review, lack of a comparator arm, and potential selection bias related to access through managed-access programs. The ongoing phase 3 DESTINY-Lung04 trial (NCT05048797),⁵ comparing first-line T-DXd with platinum-based chemoimmunotherapy, is expected to help clarify the agent's optimal position in the treatment sequence for HER2-mutant NSCLC.

REFERENCES

1. Illini O, Hund AC, Kopp HG, et al. Systemic and intracranial efficacy and safety of trastuzumab deruxtecan in patients with HER2-mutant NSCLC across treatment lines: evidence from the TRACER/HERTras real-world cohort. J Thorac Oncol. 2026;21(7):103651. doi:10.1016/j.jtho.2026.103651

2. 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;41:4852-4863.

3. Li BT, Smit EF, Goto Y, et al. Trastuzumab deruxtecan in HER2-mutant non-small-cell lung cancer. N Engl J Med. 2022;386:241-251.

4. Cheng Y, Wu L, Fang Y, et al. Trastuzumab deruxtecan (T-DXd) in Chinese patients (pts) with previously treated HER2 mutant non-small cell lung cancer (NSCLC): primary analysis from the phase 2 DESTINY-Lung05 (DL-05) trial. Cancer Res. 2024;84(7_Suppl):CT248.

5. Li BT, Ahn MJ, Goto K, et al. 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). J Clin Oncol. 2022;40:TPS9137.