Real-world outcomes of trastuzumab deruxtecan as second- or further-line treatment in patients with HER2-mutant metastatic non-small cell lung cancer: a retrospective study
Highlight box
Key findings
• Trastuzumab deruxtecan (T-DXd) showed favorable effectiveness in Chinese patients with human epidermal growth factor receptor 2 (HER2)-mutant advanced non-small cell lung cancer (NSCLC), with a median progression-free survival (PFS) of 7.85 months and an objective response rate (ORR) of 51.4% in the second- or further-line setting.
What is known and what is new?
• Previous pivotal clinical trials (DESTINY-Lung01, DESTINY-Lung02, and DESTINY-Lung05) established the key role of T-DXd in the treatment of patients with pretreated HER2-mutant metastatic NSCLC, achieving an ORR of 50–58%, a duration of response of 9.0–12.6 months, and a PFS of 8.2–12.9 months.
• This study firstly introduced the real-world validation in Chinese patients with HER2-mutant advanced NSCLC, confirming clinical benefit despite potential prognostic challenges from previous anti-angiogenic therapy and highlighting possible advantages for elderly population.
What is the implication, and what should change now?
• T-DXd should be prioritized for HER2-mutant NSCLC in China, especially elderly patients, while closely monitoring the impact of previous anti-angiogenic therapy.
• Urgent implementation of routine HER2 gene testing in NSCLC and prospective studies to validate these real-world findings is critical to optimize treatment strategies.
Introduction
Lung cancer is the most life-threatening cancer, with the highest incidence of new cases and mortality among all cancers worldwide (1). Non-small cell lung cancer (NSCLC) accounts for 80–85% of lung cancer cases. Human epidermal growth factor receptor 2 (HER2) mutations can be found in 1–4% of NSCLC cases, predominantly in adenocarcinoma subtype (2-4). Despite the continuous evolution of HER2-directed therapies, the efficacy of monoclonal antibodies and tyrosine kinase inhibitors (TKIs) shows inconsistency in HER2-mutant NSCLC (5-12). Current standard first-line therapy remains platinum-based chemotherapy and immunotherapy (13), but the patient prognosis is unsatisfactory. Novel treatment strategies need to be explored.
Antibody-drug conjugate (ADC) is composed of a monoclonal antibody, a cleavable or non-cleavable linker, and a cytotoxic drug as a payload. ADCs bind to specific antigens on the surface of tumor cells through monoclonal antibodies, enter the tumor cells via endocytosis, and release cytotoxic drugs to exert their antitumor effects. This class of agent has the advantages of strong targeting, potent antitumor activity, and relatively mild adverse reactions, which has received widespread attention in the field of anti-cancer therapy in recent years (14).
Trastuzumab deruxtecan (T-DXd) is a novel HER2-directed ADC that links trastuzumab (a humanized anti-HER2 monoclonal antibody) to deruxtecan (a DNA topoisomerase I inhibitor) (15). The drug-to-antibody ratio of eight allows T-DXd to carry highly potent payload and induce direct cytotoxicity in HER2-expressing cancer cells (15). Neighboring cancer cells without HER2 expression can also be killed through the bystander effect of T-DXd (16), which is of significance for NSCLC with high tumor heterogeneity. In addition, the cleavable tetrapeptide-based linker allows stable delivery of the cytotoxic drug to cancer cells, with reduced release in blood circulation and decreased occurrence of adverse reactions (15). Previous pivotal clinical trials (DESTINY-Lung01, DESTINY-Lung02, and DESTINY-Lung05) have demonstrated the efficacy and safety of T-DXd in patients with previously treated HER2-mutant metastatic NSCLC, with a high objective response rate (ORR; 50.0–58.3%) and long duration of response (9.0–12.6 months) and progression-free survival (PFS; 8.2–12.9 months) (17-20). However, real-world data on the application of T-DXd in China have not been reported.
This study aimed to observe the effectiveness and safety of T-DXd for the treatment of Chinese patients with HER2-mutant advanced NSCLC in the real-world setting. In addition, we preliminarily analyzed the gene mutation profile and co-alteration status of these patients, and the potential factors associated with the effectiveness of T-DXd, providing a reference for individualized treatment. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-916/rc).
Methods
Patients
This retrospective study was conducted at two centers (Shanghai Chest Hospital and Fudan University Shanghai Cancer Center) in China. The inclusion criteria were: (I) histologically or cytologically confirmed NSCLC; (II) inoperable locally advanced or metastatic disease; (III) HER2 mutation confirmed by next-generation sequencing (NGS) or polymerase chain reaction (PCR); (IV) at least one measurable lesion according to the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1; (V) at least two cycles of treatment with T-DXd; and (VI) complete clinical information. Patients accompanied with immune dysfunction, myeloid anemia, or multi-organ dysfunction, or those who received other concomitant anti-cancer therapies during T-DXd treatment were excluded from this study.
The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the ethics committees of Shanghai Chest Hospital (No. IS25019) and Fudan University Shanghai Cancer Center (No. 2503-Exp159). Informed consent was waived in this retrospective study.
Data collection
Demographics and clinical information were all derived from electronic medical records, including age, sex, smoking history, histology type, disease stage, metastatic sites, Eastern Cooperative Oncology Group (ECOG) performance status, previous treatments, current treatment line, treatment information of T-DXd, tumor response, follow-up results, and adverse events (AEs). T-DXd was initiated at a dose of 200–400 mg based on body weight, administered every 3 weeks. Tumor response was evaluated according to RECIST 1.1. The last follow-up date was June 25, 2025.
HER2 mutations, co-alterations, and programmed cell death-ligand 1 (PD-L1) expression were detected using the biopsy tissue specimens. NGS or PCR was used for the detection of HER2 mutations. Immunohistochemistry was adopted for the determination of PD-L1 expression, and tumor proportion score (TPS) was calculated.
Outcomes
The primary outcomes were PFS and ORR. Secondary outcomes were overall survival (OS), disease control rate (DCR), and AEs.
Statistical analysis
Continuous variables were expressed as median (range). Categorical variables were expressed as frequency and percentage. The 95% confidence interval (CI) of ORR was calculated using the Clopper-Pearson methods. PFS and OS were estimated using the Kaplan-Meier method, and the corresponding 95% CIs were calculated using the Brookmeyer-Crowley method. Due to small sample size, subgroup analysis was performed using descriptive statistics without statistical test. Statistical analysis was performed using R software version 4.4.3.
Results
Patients
Between April 2023 and January 2025, a total of 35 patients were included in this study. All patients had stage IV lung adenocarcinoma. Median age was 58 years (range, 33–87), and 18 (51.4%) patients were female. Four (11.4%) patients had ECOG performance status ≥2. Nineteen (54.3%) patients had bone metastases, 13 (37.1%) had brain metastases, 13 (37.1%) had contralateral lung metastases, 11 (31.4%) had pleura metastases, and 5 (14.3%) had liver metastases. All patients received T-DXd as second- or further-line treatment, and the majority of them [29 (82.9%)] received third- or further-line treatment. Seventeen (48.6%) patients had previously received immunotherapy. Eleven (31.4%) patients had previously received anti-angiogenic therapy (Table 1), including bevacizumab (n=8), anlotinib (n=1), and both (n=2; bevacizumab and anlotinib sequentially in different treatment lines; Table S1).
Table 1
| Characteristics | Values (n=35) |
|---|---|
| Age (years) | 58 [33–87] |
| <65 | 25 (71.4) |
| ≥65 | 10 (28.6) |
| Sex | |
| Male | 17 (48.6) |
| Female | 18 (51.4) |
| Smoking history | |
| Yes | 7 (20.0) |
| No | 28 (80.0) |
| ECOG performance status | |
| 0 | 6 (17.1) |
| 1 | 25 (71.4) |
| ≥2 | 4 (11.4) |
| Metastatic sites | |
| Bone | 19 (54.3) |
| Lymph nodes | 17 (48.6) |
| Brain | 13 (37.1) |
| Contralateral lung | 13 (37.1) |
| Pleura | 11 (31.4) |
| Liver | 5 (14.3) |
| Pancreas | 1 (2.9) |
| Number of previous treatment lines | |
| 1 | 6 (17.1) |
| 2 | 16 (45.7) |
| ≥3 | 13 (37.1) |
| Previous pulmonary surgery | 7 (20.0) |
| Previous systemic therapies | |
| Chemotherapy | 23 (65.7) |
| Immunotherapy | 17 (48.6) |
| Anti-angiogenic therapy | 11 (31.4) |
| Antibody-drug conjugate | 2 (5.7) |
Data are presented as median [range] or n (%). ECOG, Eastern Cooperative Oncology Group.
Regarding HER2 mutations, most patients [24 (68.6%)] had exon 20 mutations, and the most common mutation type was Y772_A775dup in 15 (42.9%) patients, followed by A775_G776insYVMA in eight (22.9%) patients. Eighteen (51.4%) patients had co-alterations, including 11 (31.4%) with TP53 co-mutation. Eight (22.9%) patients had PD-L1 TPS ≥1% (Table 2).
Table 2
| Variable | Values (n=35), n (%) |
|---|---|
| HER2 mutation detection method | |
| NGS | 33 (94.3) |
| PCR | 2 (5.7) |
| HER2 mutation location | |
| Kinase domain | 28 (80.0) |
| Exon 20 | 24 (68.6) |
| Exon 19 | 2 (5.7) |
| Others | 2 (5.7) |
| Others | 7 (20.0) |
| HER2 mutation type | |
| Y772_A775dup | 15 (42.9) |
| A775_G776insYVMA | 6 (17.1) |
| M774_A775insAYVM and A775_G776insYVMA | 2 (5.7) |
| G778_S779insCPG | 1 (2.9) |
| V777delinsVGSP | 1 (2.9) |
| L755P | 1 (2.9) |
| Q709L and V777L | 1 (2.9) |
| S310F | 1 (2.9) |
| Others | 7 (20.0) |
| Co-alteration | |
| TP53 mutation | 11 (31.4) |
| HER2 amplification | 3 (8.6) |
| CDK4 amplification | 2 (5.7) |
| BRCA1 exon 10 missense mutation | 1 (2.9) |
| C-Met amplification | 1 (2.9) |
| C-Met frameshift mutation | 1 (2.9) |
| EGFR L858R | 1 (2.9) |
| NTRK exon 15 missense mutation | 1 (2.9) |
| PIK3CA exon 10 missense mutation | 1 (2.9) |
| STK11 exon 8 missense mutation | 1 (2.9) |
| None | 14 (40.0) |
| Unknown/not detected | 3 (8.6) |
| PD-L1 TPS | |
| <1% | 12 (34.3) |
| 1–49% | 6 (17.1) |
| ≥50% | 2 (5.7) |
| Not detected | 15 (42.9) |
HER2, human epidermal growth factor receptor 2; NGS, next-generation sequencing; PCR, polymerase chain reaction; PD-L1, programmed cell death-ligand 1; TPS, tumor proportion score.
Effectiveness
By the last follow-up data on June 25, 2025, the median follow-up duration was 9.7 months (range, 2.0–22.1 months). Median treatment duration was 5.5 months (range, 1.4–18.6 months). Twenty-two (62.9%) PFS events occurred, and the median PFS was 7.85 months (95% CI: 6.64–15.05; Figure 1). Median OS was not reached (NR). Eighteen patients achieved partial response, with an ORR of 51.4% (95% CI: 34.0–68.6%). DCR was 94.3% (33/35).
Further analyses showed generally consistent trends of PFS benefit and ORR in different subgroups by baseline characteristics. Median PFS seemed to be numerically shorter in patients who had previously received anti-angiogenic therapy [6.37 months (95% CI: 2.76–NR); Table 3 and Figure S1]. Patients who received T-DXd as fourth- or further-line treatment [38.5% (95% CI: 13.9–68.4)] or those who had previously received anti-angiogenic therapy [36.4% (95% CI: 10.9–69.2)] seemed to have a numerically lower ORR (Figure 2). Patients with TP53 co-mutation seemed to have numerically better median PFS [10.41 months (95% CI: 7.56–NR) vs. 6.83 months (95% CI: 3.45–NR)] and ORR [72.7% (95% CI: 39.0–94.0) vs. 38.1% (95% CI: 18.1–61.6)] than those without TP53 co-mutation.
Table 3
| Subgroup | Events/patients | PFS (months), median (95% CI) |
|---|---|---|
| Total | 22/35 | 7.85 (6.64–15.05) |
| Age (years) | ||
| <65 | 14/25 | 9.99 (6.83–NR) |
| ≥65 | 8/10 | 7.18 (5.32–NR) |
| Sex | ||
| Male | 11/17 | 10.09 (6.83–NR) |
| Female | 11/18 | 7.56 (6.37–NR) |
| Smoking history | ||
| Yes | 4/7 | 10.41 (6.83–NR) |
| No | 18/28 | 7.72 (6.37–NR) |
| ECOG performance status | ||
| 0 | 4/6 | 6.42 (5.32–NR) |
| 1 | 16/25 | 7.85 (6.83–15.05) |
| ≥2 | 2/4 | 10.09 (2.99–NR) |
| Metastatic sites | ||
| Bone | 13/19 | 7.72 (5.32–NR) |
| Lymph nodes | 10/17 | 7.85 (6.64–NR) |
| Brain | 10/13 | 7.89 (4.37–NR) |
| Contralateral lung | 11/13 | 6.37 (2.66–NR) |
| Pleura | 6/11 | 6.83 (6.21–NR) |
| Liver | 4/5 | 7.56 (6.83–NR) |
| No. of previous treatment lines | ||
| 1 | 4/6 | 7.56 (6.21–NR) |
| 2 | 9/16 | 9.99 (6.64–NR) |
| ≥3 | 9/13 | 7.89 (4.37–NR) |
| Previous treatments | ||
| Surgery | 4/7 | 9.99 (2.99–NR) |
| Chemotherapy | 14/23 | 9.99 (6.37–NR) |
| Immunotherapy | 10/17 | 10.41 (6.64–NR) |
| Anti-angiogenic therapy | 8/11 | 6.37 (2.76–NR) |
| TP53 co-mutation | ||
| Yes | 5/11 | 10.41 (7.56–NR) |
| No | 14/21 | 6.83 (3.45–NR) |
CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; NR, not reached; PFS, progression-free survival.
Adverse events
AEs were reported in 23 (65.7%) patients. The most common AE was fatigue [14 (40.0%)]. No grade ≥3 AEs occurred (Table 4). Owing to AEs, 3 (8.6%) patients reduced the dose of T-DXd (one due to grade 1 fatigue, one due to grade 1 vomiting, and one due to grade 2 weakness of the lower limbs), and no patients discontinued T-DXd treatment.
Table 4
| Event | Patients (n=35), n (%) | |
|---|---|---|
| Any grade | Grade ≥3 | |
| Any event | 23 (65.7) | 0 |
| Fatigue | 14 (40.0) | 0 |
| Loss of appetite | 3 (8.6) | 0 |
| Vomiting | 3 (8.6) | 0 |
| Constipation | 2 (5.7) | 0 |
| Headache and vomiting | 2 (5.7) | 0 |
| Numbness in the hands and feet | 2 (5.7) | 0 |
| Platelet count decreased | 2 (5.7) | 0 |
| Pneumonia | 2 (5.7) | 0 |
| Hematochezia | 1 (2.9) | 0 |
| Hemoglobin decreased | 1 (2.9) | 0 |
| Weakness of the lower limbs | 1 (2.9) | 0 |
| White blood cell count decreased | 1 (2.9) | 0 |
| Leading to dose reduction | 3 (8.6) | 0 |
| Fatigue | 1 (2.9) | 0 |
| Vomiting | 1 (2.9) | 0 |
| Weakness of the lower limbs | 1 (2.9) | 0 |
| Leading to treatment discontinuation | 0 | 0 |
Discussion
To our best knowledge, this is the first study reporting real-world data on the application of T-DXd in Chinese patients with HER2-mutant advanced NSCLC. All 35 patients received T-DXd as second- or further-line treatment. Median PFS was 7.85 months, and the ORR was 51.4%. No grade ≥3 AEs occurred. These data supported the use of T-DXd for previously treated patients with HER2-mutant advanced NSCLC in clinical practice.
T-DXd has been approved by both the United States Food and Drug Administration (FDA) and China National Medical Products Administration for the treatment of patients with previously treated HER2-mutant advanced NSCLC based on the pivotal global trials (DESTINY-Lung01 and DESTINY-Lung02) and bridging trial in China (DESTINY-Lung05) (17-20). At the approved dose of 5.4 mg/kg, T-DXd resulted in a median PFS of 10.0 months and an ORR of 50.0% in DESTINY-Lung02 (19), and a 12-month PFS rate of 55.1% and an ORR of 58.3% in DESTINY-Lung05 (20). Compared with these two studies, our study showed a similar ORR but a lower median PFS. This might be due to the fact that our study enrolled a broader population in the real-world setting, including some fragile patients who were commonly excluded from clinical trials. Nevertheless, our results were still better than those with trastuzumab emtansine [median PFS, 5 months; ORR, 44% (8/18) (21)], which is a previously recommended therapy for this population (13). Regarding other newly developed therapies, the HORIZON-Lung trial showed a median PFS of 11.5 months and an ORR of 73% with trastuzumab rezetecan (a HER2-directed ADC) in patients with previously treated advanced NSCLC harboring an activating HER2 mutation (22), which has been approved in China. The Beamion LUNG-1 trial showed a median PFS of 12.4 months and an ORR of 71% with zongertinib (a HER2-TKI) in patients with previously treated advanced NSCLC harboring a HER2 mutation in the tyrosine kinase domain (12), which has been approved by FDA and has become another preferred option besides T-DXd (13). The development of another promising HER2-TKI (BAY 2927088) is ongoing, with a median PFS of 7.5 months and an ORR of 72% in the SOHO-01 trial (23). Given the retrospective nature of our study and the small sample size, cross-study comparisons should be interpreted with caution. In addition, all these previous data were generated from single-arm trials. Head-to-head comparisons are warranted to determine the optimal treatment option.
Consistent with previous reports (24,25), HER2 mutations predominantly occurred in exon 20 [68.6% (24/35)] in our study. Unfortunately, subgroup analysis by mutation type could not be performed because very limited patients in our study had other HER2 mutations and HER2 mutation was detected by PCR rather than NGS in 2 (5.7%) patients. The impact of T-DXd in patients with advanced NSCLC harboring uncommon HER2 mutations still needs further investigation. Regarding co-alterations, previous studies revealed the negative impact of TP53 co-mutation on prognosis in patients with HER2-mutant advanced NSCLC treated with HER2-TKIs (26,27). However, an opposite phenomenon was observed in our study. It seemed that patients with TP53 co-mutation achieved better median PFS (10.41 vs. 6.83 months) and ORR (72.7% vs. 38.1%) than those without TP53 co-mutation. A previous research supported our finding although it explored B7H3-ADC and was conducted in prostate cancer models (28). The exact predictive role of TP53 co-mutation in patients treated with HER2-directed ADC still needs further investigations.
Our subgroup analyses also indicated that the response and PFS benefit were observed in patients who had previously received chemotherapy (median PFS: 9.99 months; ORR, 52.2%) or immunotherapy (median PFS: 10.41 months; ORR, 47.1%), and in those who had brain metastases at baseline (median PFS: 7.89 months; ORR, 46.2%). These meaningful findings are supported by previous clinical trials (17,18). However, patients who had previously received anti-angiogenic therapy appeared to have a worse prognosis during T-DXd treatment (median PFS: 6.37 months; ORR, 36.4%). We speculated that this unexpected finding was an incidental phenomenon due to the limited sample size. Whether previous anti-angiogenic therapy truly affects the antitumor activity of T-DXd remains to be further investigated. On the other hand, elderly patients are generally underrepresented in clinical trials. Ten (28.6%) of the patients in our study were aged ≥65 years. The results preliminarily suggest that these elderly patients could also benefit from T-DXd (median PFS: 7.18 months; ORR, 60.0%) with good tolerability, which deserves further validation.
Interstitial lung disease (ILD) is one of the major safety concerns that need attention during T-DXd treatment. In our study, the overall incidence of AEs (65.7%) was greatly lower than that documented in previous reports (97–100%) (17,18), and no ILD events occurred. This might be due to the fact that AE monitoring and collection in this retrospective study could not be as strict as clinical trials. Thus, large sample data are warranted to observe the occurrence of ILD associated with T-DXd in the real-world setting.
There are some limitations in this study. First, bias was inevitable given the retrospective design. Second, multivariate analysis was hard to be performed given the small sample size, and the subgroup analyses were underpowered to draw any conclusions. All the insights from the subgroup analyses need further validations. Third, the follow-up time was relatively short, with immature OS data. Finally, AEs might be underreported, such as grade ≥3 hematological toxicities that are not easily perceived by patients. A large-scale study with long-term follow-up is needed to comprehensively evaluate the effectiveness and safety of T-DXd for the treatment of Chinese patients with HER2-mutant advanced NSCLC in the real-world setting.
Conclusions
In conclusion, this study supplements real-world evidence on T-DXd treatment in Chinese patients with previously treated HER2-mutant advanced NSCLC. The results preliminarily showed the favorable antitumor activity and acceptable safety profile of T-DXd in this population, which deserves to be validated in a larger prospective study.
Acknowledgments
None.
Footnote
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-916/rc
Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-916/dss
Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-916/prf
Funding: This study was supported by
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-916/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the ethics committees of Shanghai Chest Hospital (No. IS25019) and Fudan University Shanghai Cancer Center (No. 2503-Exp159). Informed consent was waived in this retrospective study.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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