ERBB2 Exon 20 Mutation-Guided Trastuzumab Deruxtecan Therapy in Metastatic Lung Adenocarcinoma with Low HER2 Expression: A Case Report

Abstract

HER2 mutations are uncommon in lung adenocarcinoma, and treatment options become limited after failure of standard systemic therapies. We report a 69-year-old woman with metastatic lung adenocarcinoma involving multiple lymph nodes, bone, and the left adrenal gland. Histopathological and immunohistochemical examinations strongly supported a diagnosis of primary pulmonary adenocarcinoma. Targeted next-generation sequencing (NGS) performed at initial diagnosis in January 2024 identified an ERBB2 exon 20 in-frame insertion mutation (p.Y772_A775dup). The patient received six sequential treatment regimens, including platinum-based chemotherapy, PD-1 inhibitor therapy, antiangiogenic therapy, and palliative radiotherapy. Initial tumor regression was observed, but sustained disease control was not achieved. Following further disease progression, the previously identified ERBB2 mutation was reassessed by the multidisciplinary team in 2025. HER2 immunohistochemistry showed an IHC score of 1+. Based on the activating ERBB2 mutation, trastuzumab deruxtecan (T-DXd) was initiated in June 2025 at a fixed dose of 200 mg per administration (approximately 3.2 mg/kg), lower than the standard starting dose for HER2-mutant NSCLC. Five doses were administered between June and November 2025. Serum carcinoembryonic antigen and carbohydrate antigen 19–9 levels decreased markedly after treatment. Serial chest computed tomography indicated radiological disease stabilization for approximately 5 months, with no clinically significant treatment-related adverse events documented. This case highlights the value of molecular profiling in identifying actionable ERBB2 mutations despite low HER2 protein expression. It also provides a real-world observation of disease stabilization with a lower-than-standard initial dose of T-DXd, although conclusions regarding reduced-dose efficacy cannot be drawn from a single case.

Introduction

Non-small-cell lung cancer (NSCLC) is characterized by molecular heterogeneity, with multiple signaling pathways contributing to tumor progression. Recent research has shown that RAB5IF promotes NSCLC cell proliferation and migration through the AKT–mTOR signaling pathway.¹ Human epidermal growth factor receptor 2 (HER2), encoded by ERBB2, represents an uncommon oncogenic driver in NSCLC. ERBB2 mutations occur in approximately 1–3% of lung adenocarcinomas, with exon 20 insertions being the most common mutation type.^2,3

Trastuzumab deruxtecan (T-DXd) is a HER2-targeted antibody-drug conjugate, which is composed of a humanized anti-HER2 antibody, and linked through a cleavable linker to a topoisomerase I inhibitor payload. Once bound to HER2, the drug is internalized, and the cytotoxic payload is released intracellularly, leading to DNA damage and tumor-cell death.⁴ Clinical trials have established T-DXd as an active treatment for previously treated HER2-mutant NSCLC, with 5.4 mg/kg every 3 weeks showing the most favorable benefit–risk profile.^5,6 T-DXd is associated with clinically significant adverse events, particularly interstitial lung disease (ILD) and pneumonitis, and its toxicity profile may vary with the administered dose. The efficacy and safety of starting doses below the recommended 5.4 mg/kg regimen remain uncertain.

Here, we report a patient with metastatic lung adenocarcinoma harboring an ERBB2 exon 20 p.Y772_A775dup mutation who experienced disease progression after multiple systemic therapies. T-DXd was then administered at a fixed dose of 200 mg, corresponding to approximately 3.2 mg/kg. This dose was lower than the standard starting dose used in HER2-mutant NSCLC. During treatment, serum tumor markers decreased markedly. Radiological stable disease was maintained for approximately 5 months. No clinically significant treatment-related adverse events were observed. This case provides a real-world example of individualized T-DXd treatment in a later-line setting and suggests that alternative dosing strategies warrant further study.

Case Presentation

A 69-year-old woman presented on 7 January 2024 with progressive low-back pain lasting approximately 2 months. She had no respiratory symptoms, gastrointestinal bleeding, changes in bowel habits, fever, or unintentional weight loss. Ten years ago, she had undergone R0 resection for rectal cancer. She had not received regular oncological follow-up during the previous 4 years. She had no major chronic disease, and no family history of lung or colorectal cancer. She had never smoked and did not consume alcohol. Physical examination showed mild tenderness over the L2-S1 vertebral region and an enlarged right supraclavicular lymph node, without focal neurological deficits or clinically significant cardiopulmonary or abdominal abnormalities.

Non-contrast chest computed tomography (CT) performed on 7 January 2024 showed a 51×49 × 50 mm mass in the right upper lobe with obstructive pneumonic changes (Figure 1A). Osteolytic destruction of the T11 vertebral body was also observed (Figure 1B). Positron emission tomography-CT (PET-CT) performed on 9 January demonstrated intense fluorodeoxyglucose uptake in the primary lung lesion. Metastatic lesions were detected in the mediastinal, right hilar, and right supraclavicular lymph nodes, as well as the left adrenal gland and multiple skeletal sites. A left occipital dural-based lesion showed no fluorodeoxyglucose uptake and was considered radiologically compatible with a meningioma (Figure 2A). Follow-up PET-CT on 12 June 2024, after initial systemic treatment, showed marked regression of the primary lung lesion and decreased metabolic activity in the involved lymph nodes. However, the left adrenal lesion persisted, and the bone lesions showed a mixed response. A new low-density area in the right parietal region was also observed and was considered likely to represent edema (Figure 2B).

Figure 1.

Baseline chest CT findings. (A) Axial CT showing the right upper-lobe mass (red arrow). (B) Axial CT showing osteolytic destruction of the T11 vertebral body (red arrow).

Figure 2.

PET-CT findings before and after initial systemic treatment. (A) Baseline examination on 9 January 2024 with multiple fluorodeoxyglucose-avid lesions. (B) Follow-up examination on 12 June 2024 with a marked reduction in the size and metabolic activity of the right upper-lobe lesion and a mixed response at other metastatic sites.

A CT-guided biopsy of the lung mass was performed on 11 January 2024. Histopathological examination confirmed adenocarcinoma (Figure 3). Immunohistochemical analysis showed strong nuclear staining for thyroid transcription factor 1 (TTF-1) and diffuse positivity for Napsin A. CK5/6, P40, and P63 were negative, and the Ki-67 proliferation index was approximately 40% (Figure 4). These findings strongly supported a primary pulmonary origin. However, in the absence of CDX2 and CK20 staining results, metastatic colorectal adenocarcinoma could not be definitively excluded based on the available immunohistochemical findings alone. The patient was clinically staged as cT4N3M1c (stage IVB) NSCLC with extensive lymph-node, bone and left adrenal metastases.

Figure 3.

Hematoxylin and eosin staining of the CT-guided lung biopsy specimen. Scale bar = 300 μm.

Figure 4.

Immunohistochemical staining of the lung biopsy. (A) CK5/6 negative. (B) TTF-1 positive. (C) Ki-67 proliferation index approximately 40%, as determined by the hospital’s Department of Pathology. (D) Napsin A positive. (E) P40 negative. (F) P63 negative. Scale bar = 300 μm.

Following diagnosis, the patient underwent seven sequential treatment phases, as summarized in Table 1. Treatment response was assessed by serial imaging and longitudinal monitoring of serum CEA and CA19-9 levels (Figure 5).

Table 1.

Summary of the Treatment History of the Patient

Treatment phase	Treatment period	Treatment regimen
Round 1	Jan 27–Apr 16, 2024	Carboplatin (300 mg) + pemetrexed (500 mg) + tislelizumab (200 mg), 4 administrations
Round 2	May 7–29, 2024	Tislelizumab (200 mg), 2 administrations
Round 3	Jun 17–Oct 3, 2024	Carboplatin (300 mg) + pemetrexed (500 mg) + tislelizumab (200 mg), 5 administrations
Round 4	Oct 15–Dec 27, 2024	Tislelizumab (200 mg) + bevacizumab (400 mg), 3 administrations
Round 5	Jan 10–May 12, 2025	Gemcitabine (1.3 g) + cisplatin (45 mg), 5 administrations
Round 6	May 12–Jun 3, 2025	Palliative radiotherapy for painful bone metastases
Round 7	Jun 10–Nov 4, 2025	Trastuzumab deruxtecan (T-DXd), 200 mg per administration (approximately 3.2 mg/kg), 5 doses

Figure 5.

(A) Serum CEA and CA19-9 levels during treatment rounds 1–4 in 2024. (B) Serum CEA and CA19-9 levels during treatment rounds 5–7 in 2025. T-DXd was initiated in treatment round 7.

Round 1 (27 January–16 April 2024)

The patient received carboplatin 300 mg, pemetrexed 0.5 g, and tislelizumab 200 mg on 27 January, 21 February, 18 March, and 16 April 2024. Before treatment, PET-CT on 9 January 2024 revealed a hypermetabolic right upper-lobe lesion with multiple lymph-node, left adrenal, and skeletal metastases (Figure 2A). Serum CEA and CA19-9 levels decreased substantially during this treatment period (Figure 5A).

Round 2 (7–29 May 2024)

Tislelizumab 200 mg was administered on 7 and 29 May. Follow-up PET-CT on 12 June 2024 demonstrated marked regression of the primary lung lesion and decreased metabolic activity in the involved lymph nodes. However, the left adrenal lesion persisted, and the bone metastases showed a mixed response (Figure 2B). Serum CEA and CA19-9 levels also began to rise again after their initial decline (Figure 5A).

Round 3 (17 June–3 October 2024)

Carboplatin 300 mg, pemetrexed 0.5 g, and tislelizumab 200 mg were reintroduced on 17 June, 15 July, 12 August, 8 September, and 3 October. Serum CEA and CA19-9 levels fluctuated but showed an overall upward trend, indicating loss of the initial treatment benefit (Figure 5A).

Round 4 (15 October–27 December 2024)

The regimen was changed to tislelizumab 200 mg plus bevacizumab 400 mg. Treatment was administered on 15 October, 13 November, and 27 December 2024. Tumor-marker levels remained elevated despite the change in treatment (Figure 5A).

Round 5 (10 January–12 May 2025)

The patient received gemcitabine 1.3 g and cisplatin 45 mg on 10 January, 7 February, 24 March, 24 April, and 12 May 2025. Serum CEA and CA19-9 levels increased markedly during this period (Figure 5B).

Round 6 (12 May–3 June 2025)

Palliative radiotherapy was administered for painful bone metastases. However, systemic disease control remained poor, and serum CEA and CA19-9 levels reached their highest recorded levels before the subsequent treatment phase. Given disease progression after multiple systemic regimens, the case was reassessed by the multidisciplinary team. The molecular profiling results obtained at initial diagnosis in January 2024 were reviewed. Targeted NGS of the original lung biopsy specimen had identified an ERBB2 exon 20 in-frame insertion, NM_004448.4:c.2313_2324dup (p.Y772_A775dup), with a variant allele frequency of 24.48%. Although this mutation had been identified at initial diagnosis, T-DXd was not a standard first-line treatment option for HER2-mutant NSCLC at that time. Therefore, platinum-based chemotherapy combined with PD-1 inhibitor therapy was initially selected. Following disease progression despite multiple systemic treatments, the previously identified ERBB2 mutation provided the molecular basis for reconsidering HER2-directed therapy. HER2 immunohistochemistry of the archived tumor specimen showed weak membranous staining with an IHC score of 1+ (Figure 6). Based primarily on the activating ERBB2 mutation, T-DXd was subsequently selected for treatment.

Figure 6.

Histopathology and HER2 immunohistochemistry of the lung biopsy specimen. (A) Hematoxylin and eosin (H&E) staining of the lung adenocarcinoma specimen. (B) HER2 immunohistochemical staining, with an IHC score of 1+, as determined by the hospital’s Department of Pathology. Scale bar = 200 μm.

Round 7 (10 June–4 November 2025)

Based on the NGS finding of an activating ERBB2 exon 20 mutation, together with HER2 immunohistochemical assessment (IHC 1+), trastuzumab deruxtecan (T-DXd) was selected as HER2-directed treatment. The patient weighed approximately 62 kg at treatment initiation. Based on the recommended dose of 5.4 mg/kg, the calculated dose was approximately 334.8 mg, requiring four 100-mg vials per administration. Considering the patient’s financial constraints and the additional medication costs, a fixed dose of 200 mg per administration (approximately 3.2 mg/kg, two 100-mg vials) was selected. This dose was lower than the standard starting dose of 5.4 mg/kg for HER2-mutant NSCLC. T-DXd was administered by 90-minute intravenous infusion. Five doses were given on 10 June, 7 July, 8 August, 5 September, and 4 November 2025. Treatment intervals were prolonged because of anemia, and subsequent administrations were postponed until the anemia had been corrected, particularly between September and November 2025.

After T-DXd initiation, serum CEA and CA19-9 levels decreased markedly and remained substantially lower during follow-up (Figure 5). Serial chest CT scans from July to November 2025 showed that the measured diameter of the right upper-lobe lesion was 69.23, 64.38, 63.88, 64.32, and 63.32 mm, respectively (Figure 7 and Table 2). The lesion diameter decreased by approximately 8.5% between July and November 2025. However, these measurements were limited to the primary lung lesion, and a comprehensive RECIST 1.1 response assessment was not available. Radiological disease stabilization was maintained for approximately 5 months. No clinically significant treatment-related adverse events were documented during the follow-up period.

Figure 7.

Serial chest CT scans during trastuzumab deruxtecan (T-DXd) treatment. (A) July 2025. (B) August 2025. (C) September 2025. (D) October 2025. (E) November 2025. Red arrows indicate the right upper-lobe lesion.

Table 2.

Serial CT Measurements of the Right Upper-Lobe Lesion During T-DXd Treatment

CT Examination	Lesion Diameter (mm)
July 2025	69.23
August 2025	64.38
September 2025	63.88
October 2025	64.32
November 2025	63.32

Discussion

HER2-mutated NSCLC is a rare molecular subtype of lung cancer. ERBB2 mutations occur mainly in the kinase domain, and exon 20 insertions are the predominant subtype in lung adenocarcinoma.^2,3 In the present case, targeted NGS identified an ERBB2 exon 20 in-frame insertion mutation (p.Y772_A775dup) at initial diagnosis in January 2024. As T-DXd was not a standard first-line treatment option at that time, the patient initially received platinum-based chemotherapy combined with PD-1 inhibitor therapy. Following disease progression after multiple treatment regimens, the previously identified ERBB2 mutation was reassessed during multidisciplinary review and guided subsequent HER2-directed therapy.

An important feature of this case was the difference between HER2 mutation status and HER2 protein expression. HER2 immunohistochemistry was scored as IHC 1+, whereas NGS identified an activating ERBB2 mutation. HER2 mutation, amplification, and protein overexpression are distinct molecular alterations in NSCLC.^2,3 They should not be considered interchangeable. In DESTINY-Lung01, responses to T-DXd were observed in HER2-mutant NSCLC across different levels of HER2 protein expression.⁵ Therefore, low HER2 expression did not exclude the potential benefit of HER2-directed treatment in this patient. The treatment decision was mainly based on the activating ERBB2 mutation rather than HER2 protein overexpression.

T-DXd has shown clinical activity in previously treated HER2-mutant NSCLC.^5,6 DESTINY-Lung01 demonstrated durable responses in patients who had received previous systemic treatment.⁶ DESTINY-Lung02 further confirmed the activity of T-DXd at 5.4 and 6.4 mg/kg every 3 weeks.⁵ The 5.4 mg/kg regimen showed a more favorable efficacy and safety profile and became the preferred starting dose. Several case reports have also described clinical benefit from T-DXd in patients with HER2-mutated lung adenocarcinoma after previous treatment.^7,8

The dose used in the present case differed from the standard starting dose. The patient weighed approximately 62 kg and received a fixed dose of 200 mg, equivalent to approximately 3.2 mg/kg. This dose was lower than the recommended 5.4 mg/kg starting dose. The individualized dosing regimen was selected in consideration of the patient’s financial constraints and was not part of a prospectively designed dose-reduction strategy. Furthermore, the non-standard treatment intervals limit interpretation of the observed clinical outcome. During T-DXd treatment, serum CEA and CA19-9 levels decreased markedly. Serial chest CT scans from July to November 2025 showed no clear enlargement of the right upper-lobe lesion. Radiological disease stabilization was maintained for approximately 5 months. This was the longest documented period of disease control during the treatment course. However, this observation should not be interpreted as evidence that a lower starting dose is equivalent to the standard regimen. Further data are needed to determine whether reduced-dose T-DXd can maintain antitumor activity in selected patients.

The available clinical records did not establish a comprehensive treatment-related toxicity profile during T-DXd therapy. Anemia requiring correction contributed to treatment delays, although its relationship to T-DXd could not be definitively established. T-DXd is associated with clinically important adverse events, particularly interstitial lung disease or pneumonitis.^5,6 Serial chest CT examinations were performed during follow-up; however, formal CTCAE-based adverse event grading and a dedicated ILD monitoring protocol, and DLCO measurements were not documented. The potential influence of recent radiotherapy on pulmonary toxicity risk should also be considered, particularly if thoracic structures were included in the radiation field. Therefore, the absence of documented adverse events should not be interpreted as evidence of improved tolerability with reduced-dose T-DXd.

The marked changes in serum CEA and CA19-9 provided additional information on treatment response. However, CA19-9 is not specific for lung adenocarcinoma, and its interpretation is further limited by the patient’s history of rectal cancer. Both markers increased substantially before T-DXd treatment and decreased after treatment initiation. The decrease occurred together with radiological stability. However, the potential contribution of preceding palliative radiotherapy to the observed changes in tumor markers cannot be excluded. Nevertheless, tumor-marker changes alone cannot establish antitumor efficacy. Although serial measurements of the primary lung lesion were available (Table 2), a comprehensive RECIST 1.1 assessment of all disease sites was not performed. Therefore, the approximately 5-month period of disease stabilization should be regarded as a descriptive clinical observation.

The intracranial findings also require cautious interpretation. The baseline occipital dural-based lesion was considered more consistent with a meningioma. The later right parietal low-density area was interpreted as possible edema. Neither finding provided sufficient evidence of intracranial metastasis. Although intracranial activity of HER2-directed therapies is of clinical interest in HER2-mutated NSCLC,⁹ this case cannot be used to evaluate the intracranial efficacy of T-DXd.

The findings should be interpreted in light of the single-patient design, non-standard T-DXd dosing, the absence of formal ECOG performance status assessments at initial diagnosis and before T-DXd initiation, incomplete standardized response and toxicity assessments, and limited follow-up. Nevertheless, this case highlights the value of molecular profiling in identifying actionable ERBB2 alterations at initial diagnosis and reconsidering these findings during subsequent treatment decisions. It also provides a real-world observation of disease stabilization with lower-than-standard T-DXd exposure, which warrants further investigation.

Funding Statement

This work was supported by the Jiaxing Science and Technology Program (grant no. 2025CGW137).

Artificial Intelligence

AI tools were not used in the preparation of this manuscript.

Data Sharing Statement

The raw NGS data are not publicly available due to patient privacy and ethical considerations. Relevant de-identified molecular findings supporting the conclusions of this case report are included in the article. Additional de-identified data may be available from the corresponding author, Peng-Li Wang (E-mail: Wpl1016@outlook.com).

Ethics Statement

This case report was conducted in accordance with the Declaration of Helsinki. The Ethics Committee of the Second Affiliated Hospital of Jiaxing University determined that formal ethical approval was not required for this single-patient case report. Written informed consent was obtained from the patient for publication of the clinical details and accompanying images.

Consent for Publication

Written informed consent was obtained from the patient for publication of the clinical details and accompanying images.

Author Contributions

Zhao-Feng Gao collected the clinical data, reviewed the literature, and drafted the manuscript. Xu Wen, Jia-Qi Yu and Jun Zhang participated in patient management and diagnostic evaluation. Qian-Yu Chen contributed to data analysis and the preparation of clinical records and imaging materials. Xin-Wei Zhou contributed to treatment planning. Xue-Song He interpreted the clinical data, prepared the figures, and drafted and revised the manuscript. Peng-Li Wang supervised the clinical management and critically revised the manuscript. Xue-Song He and Peng-Li Wang contributed equally to this work as co-corresponding authors. Peng-Li Wang is the lead corresponding author and serves as the primary contact for all editorial communications.

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

There are no conflicts of interest.