Trastuzumab deruxtecan (DS8201) for advanced non-small cell lung cancer with HER2 exon 20 insertion mutation: a case report

Abstract

An antibody-drug conjugate (ADC) of human epidermal growth factor receptor-2 (HER2) provides effective treatment for patients with HER2-positive non-small cell lung cancer (NSCLC). Exon 20 insertion mutations are the most common among HER2 mutations. This mutant subtype is highly drug-resistant, and patients receiving conventional treatment often have a poor prognosis. Trastuzumab deruxtecan (T-DXd), a novel anti-HER2 ADC, has emerged as a novel treatment option for HER2-positive (mutated, expressed, amplified, alternated) NSCLC, based on several studies and reported results. Herein, we report a case of stage IV NSCLC with HER2 exon 20 mutation in a 52-year-old male patient whose tumor recurred after radical resection of pulmonary carcinoma, who could not tolerate chemotherapy, and presented with bone metastasis. After treatment with T-DXd, the tumor significantly regressed and bone metastasis improved, maintaining a state of no progression for 21 months. This case report evidences the use of T-DXd in the treatment of NSCLC with HER2 exon 20 insertion mutation.

Introduction

According to the Global Cancer Statistics 2020, there were approximately 19.3 million new cancer cases and nearly 10 million deaths in 2020 due to cancer in countries and territories worldwide [1]. Lung cancer has the highest incidence and mortality rate, among which non-small cell lung cancer (NSCLC) accounts for approximately 80% of the total incidence [2]. The early stages of lung cancer have a more insidious onset, less typical early clinical symptoms, and are prone to hematogenous and lymph node metastasis at an early stage, with most patients already in the middle or late stages of the disease when detected, subverting the opportunity for radical surgical treatment. Often due to the pharmacological characteristics of drugs themselves, conventional chemoradiotherapy also causes significant damage to normal tissue cells in the process of killing tumor cells, resulting in different degrees of adverse effects.

In recent years, our enhanced understanding of the genetic level of cancer, striking advances in molecular biology, as well as the advent of precision-targeted therapy, has provided a new treatment modality for a variety of malignancies. The common driving genes of NSCLC include epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase, and epithelial-mesenchymal transition factor. Their corresponding targeted drugs have also been recommended by the American Society of Clinical Oncology and the National Comprehensive Cancer Network as treatment options [3,4]. The incidence of human epidermal growth factor receptor-2 (HER2) mutations in NSCLC is approximately 1–4% [4]. Presently, HER2 positivity is generally accepted as one of the driver genes of NSCLC, a condition that is of global concern and researched worldwide.

Since the marketing approval of trastuzumab, it has served as a powerful targeted therapy for cancer patients with HER2-positive. Among the treatments, targeted therapy for HER2 has illustrated good therapeutic effects in breast and gastric cancers. However, for many patients with HER2-positive cancer, satisfactory therapeutic effects have not been achieved.

Approximately 90% of the mutational subtypes in HER2 mutations are exon 20 insertion mutations; HER2 exon 20 insertion mutations have a similar positional structure to EGFR exon 20 insertion mutations and, likewise, present with self-intrinsic drug resistance, resulting in relatively poor drug treatment efficacy [5]. Trastuzumab and pertuzumab do not show significant survival benefits in terms of clinical treatment with HER2-positive NSCLC [6]. Conversely, trastuzumab deruxtecan (T-DXd) indicates unique advantages as a novel antibody-drug conjugate (ADC) in solid tumors with HER2-positive disease. Herein, we report the case of a patient with NSCLC and HER2 exon 20 insertion mutation. After using T-DXd, the tumor regressed significantly and bone metastasis improved significantly, with controllable adverse reactions. At the time of writing, there has been no progression for 21 months.

Case report

The patient was a 52-year-old man who had a history of diabetes for more than 20 years and regularly used insulin therapy. The patient had no smoking history and no family history of tumors. In January 2021, due to a high carcino-embryonic antigen (CEA) (21.23 ng/ml) detected during a physical examination, a PET-computed tomography (CT) examination revealed a soft tissue nodule (14.8 mm) in the right upper lobe of the lung adjacent to the mediastinum, with increased glucose metabolism. It was considered a malignant lesion (Fig. 1). Chest-enhanced CT showed a nodular shadow (1.7 cm × 1.3 cm) in the apical segment of the upper lobe of the right lung, which was defined as peripheral lung cancer. This was followed by the thoracoscopic radical resection of pulmonary carcinoma (uniportal thoracoscopic resection of the upper lobe of the right lung plus lymph node dissection).

Fig. 1.

A soft tissue nodule in the parametrium of the apical segment of the upper lobe of the right lung with increased glucose metabolism (max:12.0 SUV) is considered to be a malignant lesion.

Postoperative pathological biopsy results indicated invasive adenocarcinoma of the upper lobe of the right lung with lymph node metastasis. Next-generation sequencing (NGS) suggested HER2 exon 20 insertion mutation. In March 2021, two cycles of chemotherapy (0.9 g pemetrexed+0.5 g carboplatin) were administered. Due to decreased white blood cell levels after chemotherapy, the chemotherapy dosage was adjusted (0.7 g pemetrexed+0.4 g carboplatin). After the third cycle of chemotherapy, multiple follow-up examinations showed a progressive increase in CEA. In July 2021, a PET/CT reexamination revealed the thickening of soft tissue at the bronchial stump with increased metabolism and decreased bone density and increased metabolism in the left portion of the ninth thoracic vertebral body, indicating tumor recurrence with bone metastasis (Fig. 2). Bone metastasis was diagnosed following an additional bone scan. The patient was willing to receive further treatment and, based on previous NGS results, T-DXd 400 mg treatment was prescribed every 3 weeks.

Fig. 2.

Thickening of the soft tissue in the bronchial section of the upper lobe of the right lung with increased metabolism (a and c, max: 5.3 SUV) suggests tumor recurrence. Decreased bone density in the left part of the 9 thoracic vertebrae with increased metabolism, suggesting bone metastasis (b and d, max:13.3 SUV).

After the first treatment with T-DXd, degree III myelosuppression was observed, which improved after symptomatic treatment. The dose was adjusted to 300 mg, starting from the second cycle with T-DXd, and the CEA showed a downward trend after reexamination. Subsequent PCT/CT examinations showed significant tumor regression and improved bone metastasis (Fig. 3). This indicated that the T-DXd treatment had been effective. Continuing to receive this dose of treatment, no significant new tumor lesions were found on multiple imaging examinations, and no significant increase in CEA was observed on multiple examinations (Figs. 4 and 5). After 13 cycles of T-DXd treatment, the CEA showed a gradual increase, and the T-DXd dosage was adjusted to 400 mg every 3 weeks. Afterward, multiple follow-up CEA examinations showed a progressive decrease to the normal range, and multiple imaging examinations indicated stable disease(Fig. 6). The degree II myelosuppression after T-DXd treatment occurred intermittently, beginning with the third cycle of treatment, and improved after treatment alongside a symptomatic rise in platelet and white blood cell levels.

Fig. 3.

Soft tissue thickening in the upper lobe of the right lung at the bronchial section was reduced after two cycles of T-DXd treatment, accompanied by a lower metabolism than before (a and b, max: 4.7 SUV). Osteogenic changes on the left side of the 9 thoracic vertebrae; no metabolic increase was observed. Improvement following the treatment of bone metastases suggests effective treatment (c and d, max: 5.3 SUV).

Fig. 4.

After five cycles of T-DXd treatment, the soft tissue at the bronchial stump of the upper lobe of the right lung was lighter than before, with mild metabolic activity (a and c, max:1.8 SUV). Osteogenic changes were observed in the left part of 9 thoracic vertebrae, and no hypermetabolism was found (b and d), suggesting the disease was stable.

Fig. 5.

After nine cycles of T-DXd treatment, no significant changes in the soft tissue of the bronchial break in the upper lobe of the right lung were observed, with mild metabolic activity (a and c, max: 2.3 SUV). The left component of the 9 thoracic vertebrae is osteogenic and no metabolic increase is observable (b and d). This suggests the disease was stable with no recurrence or metastasis, indicating effective treatment.

Fig. 6.

Trends in CEA following the T-DXd treatment.

Discussion

HER2 is a proto-oncogene, a transmembrane glycoprotein with tyrosine–protein kinase activity, encoded as HER2 protein, and is a member of the ErbB family, along with the EGFR gene. HER2 gene mutations frequently occur in exons 18–21 of the tyrosine kinase (TK) domain; frameshift non-coding insertion mutations in exon 20 of the TK region are the most common, accounting for approximately 90% [7]. The most common is an insertion coding for amino acid YVMA at codon 776. The transcriptional translation of HER2 exon 20 results in α- the C-terminal of the C-helix inserts an amino acid sequence, causing the phosphate binding ring to shift into the drug binding bag following a change in spatial conformation. The result is that the spatial structure of the TK region drug binding bag is squeezed, making it difficult for the drug binding bag to bind to most TK inhibitors (TKIs), making it difficult to exert the inhibitory effect of the HER2 pathway [8].

Due to the inherent resistance carried by HER2 exon 20 insertion mutation, it has become a topic of strong focus in recent years. Multiple studies have shown that the median progression-free survival (mPFS) of HER2-positive patients with advanced lung adenocarcinoma is 11–23.4 months [9–11], and the overall survival (OS) rate for HER2-positive NSCLC is significantly shorter compared with HER2-negative NSCLC [11,12]. One result showed that in the HER2 mutation population, the mPFS and overall response rate (ORR) of patients with YVMA insertion mutation after first-line chemotherapy were significantly lower and related to the incidence rate of brain metastasis [13]. Taken together, HER2 exon 20 insertion mutation predicts poor treatment efficacy and prognosis. The European Society for Medical Oncology suggests that HER2 gene mutations should be performed early, with priority given to sequencing HER2 exon 20 insertion mutations. For unresectable stage III or IV NSCLC, HER2 mutation testing should be performed if the patient meets two or more of the following criteria: 1. female; 2. non-smoking; 3. The presence of lung adenocarcinoma or lung squamous cell carcinoma [14].

For NSCLC with HER2 mutation, treatment with mAb (e.g. trastuzumab) or TKI (e.g. afatinib) showed no obvious therapeutic effect. The NICHE study explored the efficacy of afatinib in the treatment of patients with advanced NSCLC and HER2 exon 20 insertion mutation [15]. The study included 13 patients but was terminated because the experiment did not achieve the expected results. Disease control could only be achieved for half of the patients for 12 weeks. The PFS was 15.9 weeks, and the mean OS (mOS) was 56.0 months. The efficacy was not as good as traditional chemotherapy. Another study showed an overall ORR of less than 20% in the afatinib-treated patients with HER2-positive NSCLC, in which the A775G776insYVMA subtype was associated with an ORR of 33% and a PFS of 9.6 months [16]. Trastuzumab had an objective effect in the treatment of HER2-positive breast and gastric cancers but had a poor effect on HER2-positive NSCLC [6]. In a study on trastuzumab in the treatment of HER2 amplification and the evaluation of mutation efficacy, the results showed that it was effective for a few mutations and in amplification but not for most mutations, including exon 20 insertion mutations [17].

T-DXd is a new ADC that acts on HER2. It is linked by anti-HER2 mAb immunoglobulin G1 and camptothecin derivative (DX8951 derivative, DXd), a type I topoisomerase inhibitor. The ratio of DXd to antibody is 8:1. DXd-killing cell microtubules are released after degradation in cells. Due to the ‘bystander effect’, ADC drugs can prevent the weakened efficacy of tumors due to heterogeneity [18]. In a phase I study, 11 patients withHER2-positive NSCLC who were treated with T-DXd had an ORR of 72.2% [19]. DESTINY-Lung01 is a multicenter, single-arm, phase II experiment that evaluated the efficacy of T-DXd in HER2-positive NSCLC cases [20]. The study results showed an mPFS of 8.2 months and an mOS of 17.8 months, with 50 patients achieving an objective response, including those with brain metastases. In August 2022, the Food and Drug Administration approved T-DXd for the treatment of HER2-positive NSCLC, thereby becoming the first ADC approved for NSCLC treatment. However, the toxicity and adverse reactions of T-DXd reported by DESTINY-Lung01 have also become a focus, with most patients experiencing adverse events (88/91); drug-related adverse events of grade 3 or higher occurred in 46% of these patients. The most common was neutropenia (19%). Drug-related interstitial lung disease (ILD) was present in 26% of patients and two patients died. Therefore, the treatment should be interrupted when ILD is suspected. Laboratory tests and high-resolution CT should be performed to assess the severity of the disease and start symptomatic treatment.

Mariona et al. reported two cases of drug-induced cardiotoxicity manifesting as acute myocarditis after using T-DXd [21]. The neuregulin-1 (NRG1) signaling pathway is key to the cardiac stress response. NRG1 binds to the HER2-ErbB4 receptor dimer at the plasma membrane of cardiomyocytes and activates downstream signaling molecules, thereby combating oxidative stress and inducing cell death, enabling trastuzumab to block NRG1 functioning and leading to DNA mobilization and mitochondrial apoptosis [22,23]. According to the guidelines on cardio-oncology recommendations, when cardiac dysfunction occurs with HER2-targeted therapy, treatment can be provided using an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and β-receptor blockers [24].

To address related issues, DESTINY-Lung02 conducted further exploration and analysis and received the 5.4 mg/kg and 6.4 mg/kg doses, respectively, indicating that T-DXd receiving the 5.4 mg/kg dose had a more optimal ORR (57.7%) and a lower incidence of drug-related ILD (59% vs. 14.0%) [25]. There are many more questions and challenges to explore in this context, such as the efficacy of T-DXd in first-line treatment and the combination of immunotherapy and T-DXd as a treatment.

Conclusion

This paper reported the case of a middle-aged patient with advanced NSCLC who developed tumor recurrence and bone metastasis after surgical treatment. Conventional chemotherapy was not tolerated and NGS suggested HER2 exon 20 insertion mutation. Combining the NGS results with previously published clinical studies and related data, T-DXd treatment was selected. After T-DXd treatment, the patient’s condition improved rapidly, and CEA showed a progressive decrease. The imaging examination results showed significant tumor regression and improvement concerning bone metastasis. The patient started using T-DXd at a dose of 400 mg (6.0 mg/kg), which was subsequently reduced to 300 mg (4.5 mg/kg); the dose was continued for 13 cycles, imaging review indicated the disease was stable, and adverse effects were controlled. Because CEA increased, to control the condition, the dose was adjusted to 400 mg; a review of CEA showed a decreasing trend, and assessment imaging suggested the disease was stable. At the time of writing, the patient has shown no disease progress for 21 months.

In summary, this case report confirms the significant efficacy of T-DXd for treating NSCLC with HER2 exon 20 insertion mutations.

Acknowledgements

The authors would like to thank the patient’s family for providing the information about the patient. The Internal Medicine-Oncology Ethics Committee of Shaanxi Provincial People’s Hospital approved this study, and the patient’s family members provided informed written consent to publish the case details and relevant pictures. The authors are also deeply indebted to all the tutors and teachers for their direct and indirect assistance and helpful advice.

This project was supported by the Medjaden Academy & Research Foundation for Young Scientists (Grant No. MJA202306010), Shaanxi Provincial People’s Hospital Science and Technology Talent Support project (2021JY-11), National Science Basic Research Program of Shaanxi Province (2022JQ-983).

Conceptualization, Gaili An and Xincheng He; methodology, Jun Bai; validation, Xincheng He, Gaili An and Jun Bai; investigation, Xincheng He and Lei Hou; writing – original draft preparation, Xincheng He; writing – review and editing, Jun Bai; visualization, Chao Sun; supervision, Dongjie Wang.; funding acquisition, Gaili An and Chao Sun.

Informed consent statement: The patient’s family gave informed consent to publish this report and related images.

Conflicts of interest

There are no conflicts of interest.