Dan Li,* Xin Liu,* Yang Liu, Yue Zhu, Dafu Yang, Jincheng Song, Zhaoxia Dai

Department of Medical Oncology, The Second Hospital of Dalian Medical University, Dalian, People’s Republic of China

Correspondence: Jincheng Song, Department of Medical Oncology, The Second Hospital of Dalian Medical University, No. 467, Zhongshan Road, Shahekou District, Dalian, People’s Republic of China, Email [email protected] Zhaoxia Dai, Department of Medical Oncology, The Second Hospital of Dalian Medical University, No. 467, Zhongshan Road, Shahekou District, Dalian, People’s Republic of China, Email [email protected]

Abstract: The effectiveness of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) has been established, leading the NCCN Guidelines to recommend it as a first-line treatment for patients with advanced EGFR mutation-positive non-small cell lung cancer (NSCLC). However, there is still controversy about the use of neoadjuvant TKI treatment for patients with stage III EGFR mutation-positive NSCLC. Here, we firstly report that a stage IIIA lung adenocarcinoma patient benefited from chemotherapy and dacomitinib as neoadjuvant targeted therapy based on EGFR G719X mutation, achieving a pathological downstaging and the chance of radical surgical resection. Our case describes dacomitinib use as neoadjuvant targeted therapy for EGFR positive advanced NSCLC and highlights the application of molecular testing for the better treatment decision making.

Keywords: uncommon EGFR mutations, EGFR G719X, neoadjuvant targeted therapy, dacomitinib, NSCLC

Introduction

For advanced non-small cell lung cancer (NSCLC) patients with common epidermal growth factor receptor (EGFR) mutations (exon 19 deletions or the exon 21 L858R mutation), EGFR tyrosine kinase inhibitors (TKIs) are the standard therapies.1 In addition, major uncommon EGFR mutations, such as G719X, S768I, and L861Q, have shown sensitivity to EGFR-TKIs, especially the second-generation TKI.2 Dacomitinib is a highly selective second-generation EGFR-TKI that irreversibly blocks signaling from both heterodimers and homodimers of all members of the human EGFR family.3 Dacomitinib has potential applications for patients with rare mutations.4,5 In addition, dacomitinib demonstrated strong effectiveness in patients with brain metastases, while also posing a relatively low risk of side effects.5 In a Chinese cohort study, dacomitinib demonstrated potential efficacy with manageable toxicity in advanced NSCLC patients harboring major uncommon EGFR mutations (G719X/S768I/L861Q).6

Most patients with stage III NSCLC have missed the opportunity for radical surgery at the time of initial diagnosis. In recent years, neoadjuvant and adjuvant targeted therapy has offered a convenient treatment option for NSCLC patients with EGFR mutations.7 In these patients, neoadjuvant targeted therapy is significantly more effective than chemotherapy, leading to a more noticeable reduction in the size of the primary tumor. This makes patients more likely to be eligible for radical surgery.8 Additionally, adjuvant targeted therapy provides a convenient treatment option, allowing patients to benefit from improved survival outcomes.8 Here, we firstly reported a patient with stage III NSCLC carried EGFR G719X, who was successfully treated with surgical resection following dacomitinib as neoadjuvant targeted therapy.

Case Presentation

A 54-year-old Chinese male with 30 years of smoking history presented with a worsening cough for 3 months, with a performance status score of 1. In April 2023, an enhanced computed tomography (CT) revealed a 22 mm × 12 mm × 16 mm mass in the right upper lobe with invasion in the right hilum and mediastinal (Figure 1A and B), which were confirmed by positron emission tomography-CT (PET-CT) scan. Immunohistochemistry (IHC) analysis of the biopsy from the lesion in the upper right lobe of the lung was positive for TTF-1, NpA, CK7, CD5/6 and Ki67 (60%); and negative for p40, p63 and CD56. The patient was diagnosed with stage IIIA lung adenocarcinoma (cT1cN2M0). The follow-up targeted NGS analysis of his lung lesion biopsy identified an EGFR G719X with a mutant allele frequency (MAF) of 3.8%. After a multiple disciplinary team (MDT) discussion, the initial tumor was considered unresectable due to metastasis in the right hilum and mediastinum. In May 2023, two cycles of PC chemotherapy (pemetrexed with 0.9g d1 and carboplatin with 600mg d1) and dacomitinib (30mg) were given. The chest CT showed obvious shrinkage in the lesions in the right upper lung lobe and the lymph nodes of the mediastinum, contributing to partial response (PR) (Figure 1B). In July 2023, video-assisted thoracic surgery (VATS) with right upper lobectomy was performed. Intraoperative exploration revealed that the tumor was located in the right upper lobe, measuring approximately 1.5*1.5 cm with unclear boundaries. The postoperative pathology results indicated that 10% of the tumor cells remained alive, surrounded by significant fibrosis, necrosis, as well as inflammatory and immune cells (Figure 2A and B). After chemotherapy and dacomitinib induction, there were no lymph node metastases, and the pathological stage was ypT1bN0M0. After the surgery, two cycles of PC chemotherapy were administered, followed by targeted therapy with dacomitinib as adjuvant treatment for 2 more years in accordance with the diagnosis and treatment guidelines. At the final follow-up in September 2024, no adverse events or disease progression had occurred. A progression-free survival (PFS) of more than 14 months was achieved.

Figure 1 Representative clinical images during the treatment course. (A) Disease time line illustrated the different treatment received by the patient. (B) Radiological evaluation of the primary tumor and lymph nodes both at the baseline and after neoadjuvant therapy.

Abbreviations: LUAD, lung adenocarcinoma; NGC, next-generation sequencing; PC, pemetrexed and carboplatin.

Figure 2 The photograph and hematoxylin and eosin (HE) staining for the lesions. (A) The photograph shows the lesion in the upper right lobe of the lung that was removed during surgery. (B) HE staining (200×) of the lesion in the upper right lobe of the lung following neoadjuvant therapy.

Discussion

Because stage III NSCLC is highly heterogeneous, a single treatment strategy may not sufficiently meet the clinical needs of all patients with this condition. Patients who are potentially operable may have the opportunity for radical resection through neoadjuvant therapies. Previous case reports have demonstrated the effectiveness of neoadjuvant targeted therapy in controlling the disease and achieving pathological downstaging in NSCLC.8,9 To our knowledge, this is the first case of neoadjuvant chemotherapy and dacomitinib for NSCLC patients with EGFR G719X.

Approximately 50% of NSCLCs in Asians have the EGFR mutation. The G719X mutation occurs at exon 18 of the EGFR gene, including G719S, G719A, G719C and G719D.10 The G719X mutation accounts for about 3% among all EGFR mutations and is considered an uncommon type of EGFR mutation.11 G719X is considered moderately sensitive to first-generation EGFR-TKI.10 However, it is more sensitive to the second-generation EGFR-TKI.12,13 This sensitivity is due to the mutation increasing the distance between L718 and G796, which in turn makes the binding pocket for adenosine triphosphate more open and better able to interact with EGFR-TKIs.14

Dacomitinib is a highly selective and irreversible second-generation EGFR-TKI that inhibits all human EGFR signaling pathways. Some clinical trials have investigated its use in patients with advanced NSCLC with uncommon EGFR mutations, including G719X, L861X and S768I. Moreover, the adverse effects were found to be within acceptable and tolerable limits.5 Dacomitinib could be a treatment option for patients with uncommon EGFR mutations in first-line therapy.

Previous studies demonstrated that neoadjuvant targeted therapy significantly benefits patients with EGFR mutation-positive stage IIIA NSCLC, offering advantages over neoadjuvant chemotherapy in terms of toxicity and tumor response rates.15–17 Zhang et al reported on a patient diagnosed with right upper lung adenosquamous carcinoma (c-T3N2M0) who had an EGFR L858R mutation. The patient was treated with dacomitinib as neoadjuvant therapy and achieved a PR and a successful R0 resection.18 The current literatures suggest that neoadjuvant therapy with EGFR-TKI increase the rate of radical surgical resection, reduce tumor volume and improve imaging response, but does not translate into disease downstaging or pathological remission.19 However, in our case following chemotherapy and dacomitinib induction, pathological downstaging was observed. This might be due to the positive response of EGFR G719X to dacomitinib, so molecular testing and biomarker screening are necessary to optimize the clinical outcomes of targeted neoadjuvant therapy. The limitation of presenting a single case in this study should be noted. Thus, the efficacy and adverse events of the neoadjuvant chemotherapy and targeted therapy must be further evaluated in larger cohorts.

Conclusion

In summary, we reported the first case of a stage IIIA lung adenocarcinoma with an EGFR G719X mutation, who received the neoadjuvant chemotherapy and dacomitinib targeted therapy and achieved the pathological downstaging and the chance of radical surgical resection. This report provides a promising option for stage III EGFR-positive NSCLC. Moreover, we also highlighted the importance of molecular testing for the use of neoadjuvant targeted therapy. Because this study is based on a single case, additional clinical evidence is required for further investigation.

Ethics Approval

Institutional approval was not required to publish the case details.

Consent for Publication

Written informed consent was obtained from the patient for publication of this paper and any accompanying images.

Acknowledgment

We would like to thank our patient and his family for their support.

Funding

This work was supported by the Special Fund for Clinical Research of Wu Jieping Medical Foundation under Grant 320.6750.2021-16-28.

Disclosure

The authors have no competing interests to declare.

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