JONT

Introduction

Over the last decade, non-small cell lung cancer (NSCLC) has become treatable through targeted therapy thanks to the identification of driver mutations using Next Generation Sequencing (NGS) analysis. These mutations are defined as actionable, as they are amenable to treatment with targeted agents that have dramatically improved survival rates in this patient population. In particular, the percentage of patients with epidermal growth factor receptor (EGFR) mutations is estimated to represent approximately 12% of all non-Asian patients with NSCLC [1].

This group of patients is further subdivided based on the type of EGFR mutation, which can be common or uncommon [2].

Common mutations, represented by exon 19 deletion and the L858R point mutation in exon 21, account for approximately 85-90% of EGFR-mutated cases and respond to first- and thirdgeneration TKIs [3, 4]. Uncommon mutations, on the other hand, account for 10-15% of EGFR-mutated cases and are characterized by enormous heterogeneity related to a different response to TKIs. The different therapeutic response depends on the mutated protein structure. Among the uncommon mutations, the most frequent are G719X (exon 18), L861Q (exon 21), exon 20 insertion (nonT790M), and S768I (exon 20) mutations. These are mutations that respond differently to second- or third-generation TKIs, and for which there is little data in the literature [5].

One of the drugs that has proven most effective in treating some of the uncommon mutations is Afatinib. It is an irreversible inhibitor of the ErbB family with simultaneous inhibitory action on both wild-type and mutated EGFR, ErbB2 and ErbB4 [1]. As described in the analysis conducted by Yang JC et al., which collected data from the LUX-Lung 2, 3 and 6 trials, Afatinib demonstrated objective response rates (ORR) of 60% and a duration of response (DoR) of 17.1 months in patients with major uncommon mutations (G719X, L861Q, and S768I) [6]. Available evidence suggests a potential role for TKIs in the management of ultra-rare EGFR mutations; notably, the therapeutic landscape is evolving and includes novel third-generation inhibitors, such as furmonertinib, that are currently being investigated [7].

The S645C point mutation of EGFR on exon 17 is based on the substitution of a serine with a cysteine on the tyrosine kinase domain of EGFR, resulting in a different intracellular response to TKIs. Preclinical studies have demonstrated resistance to Osimertinib in the S645C mutation [8, 9]. Furthermore, there is little data in the literature regarding the best therapeutic strategy for this class of patients. In the case report published by Shen CI et al. [10], the efficacy of using Afatinib plus Bevacizumab in the treatment of a patient with NSCLC with EGFR S645C mutation was demonstrated.

Our case report further reinforces the efficacy of Afatinib in the treatment of patients with the EGFR S645C point mutation, providing a therapeutic opportunity for this class of patients for whom the action of the target therapy typically used for common EGFR mutations is associated with resistance. Furthermore, this study highlights the importance of using liquid biopsy as a diagnostic tool in uncommon EGFR mutations [11].

Case Presentation

In March 2022, a 65-year-old female, never-smoker, with a personal history of estrogen receptor-positive (ER+) breast cancer and a family history of breast and gastric cancer, was evaluated due to an increase in carcinoembryonic antigen (CEA) levels. Imaging studies, including 18F-FDG PET/CT, revealed a solitary pulmonary nodule in the left upper lobe. The patient underwent wedge resection of the left upper lobe, and histopathological analysis identified a papillary-predominant invasive lung adenocarcinoma with a lepidic growth pattern, moderately differentiated (PL2), staged as pT2a pN0 (according to the 8th edition of the American Joint Committee on Cancer, AJCC).

At 6-month follow-up, due to persistently elevated CEA levels, radiological and PET/CT examinations demonstrated recurrence of pleural disease on the left side, which proved challenging to biopsy, even with minimally invasive approaches. In January 2023, a CT-guided biopsy of a left paravertebral pleural lesion confirmed recurrence of lung adenocarcinoma, TTF-1 positive and p40 negative. Programmed death-ligand 1 (PD-L1) expression was >50%, and next-generation sequencing (NGS) performed on pleural tissue sample, using Oncomine Comprehensive Assay (v3) NGS panel revealed pathogenic variants pathogenic variants in the BRCA2, TP53, and STK11 genes, none of which were considered actionable according to the European Society for Medical Oncology (ESMO) ESCAT level I–II classification at the time [12].

Based on these findings, first-line immunotherapy with immune checkpoint inhibitors was indicated by national and international guidelines. Baseline CT staging showed pleural effusion, multifocal pleural thickening, a newly detected round lymph node in the left mammary region, and enlargement of the ipsilateral anterior cardio-phrenic lymph node. PET/CT confirmed the presence of metabolically active disease. Target lesions as per RECIST criteria included: left apical parietal pleural thickening (11 mm), left pericardial thickening (10 mm), internal mammary lymph node (7 mm), and anterior cardio-phrenic adenopathy (13 mm).

Treatment with Atezolizumab was started in March 2023. The disease remained radiologically stable under close CT surveillance for 10 months. In May 2024, CT imaging indicated possible disease progression, which was not confirmed on PET. The case was then reviewed by a multidisciplinary team and radiological progression of the disease at the lymph node level was confirmed. To further assess disease status, endobronchial ultrasound (EBUS)-guided biopsy was performed on left hilar lymph node (10L). Cytological analysis confirmed malignant epithelial cells consistent with carcinoma of no special type (NST), although the sample was inadequate for molecular profiling.

Treatment with Atezolizumab was discontinued and the patient was subsequently enrolled in the pre-screening of the B-FAST study in July 2024, a phase 2 trial based on ctDNA analysis on peripheral blood via liquid biopsy with the aim of identifying targetable mutations [13]. Liquid biopsy performed with FoundationOne Liquid CDx confirmed mutations in BRCA2 and TP53 genes and identified also EGFR exon 17 S645C mutation.

Literature review and discussion within an internal molecular tumor board supported initiation of Afatinib at a dose of 40 mg/day in August 2024. However, treatment was poorly tolerated, with Grade 3 diarrhea, Grade 2 cutaneous rash, G2 scalp lesions, Grade 1 onychopathy, and electrolyte imbalances (requiring intravenous supplementation for hypo-/hypercalcemia). The dose was then reduced to 30 mg/day.

In October 2024, PET/CT imaging demonstrated a partial metabolic and dimensional response. Due to persistent grade 2 gastrointestinal adverse events, the dosage was further reduced to 20 mg/day from the fourth treatment cycle onwards, achieving excellent tolerability to treatment.

By January 2025, follow-up CT and PET/CT scans revealed a complete radiological and metabolic response, which was also confirmed at the May 2025 follow-up. In October 2025, after TC-PET scan, stable disease was observed in accordance with RECIST (Response Evaluation Criteria in Solid Tumors) morphological criteria, with increased metabolic activity in two mediastinal lymph nodes and two abdominal lesions. The regions with increased metabolic activity underwent radiation treatment in 10 fractions, as per decision of the multidisciplinary oncology group. The patient continues Afatinib at a maintenance dose of 20 mg/day. The patient’s clinical timeline is best described in Figure 1 and Table 1.

Figure 1: Figure 1 shows the main events in the patient’s clinical history. The diagnostic phases are shown in red, while the treatments initiated are shown in blue, first immunotherapy with Atezolizumab and then the use of TKI with Afatinib. Radiological reassessments using PET/CT are highlighted in green.

Table 1: Table 1 describes the patient’s clinical timeline, treatments performed, therapeutic response and associated toxicity.