High-Dose Furmonertinib Management of Advanced NSCLC Harboring an EGFR Exon 14 Missense Mutation: A Case Report and Literature Review

Introduction

EGFR is one of the most frequently mutated driver genes in lung adenocarcinoma, with mutation rates approaching 50% among Chinese patients with lung adenocarcinoma [1]. The most common EGFR mutations are exon 19 deletions and the exon 21 L858R point mutation, which together account for 85–90% of all EGFR mutations. However, there is a subset of rare mutations, such as G719X (2–4%), S768I (<5%), L861Q (2%), exon 20 insertions (1–10%), and other complex mutations [2,3]. EGFR exon 14 missense mutations are also included in this rare category. If a missense mutation occurs in EGFR exon 14, it will disrupt the spatial conformation of the juxtamembrane domain (JM domain) of the transmembrane protein encoded by EGFR, leading to reduced EGFR degradation efficiency and uncontrolled activation [4]. To date, clinical reports on EGFR exon 14 missense mutations remain limited, and there is a lack of robust studies to define the most effective treatment strategies.

Furmonertinib is a third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI) with a main active metabolite, AST5902, which exhibits anti-tumor activity comparable to that of its parent compound. Both compounds irreversibly bind to EGFR via unsaturated amide bonds, exerting dual anti-tumor activity [5,6]. In China, furmonertinib has been approved for treating locally advanced or metastatic NSCLC with confirmed EGFR T790M mutations following disease progression on prior EGFR-targeted therapies [7]. The FURMO-002 trial (2024) demonstrated that a 240 mg dose of furmonertinib had an overall response rate (ORR) of 63.6% against EGFR p-loop and αc-helix compressing (PACC) mutations. Moreover, the ORR for exon 20 insertion mutations (such as A763_Y764insFQEA) reached 78.6%, making it the first approved third-generation TKI covering multiple types of rare mutations [8]. There are no prospective data for EGFR exon 14 missense mutations and furmonertinib so far, making single-case experiences important but preliminary.

Case Report

DIAGNOSIS:

The patient was diagnosed with left upper lobe adenocarcinoma (cT3N3M1, stage IV), with metastases to the brain, bone, and bilateral lungs.

INTERVENTION AND TREATMENT:

The patient was admitted to our department on November 23, 2023, and her baseline data are summarized in Table 2. Upon admission, her performance status (PS) score was 4, and physical examination revealed coordinated movements, bilateral pupils of equal size and round shape, and grade IV limb muscle strength, with no pathological signs noted on neurological examinations. A rehabilitation function assessment showed the following results: physical therapy (PT) indicated sitting balance at level 1, inability to stand, and balance dysfunction; occupational therapy revealed significant limitations in practical hand function; and speech therapy demonstrated impairments in memory, orientation, comprehension, and handwriting. Given the patient’s poor clinical condition, her family tended to opt for a conservative approach when selecting the method to obtain genetic testing specimens. Notably, her lumbar metastases with associated bone destruction may have rendered lumbar puncture technically challenging and risky; therefore, collecting blood samples for next-generation sequencing (NGS) was considered a safer approach, while also enhancing acceptability among the patient’s family. It should be acknowledged, however, that plasma testing can miss subclonal or central nervous system (CNS)-restricted mutations, and the lack of tissue or cerebrospinal fluid (CSF) confirmation limits certainty regarding the true driver status. Consequently, an EGFR exon 14 missense mutation (EGFR NM_005228.5 c.1658C>A.P.S553Y, exon 14 missense variation, variant allele frequency=0.45%) was detected, with the NGS panel specifications shown in Table 3. On November 28, 2023, the patient began fifth-line targeted therapy with oral furmonertinib at a dosage of 160 mg/day. By December 30, 2023, a follow-up chest CT showed that the metastatic lesion in the upper lobe of the left lung had stabilized at 24 × 17 mm (Figure 1B), and her condition had improved over the past month; her cognitive function and limb muscle strength returned to normal, and rehabilitation training resulted in significant functional gains, including improvements in sitting and standing balance (both increased to level 3) and the ability to walk independently with assistance. Additionally, her memory, orientation, comprehension, and handwriting showed noticeable improvement compared to baseline. On April 4, 2024, chest CT revealed that the left upper lobe metastasis remained stable at 24×18 mm (Figure 1B); however, contrast-enhanced brain MRI identified a few newly enhanced lesions in the cerebellum and left frontal lobe, with the largest lesion measuring approximately 3 mm along its major axis, located in the left frontal lobe (Figure 1C). In response to these new findings, the furmonertinib dose was increased to 200 mg/day.

On June 26, 2024, chest CT again demonstrated a stable left pulmonary lesion (Figure 1B), while contrast-enhanced brain MRI exhibited scattered, abnormally enhanced nodules in the left frontoparietotemporal lobe and both cerebellar hemispheres, with the largest lesion (4 mm in diameter) located in the left temporal lobe (Figure 1C). Due to the CNS progression, the furmonertinib dose was further increased to 240 mg/day. On September 2, 2024, follow-up chest CT revealed that the left upper lobe mass had slightly reduced in size to 23×16 mm (Figure 1B) and remained stable; however, she had significant lower back pain, which prevented her from maintaining a prone position long enough to complete an MRI. Despite the lack of imaging evaluation, the 240 mg/day dose of furmonertinib was continued, and her family members declined imaging examinations during subsequent follow-up.

On December 25, 2023, 1 month after taking 160 mg furmonertinib, the patient developed blurred vision and decreased photosensitivity, attributed to cataracts in both eyes based on results of an ophthalmological consultation. Over time, her visual acuity worsened with obstructed central vision. By February 2024, follow-up evaluations revealed optic nerve damage and treatment was initiated to support the optic nerve. Unfortunately, subsequent assessments indicated progressive optic nerve atrophy, resulting in complete blindness. No other adverse reactions were observed in the patient (Figure 2).

LABORATORY TESTS:

Elevated carcinoembryonic antigen (CEA) levels were the primary abnormal tumor marker in this patient. CEA peaked at 546.05 ng/mL(reference ranges <5.00 ng/ml) in July 2022, fluctuating with treatment over time. By November 24, 2023, CEA levels had decreased to 383.71 ng/mL. Following the initiation of extended-dose furmonertinib therapy at 160 mg/day, CEA levels continued to decline, reaching a nadir of 127.19 ng/mL on March 2, 2024. This reduction, combined with imaging studies, suggested that the higher furmonertinib dose was effective. However, by April 4, 2024, CEA levels rose again to 134.23 ng/mL, correlating with disease progression. The fluctuations in CEA levels over time are shown in Figure 3.

Discussion

The Lung Cancer Center of Huaxi Hospital, affiliated with Sichuan University in China, first proposed the concept of complex and refractory lung cancer (CRLC) [9]. CRLC refers to a group of diseases associated with a high risk of diagnostic and therapeutic challenges due to the progression of lung cancer itself, coexisting conditions, or poor physical status (PS scores of 2–4). The patient in this case was classified as having CRLC due to poor physical condition (PS 3–4) and the absence of a standard treatment protocol for lung cancer beyond the third line. The EGFR-TKI yielded good control over the patient’s pulmonary lesions, with no metastases detected outside the CNS. The combination of EGFR-TKI and radiotherapy exerted a synergistic suppressive effect on the CNS lesions. Radiologically, the progression of the patient’s CNS lesions was relatively slow, which distinguished them from those driven by highly aggressive tumor cells.

The efficacy of EGFR-TKIs in treating intracranial metastasis disease is closely related to the drug concentration in cerebrospinal fluid (CSF). Pharmacokinetic studies have shown that as the dose of furmonertinib increases from 80 mg to 240 mg, the area under the curve from 0 to 24 h (AUC0-24h) and Cmax gradually increases, albeit at a slightly lower rate than the dose escalation. AST5902, the primary active metabolite of furmonertinib, has activity and selectivity similar to the parent compound, although furmonertinib achieves higher metabolic rates and in vivo concentrations [10]. Notably, furmonertinib exhibits superior blood-brain barrier penetration compared to first- and second-generation EGFR-TKIs, resulting in higher CSF concentrations. These mechanisms may be theoretically feasible, but no pharmacokinetic or cerebrospinal fluid (CSF) drug concentration data were obtained in this patient.

Considering that when the patient was administered vormetinib at a dose of 160 mg qd, 3 weeks had passed since she received chemotherapy drugs (bevacizumab, pemetrexed, carboplatin). By then, the chemotherapy drugs had been completely metabolized, and there was no clear literature indicating that the aforementioned chemotherapy drugs would affect the efficacy of furmonertinib. Therefore, we believe that the evidence supporting the claim that chemotherapy drugs affect the efficacy of vormetinib is insufficient. Radiotherapy can exert a persistent effect on the brain and can synergize with furmonertinib in the treatment of brain metastases.

Since initiating 80 mg of furmonertinib in January 2023, the patient has not experienced liver or kidney dysfunction, hematologic abnormalities, or common adverse events associated with furmonertinib, such as rash, diarrhea, or QTc interval prolongation. Her visual disturbances may have been associated with radiation-induced injury and intracranial metastatic lesions, and the adverse reaction to furmonertinib cannot be ruled out. In the Phase IV clinical trial of fumetinib, 12 patients (2.7%) who received fumetinib treatment at 80 mg qd developed eye organ diseases, presenting as 4 cases of vision loss, 2 cases of dry eye syndrome, 2 cases of blurred vision, 1 case each of presbyopia, increased lacrimation, pruritus and eye pain, all of which were grade 1–2. The incidence and severity of ocular disorders may exhibit a dose-dependent increase. During Phase I and I/II clinical trials [11], the most notable adverse reactions (≥5% increased incidence) in the 160–240 mg dose group compared to the 80 mg group included elevated alanine aminotransferase, decreased white blood cell and neutrophil counts, rash, increased serum creatinine, proteinuria, anemia, and decreased appetite. Grade 3 adverse events (≥2% increased incidence) primarily involved anemia. No dose-limiting toxicity was observed. A retrospective analysis of 16 patients with osimertinib resistance treated with double-dose furmonertinib (160 mg, once daily) found a 62.5% incidence of adverse reactions, mostly mild gastrointestinal or skin-related events (grade 1–2), with no treatment discontinuations [12]. However, 1 report described liver injury in a patient treated with an extended dose of 160 mg furmonertinib after resistance to multiple EGFR-TKI types, although this reaction occurred after 1 month of treatment [13]. However, single-patient tolerance does not establish safety, particularly for prolonged 240 mg exposure, and cumulative toxicity risk remains undefined. In cases of furmonertinib overdose, immediate monitoring and symptomatic treatment should be implemented as needed.

Conclusions

EGFR exon 14 point mutations in lung cancer are rare, and their clinical significance remains unclear due to limited case reports. Consequently, there are currently no evidence-based, targeted therapies specifically approved for these mutations. Extended doses of furmonertinib have shown promise in the NSCLC patients with rare EGFR mutations and EGFR-TKI resistance, demonstrating good safety with a low incidence of grade 3 or higher adverse events and no dose-limiting toxicity. The case suggests feasibility and raises the hypothesis that dose escalation may be considered in selected, refractory cases with rare EGFR mutations, pending systematic study.