Empirical gefitinib response in mutation-negative lung adenocarcinoma with comorbidities: A case report

INTRODUCTION

Lung adenocarcinoma, the predominant subtype of non-small cell lung cancer (NSCLC), remains a major contributor to cancer-related mortality worldwide, with a 5-year survival rate of approximately 16.8%.^[1] Progress in molecular diagnostics has facilitated the identification of actionable genetic alterations, such as mutations in the epidermal growth factor receptor (EGFR) and rearrangements involving the ALK and ROS1 genes, paving the way for targeted therapies that enhance patient outcome.^[2] However, a subset of patients, known as EGFR/ALK/ROS1-negative or “driver mutation negative” for these mutations, are unable to benefit from targeted therapies and consequently have fewer treatment options. We present a case of a 65-year-old female with advanced Stage IV non-mutated lung adenocarcinoma and poor performance status, detailing her outcome with empirical treatment.

CASE REPORT

A 65-year-old female, non-smoker, with a history of Type 2 diabetes mellitus and chronic obstructive pulmonary disease, presenting with respiratory failure and an Eastern Cooperative Oncology Group Performance Status of 3, reported worsening Grade III dyspnea on exertion, cough, and back pain persisting for 2 months. Clinical examination revealed bilateral crepitations on auscultation.

Initial computed tomography (CT) imaging of the chest showed a benign lesion in the right upper lobe consistent with a hematoma and cystic bronchiectasis, alongside patchy ground-glass opacities, mild bilateral pleural effusion, and mediastinal and para-aortic lymphadenopathy. Further investigation with pleural fluid cytology confirmed the presence of malignancy. The Expert mycobacterium tuberculosis/rifampicin assay (MTB/RIF) assay and fungal smear tests were negative. Positron emission tomography-CT (PET-CT) imaging identified a metabolically active, fluorodeoxyglucose (FDG)-avid soft tissue lesion measuring 37 × 31 mm (SUVmax 4.5) located in the upper and anterior segment of the right upper lobe, extending to the right parahilar region. This finding was consistent with a primary malignancy. In addition, FDG-avid interlobular septal thickening and peribronchovascular nodularity arising from the bilateral perihilar regions were observed, suggesting lymphangitic carcinomatosis. The scan further demonstrated FDG-avid mediastinal lymphadenopathy (SUVmax 3.4) and sclerotic lesions in both the axial and appendicular skeleton (SUVmax 2.8), indicative of metastatic involvement of lymph nodes and bone. A cryo-guided lymph node biopsy confirmed metastatic adenocarcinoma. Molecular profiling through polymerase chain reaction and immunohistochemistry revealed no evidence of EGFR, ALK, or ROS1 mutations, and the tumor was classified as microsatellite stable (microsatellite instability-stable). To complement these findings, a liquid biopsy was performed, which also demonstrated the absence of detectable mutations in circulating tumor deoxyribonucleic acid. Taken together, both the somatic tumor analysis and liquid biopsy confirmed the absence of targetable mutations, indicating a mutation-negative profile across both tissue and liquid biopsy platforms.

Given the patient’s poor general condition and concerns regarding chemotherapy tolerance, empirical therapy with the tyrosine kinase inhibitor (TKI) gefitinib (250 mg once daily) was initiated, along with monthly administration of the bone-modifying agent zoledronic acid. After 10 days of treatment, the patient reported subjective improvement, prompting continuation of gefitinib. After 3 months of gefitinib therapy, follow-up PET-CT imaging revealed significant improvements. The right upper lobe soft tissue lung lesion showed complete metabolic resolution, with a moderate reduction in size to 27 × 20 mm, now appearing FDG non-avid. In addition, there was complete metabolic resolution and a moderate reduction of the interlobular septal thickening and peribronchovascular nodularity initially noted in the bilateral perihilar regions. The previously enlarged mediastinal lymph nodes and sclerotic skeletal lesions also demonstrated complete anatomic and metabolic resolution. The patient demonstrated an exceptional response to empirical TKI therapy with gefitinib, despite the absence of EGFR mutations, achieving significant clinical and radiologic improvements. The patient remains asymptomatic, and the treatment regimen has been well-tolerated. This case underscores the potential of empirical TKI therapy in carefully selected patients with poor performance status and limited therapeutic options

DISCUSSION

NSCLC continues to be the primary cause of cancer-related mortality worldwide, underscoring the urgent need for ongoing advancements in both diagnosis and therapy. Innovations in diagnostic techniques, including enhanced imaging technologies and molecular biomarkers, have markedly improved early detection and facilitated personalized treatment approaches.^[3] Prognostic factors such as early-stage diagnosis, favorable performance status, minimal weight loss (<5%), and female sex have been linked to improved survival outcomes in patients with NSCLC.^[4,5] However, this patient presented with a poor performance status and advanced disease, highlighting the management challenges in non-mutated lung adenocarcinoma, where chemotherapy could not be utilized as the primary treatment option. Complete or near-complete responses to EGFR TKIs in patients lacking detectable EGFR, ALK, or ROS1 alterations are exceptionally uncommon, with only sporadic cases reported globally. The magnitude of response observed in this patient, therefore, represents an important clinical observation supporting individualized treatment decisions in highly select patients.

Precision medicine, driven by progress in advanced molecular technologies, aims to identify genetic alterations in lung cancer cells, referred to as “driver mutations,” to facilitate the development of targeted inhibitors that block the activity of dysfunctional proteins.^[6] An increasing number of approved targeted therapy agents for NSCLC now enables the treatment of mutated proteins, including EGFR (ERBB-1, ERBB-2), ALK, ROS1, MET, RET, NTRK, and RAF.^[7] EGFR, a key receptor in the Erb family that regulates cell growth and survival, is often overactive in NSCLC, making small-molecule TKIs such as gefitinib and erlotinib effective and widely used treatment options. However, in the absence of a driver mutation, where specific inhibitors serve as the primary treatment option, platinum-based doublet combination chemotherapy remains the cornerstone of first-line systemic therapy for patients with advanced NSCLC.

The INTEREST study, the patients were randomized to receive either gefitinib or docetaxel, showed similar survival and response rates between the two treatments for EGFR mutation-negative patients, with no statistically significant differences, and gefitinib was not found to harm those patients.^[8] Several studies have investigated whether metastasis to specific organs, such as pulmonary metastases and malignant pleural effusion, can predict the efficacy and outcomes of EGFR TKI therapy in patients with EGFR mutation-negative NSCLC.^[9] In the current study, the case was thoroughly analyzed for EGFR mutations, including rare mutations like exon 20 insertions and G719X in exon 18. Despite no EGFR mutations being detected, the patient’s response to gefitinib suggests that the drug may still be effective in select cases of EGFR mutation-negative NSCLC. The potential efficacy of gefitinib in EGFR mutation-negative NSCLC may be explained by its ability to inhibit EGFR signaling, though at higher concentrations. Gefitinib exhibits superior potency in inhibiting EGFR mutation-negative NSCLC tumor cells, with a 50% inhibitory concentration ranging from 6 to 60 nmol/L – approximately 3 times more effective than erlotinib, highlighting its enhanced therapeutic potential.^[10]

Despite her Stage IV and non-mutated disease, she received TKI, which is a deviation from the standard guidelines. This regimen was opted in view of her age, poor PS, and metastatic disease. However, the intent was disease control rather than definitive treatment. Over the past year, significant progress has been achieved in the treatment of Stage IV NSCLC with the approval of novel therapies, including the combination of the vascular endothelial growth factor-2 inhibitor ramucirumab with docetaxel, as well as immune checkpoint inhibitors such as nivolumab and pembrolizumab, for use in the relapsed setting. These treatments would have been suitable options for our patient if the disease had progressed further. This case report highlights the potential role of empirical TKI therapy in carefully selected patients with advanced-stage, mutation-negative NSCLC. The key strength of this study lies in its documentation of an exceptional clinical and radiological response to gefitinib in a patient lacking EGFR, ALK, or ROS1 mutations. It underscores the importance of exploring unconventional therapeutic options for patients who are ineligible for standard systemic therapies due to comorbidities or poor general condition.

However, the findings are subject to certain limitations. This report focuses on a single patient, limiting its generalizability to broader populations. The absence of a controlled trial or comparative analysis restricts the ability to definitively attribute the observed outcomes to gefitinib therapy alone. This case underlines the need for a personalized, patient-centric approach in the management of lung adenocarcinoma, particularly in challenging clinical situations. Future research should focus on broader liquid biopsy panels and clearer patient selection criteria to better identify the rare subset of mutation-negative NSCLC patients who may still benefit from empirical TKI therapy.

CONCLUSION

This case report emphasizes the potential utility of empirical TKI therapy in EGFR/ALK/ROS1-negative NSCLC patients with limited treatment options due to advanced disease and poor performance status. The remarkable response observed in this patient suggests that molecularly unselected use of TKIs, though not standard, may provide clinical benefits in select cases.