Complete response in disseminated EGFR-mutated lung adenocarcinoma through chemosensitivity-guided chemotherapy, osimertinib, and stereotactic ablative body radiotherapy: a case report

Introduction

Lung cancer continues to dominate as the leading cause of cancer-related mortality worldwide, claiming nearly 1.8 million lives each year and imposing a striking global health burden (1). Among its subtypes, non-small cell lung cancer (NSCLC) accounts for about 85% of cases, comprising a biologically diverse array of malignancies driven by distinct molecular alterations, variable clinical routes, and heterogeneous responses to therapy (2). Even with advancements in early detection through low-dose computed tomography (CT) screening and different multimodal testing, patients with advanced or metastatic NSCLC face a gloomy prognosis, with 5-year survival rates below 20% (3).

The past two decades have witnessed a revolutionary shift in NSCLC management, driven by the discovery of functional oncogenic drivers. Activating mutations in the epidermal growth factor receptor (EGFR) gene stand out as one of the most pivotal targets, occurring in 10–15% of Caucasian patients with lung adenocarcinoma and up to 50% in Asian cohorts, with higher prevalence among never-smokers, women, and those with adenocarcinoma histology (4). These mutations, predominantly exon 19 deletion or L858R point mutation in exon 21, lock the EGFR kinase in an active conformation, triggering uncontrolled cell proliferation via downstream PI3K/AKT and MAPK pathways (5).

Pioneering randomized controlled trials, such as IPASS and EURTAC, firmly established first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) like gefitinib, erlotinib, and afatinib as superior to platinum-doublet chemotherapy in EGFR-mutated advanced NSCLC, achieving objective response rates (ORRs) of 60–75% and progression-free survival (PFS) extensions of 9–10 months (6-8). Osimertinib, a third-generation irreversible EGFR TKI, introduced a significant improvement in patient care. Designed to overcome the T790M resistance mutation that commonly occurs after first- and second-generation TKI failure, osimertinib shoves the increased potency, superior central nervous system (CNS) penetration due to its ability to cross the blood-brain barrier, and a more improved safety profile (9). The landmark FLAURA trial randomized 556 patients to osimertinib vs. standard EGFR-TKIs, revealing a median PFS of 18.9 vs. 10.2 months, alongside improved overall survival (OS) at 38.6 vs. 31.8 months in updated analyses (10,11). Long-term follow-up of patients with stage II to IIIA tumors confirmed a 5-year OS rate of 85% with osimertinib, confirming its role as the first-line therapy in EGFR-mutated NSCLC (12).

Despite these gains, complete responses remain elusive in metastatic tumors, with most patients progressing within 2–3 years due to acquired resistance via EGFR-independent pathways like MET amplification, HER2 alterations, histologic transformation to small cell carcinoma, or epithelial-mesenchymal transition (EMT) (13,14). Current paradigms rely heavily on guidelines from bodies like the European Society for Medical Oncology (ESMO) and National Comprehensive Cancer Network (NCCN), which synthesize evidence from phase III trials to recommend standardized treatment protocols (15,16). These frameworks prioritize population-averaged outcomes but often overlook interpatient variability in tumor genomics, microenvironmental factors, and pharmacodynamics.

Chemotherapy selection in NSCLC is a clear example: platinum-based cytostatics (e.g., cisplatin-pemetrexed) are chosen based on histology and performance status, without assessing individual tumor chemosensitivity (17). Functional precision oncology offers an alternative to such approach, employing ex vivo assays on patient-derived tumor cells or circulating tumor cells (CTCs) to quantify drug-induced apoptosis, thereby tailoring patient-specific therapy (18,19). Such assays measure dynamic hallmarks of cell death, including mitochondrial outer membrane permeabilization and caspase activation, revealing sensitivities undetectable by next-generation sequencing (NGS) alone (20).

Adopting these individualized strategies, however, engages professional and institutional obstacles. Clinicians deviating from guidelines risk peer judgment, regulatory barriers, and personal liability, inhibiting a personalized approach to patient care despite ethical imperatives (21). This case report challenges that status quo, showing how personalized chemotherapy, chosen according to chemosensitivity assay results rather than according to guidelines, supplemented by osimertinib and stereotactic ablative body radiotherapy (SABR), yielded a complete remission in disseminated EGFR-mutated NSCLC. We present this article in accordance with the CARE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0020/rc).

Case presentation

Patient history and initial presentation

A 75-year-old Caucasian female patient presented in October 2024 with a 10-day history of progressive generalized weakness and dyspnea, accompanied by a 20-day period of reduced appetite and unintentional weight loss. She denied cough, haemoptysis, fever, or night sweats. During the days preceding admission, she experienced localized left-sided chest pain, non-radiating and not associated with exertion. Prior to hospitalization, she had received a 6-day course of azithromycin without clinical improvement.

Her past medical history was notable only for hyperlipidemia, managed medically. She denied any history of chronic pulmonary, cardiovascular, or autoimmune disease. She was a lifelong non-smoker, with only brief and limited tobacco exposure in early adulthood, and reported no occupational exposure to asbestos, silica, or other inhalational toxins. Alcohol consumption was denied. There was no known family history of malignancy.

Due to worsening dyspnea, the patient was admitted for further evaluation. On physical examination, reduced breath sounds and dullness to percussion were noted over the left hemithorax. Vital signs were stable, and oxygen saturation was mildly reduced on room air. Laboratory tests demonstrated mildly elevated inflammatory markers (C-reactive protein 4.8 mg/L) and N-terminal probrain natriuremic peptide (NT-proBNP) of 233 pg/mL, without evidence of infection or cardiac decompensation.

A timeline

Table 1 presents relevant events in the patient’s history in chronological order.

Initial imaging and diagnostic workup

A chest radiograph revealed a large left-sided pleural effusion with mediastinal shift toward the right (Figure 1). Diagnostic and therapeutic thoracentesis was performed, evacuating approximately 1,400 mL of turbid, hemorrhagic pleural fluid. Biochemical analysis was consistent with an exudative effusion. A pleural drain was subsequently placed, and the patient was hospitalized for further diagnostic workup.

Figure 1 Radiographic resolution of pleural effusion following initiation of targeted therapy. (A) Baseline chest radiograph obtained on admission (October 2024) showing an extensive left-sided pleural effusion with complete opacification of the left hemithorax and associated passive atelectasis of the underlying lung parenchyma. The mediastinum is shifted to the contralateral side. (B) Follow-up chest radiograph obtained 3 months after initiation of therapy (January 2025) demonstrating complete radiographic resolution of the pleural effusion and full re-expansion of the left lung.

A contrast-enhanced multislice computed tomography (MSCT) of the chest, abdomen, and pelvis was performed. Imaging demonstrated a lobulated solid mass in the left lower lung lobe measuring 6.0 cm × 5.4 cm, showing significant post-contrast enhancement (Figure 2). Associated pleural thickening with hyperenhancing nodular components was noted, raising suspicion for pleural infiltration. Residual lamellar pleural effusion and a small pneumothorax were present following drainage.

Figure 2 CT-scan projections showing tumor disease evolution. Selected images of similar projections from different scans present (A) primary tumor size and position (indicated by arrows); (B) lymph node dissemination (arrows point to the site of a reactive lymph node); (C) metastasis to lung tissue (arrows point to the site of a contralateral lung metastasis). 1: the initial CT scan, performed before the initiation of chemotherapy treatment; 2: a second scan, performed after the termination of chemotherapy and before SABR therapy; 3: a control CT scan, performed 3 months after SABR therapy. CT, computed tomography; SABR, stereotactic ablative body radiotherapy.

Extensive mediastinal lymphadenopathy was identified, including necrotic lymph nodes in the right paratracheal (stations 3A and 4R), prevascular, subcarinal (station 7), and aortopulmonary regions, with the largest measuring up to 3.2 cm × 1.7 cm. Bilateral infraclavicular lymph nodes were also enlarged. Several small nonspecific pulmonary nodules (<5 mm) were observed bilaterally. No focal lesions were identified in the liver or other abdominal organs, aside from incidental renal and uterine findings unrelated to malignancy.

Magnetic resonance imaging (MRI) of the brain showed no evidence of intracranial metastases.

Histopathology and molecular profiling

A CT-guided transthoracic lung biopsy of the left lower lobe mass was performed. Histological examination revealed tumor tissue composed of irregular glandular and trabecular structures infiltrating fibrotic stroma, with focal chondroid differentiation and calcifications. Tumor cells exhibited marked nuclear pleomorphism, hyperchromasia, and moderate eosinophilic cytoplasm.

Immunohistochemical analysis demonstrated positivity for thyroid transcription factor-1 (TTF-1) and negativity for p40, confirming pulmonary adenocarcinoma. Programmed death-ligand 1 (PD-L1) expression assessed using the SP263 clone (Ventana) showed membranous staining in approximately 1% of tumor cells.

Molecular analysis using polymerase chain reaction (PCR)-based assays revealed an EGFR exon 19 deletion. Testing for ALK, ROS1, RET, and MET alterations was negative. These findings established the diagnosis of EGFR-mutated lung adenocarcinoma.

Staging

A whole-body low-dose positron emission tomography (PET)/CT demonstrated intense fluorodeoxyglucose (FDG) uptake in the primary left lower lobe mass [maximum standardized uptake value (SUVmax) 13.8], extensive hypermetabolic mediastinal, hilar, supraclavicular, and cervical lymph nodes, pleural lesions along the left costal pleura, and multiple osseous metastases involving the thoracic spine (Th4, Th8), lumbar spine (L4), and left iliac wing (Figure 3). No visceral abdominal metastases were detected.

Figure 3 Whole-body low-dose PET/CT demonstrating treatment response. Left: baseline PET/CT showing multiple hypermetabolic lymph node metastases, as well as metastatic involvement of lung parenchyma and osseous sites (indicated by arrows). Right: follow-up PET/CT performed 4 months after completion of chemotherapy demonstrating complete metabolic resolution of previously identified lesions with no new sites of disease. CT, computed tomography; PET, positron emission tomography.

Based on clinical, radiological, and pathological findings, the disease was staged as disseminated (stage IV) lung adenocarcinoma with pleural, nodal, and skeletal metastases.

Chemosensitivity testing and treatment selection

In addition to standard molecular profiling, a chemosensitivity assay based on liquid biopsy was performed. CTCs are typically present in peripheral blood at very low frequencies, usually 1–10 cells per 10⁶–10⁷ peripheral blood mononuclear cells, although higher numbers may occur in advanced disease. In this assay, peripheral blood was processed using an enrichment method that isolates viable circulating tumor-associated cells for short-term ex vivo drug sensitivity testing without requiring long-term culture or cell line establishment (20). A panel of 29 chemotherapeutic agents and 29 repurposed drugs were tested (Figure 4).

Figure 4 Workflow of liquid biopsy-based chemosensitivity testing using CTCs. Peripheral blood is collected from the patient, and CTCs are isolated through proprietary enrichment techniques. These cells, originating from both the primary tumor and metastatic sites, are cultured ex vivo and exposed to a panel of chemotherapeutic and repurposed agents. Drug-induced cytotoxicity is quantified to generate a personalized sensitivity/resistance profile. The results are then integrated into clinical decision-making to guide individualized therapy selection. This approach enables real-time, minimally invasive monitoring of treatment response and evolving resistance mechanisms, facilitating precision oncology. Created in BioRender. Marinović-Terzić I [2026]. Available online: https://BioRender.com/2vf6pii. CTC, circulating tumor cell.

The assay demonstrated the highest cytotoxic response to etoposide (71%), oxaliplatin (68%), pemetrexed (68%), 5-fluorouracil/capecitabine (62%), and irinotecan (59%). Among repurposed agents, celecoxib and indole-3-carbinol exhibited notable cytotoxic activity (Figure 5). Based on these results, a chemotherapy regimen combining 200 mg oxaliplatin and 800 mg pemetrexed was selected, despite oxaliplatin not being a conventional first-line agent for NSCLC.

Figure 5 Results of ex vivo drug-induced cytotoxicity performed on the patient’s CTCs. The left panel presents results of the chemosensitivity to cytotoxic agents, while the right panel shows sensitivities to repurposed drugs. CTC, circulating tumor cell.

Systemic therapy was initiated in November 2024 and consisted of 6 monthly cycles of oxaliplatin plus pemetrexed. In parallel, the patient began continuous targeted therapy with osimertinib at a daily dose of 80 mg, which was maintained without interruption. Following completion of chemotherapy, celecoxib (200 mg twice daily) and indole-3-carbinol (400 mg daily) were administered for an additional 3 months as exploratory adjunctive therapy based on ex vivo sensitivity findings. These agents are not part of guideline-recommended treatment for NSCLC and were used as supportive interventions with low toxicity.

Response assessment and local consolidative therapy

A follow-up PET/CT scan performed in April 2025 demonstrated a marked metabolic and morphological response. The primary lung lesion had decreased in size to 38 mm × 25 mm with only mild residual FDG uptake (SUVmax 4.0). Complete metabolic regression was observed in previously involved mediastinal, hilar, cervical, and axillary lymph nodes, pleural lesions, and all skeletal metastases (Figure 3).

Given the residual metabolically active primary lesion, a decision was made to pursue local consolidative therapy. In May 2025, the patient underwent SABR of 42 Gy divided into three fractions to the left lower lobe lesion, calculated to a 100% izodose, using the Varian EDGE HyperSight system, with advanced planning on a quantum simulation platform.

Follow-up and current status

A subsequent MSCT of the chest performed in September 2025 demonstrated post-radiation parenchymal changes in the left lower lobe, characterized by consolidation with air bronchograms consistent with radiation-induced fibrosis. No residual or recurrent tumor was identified. There was no evidence of lymphadenopathy, pleural or pericardial effusion, or new metastatic lesions in the thorax or visualized skeletal structures (Figure 2).

At 1-year follow-up from initial diagnosis, the patient remains in complete clinical and radiological remission. She continues maintenance therapy with osimertinib alone, reports good quality of life, and has experienced no significant treatment-related toxicities apart from mild fatigue.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

Limitations of guideline-based therapy in advanced NSCLC

Clinical practice guidelines from ESMO and NCCN remain foundational for NSCLC management, synthesizing phase III evidence to standardize osimertinib as first-line therapy for EGFR-mutated disease and platinum-doublet chemotherapy (pemetrexed-cisplatin/carboplatin) at progression (15,16). However, these frameworks exhibit inherent limitations in metastatic settings. Osimertinib achieves ORRs of 80% in FLAURA, yet median PFS plateaus at 18.9 months, with only 15–20% of patients being progression-free at 3 years (11,12). Complete responses occur in <10% of disseminated cases, largely due to acquired resistance via heterogeneous mechanisms including EGFR C797S mutation (7–15%), MET amplification (15–20%), HER2 alterations, histologic transformation to small cell lung cancer (5–10%), or EMT driven by AXL/YAP1 upregulation (8,13,14).

Chemotherapy selection exemplifies guideline empiricism: histology (for example, always using pemetrexed in non-squamous NSCLC) and performance status dictate regimens without assessing tumor-intrinsic chemosensitivity (16). Platinum agents induce DNA crosslinks, but efficacy varies widely (ORR 20–40%) due to interpatient differences in nucleotide excision repair (ERCC1/XPD), replication stress, and homologous recombination deficits (22). Surveys indicate 70% of oncologists hesitate to deviate from guidelines due to medicolegal risks, peer scrutiny, and lack of reimbursement for precision assays, perpetuating a “one-size-fits-most” paradigm (21). This case challenges that conservatism, demonstrating how biologically rational deviation—anchored in functional data—yielded outcomes superior to trial medians.

Functional precision oncology: bridging genomics and phenotypic response

Functional precision oncology complements NGS by directly interrogating tumor cell death dynamics. Ex vivo assays using patient-derived organoids, CTCs, or tumor explants quantify drug-induced apoptosis via caspase activation, mitochondrial priming, and phosphatidylserine externalization, predicting clinical response with 80–90% positive predictive value in prospective NSCLC cohorts (18). Here, an ex vivo assay identified oxaliplatin (68% CTCs apoptosis) and pemetrexed (68% CTCs apoptosis) as the top agents combination, despite their nonstandard status in NSCLC guidelines. Oxaliplatin’s efficacy aligns with its unique DNA-adduct profile—forming intra- and interstrand crosslinks less reparable than cisplatin in ERCC1-low tumors—and synergy with antifolates via thymidylate synthase inhibition (22-24). Repurposed agents like celecoxib (through PGE2 suppression) and indole-3-carbinol [through the activation of aryl hydrocarbon receptor (AhR)-mediated xenobiotic detoxification] targeted tumor-promoting inflammation and cancer stem cells, respectively (25,26).

NGS identifies only less than 50% of therapeutic opportunities in solid tumors, as pathway reactivation or phenotypic plasticity evades static profiling (27). Functional precision medicine, combining ex vivo drug sensitivity testing with genomic profiling, is able to identify treatment options for recurrent or refractory cancer (19).

Synergistic integration of systemic and local therapies

Combining EGFR TKIs with chemotherapy amplifies cytotoxicity through nonoverlapping mechanisms. The NEJ009 trial (gefitinib + carboplatin-pemetrexed) showed the extended median OS to 50.9 vs. 38.8 months with TKI monotherapy [hazard ratio (HR) 0.72], with ORR 84% (28). Phase II osimertinib-chemotherapy studies (FLAURA2 ClinicalTrials.gov number, No. NCT04035486) confirmed better feasibility and ORR, attributing synergy to TKI-mediated G1 arrest, enhancing platinum DNA damage (29). In this case, continuous osimertinib maintained EGFR suppression while chemotherapy cleared disseminated metastases.

Consolidative SABR further optimizes outcomes in oligoresidual disease (ClinicalTrials.gov, No. NCT01446744). Delivering ablative doses to the primary lesion eradicated minimal residual disease, aligning with SABR-COMET (No. NCT01446744) and NRG-LU002 (No. NCT03137771) trials showing 20–30% OS gains in oligometastatic NSCLC (30). EGFR inhibition (TKI) can enhance radiosensitivity via impaired DNA double-strand break repair (ATM/Chk2 pathway), while abscopal effect stimulates immune response via cGAS-STING activation (31,32).

Broader clinical implications and barriers to adoption

This case advocates three paradigm shifts: (I) routine integration of functional assays into workflows; (II) institutional support for guideline deviation when data-driven; and (III) SABR protocols for exceptional responders. Cost-effectiveness analyses project functional testing could save $10,000-20,000 per patient by averting ineffective therapies (18). Yet, adoption of such practice lags due to regulatory hurdles and cultural resistance.

Conclusions

This report documents complete, durable remission in treatment-naïve, disseminated EGFR exon 19-deleted NSCLC using chemosensitivity-guided oxaliplatin-pemetrexed combination, supplemented with osimertinib and SABR—outcomes exceeding FLAURA standards. By surpassing guideline constraints through functional precision oncology, this approach is an example of patient-centred care. While professional barriers persist, these results call for prospective randomized trials (e.g., expanding I-PREDICT) and developing guidelines to be able to incorporate phenotypic testing. Institutional policies must evolve to reward biologically justified personalization, ensuring patients with advanced NSCLC disease full access to the therapeutic spectrum. Ultimately, this case supports a future where tumor-specific sensitivities—not averaged trial data—will dictate therapy and cure.

Acknowledgments

We would like to thank Assistant Professor Dr. Darija Stupin Polancec for her valuable advice and support.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0020/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0020/prf

Funding: This work was supported by the institutional grant of the Ministry of Science, Education and Sports of the Republic of Croatia, 2025.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0020/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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