Lung cancer accounts for approximately 12% of all malignancies worldwide, with non-small cell lung cancer (NSCLC) representing nearly 80% of all cases [1][2]. Histopathologically, NSCLC encompasses several subtypes, including adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, and large cell carcinoma [3]. The 2015 World Health Organization classification introduced significant refinements, such as revised criteria for adenocarcinoma, subdivision of squamous cell carcinoma into keratinizing and non-keratinizing (basaloid) types, and a narrowed definition for large cell carcinoma. Neuroendocrine tumors were grouped under a unified framework, and a more nuanced grading approach was adopted [4].

The 2021 World Health Organization update further expanded molecular testing recommendations, reflecting the growing importance of precision oncology1. While the 2015 guidelines emphasized testing for epidermal growth factor receptor mutations and anaplastic lymphoma kinase rearrangements, the 2021 edition included additional targets such as RET, ROS1, KRAS, MET, NTRK1–3, ERBB2, and BRAF, alongside programmed death-ligand 1 (PD-L1) expression assessment by tumor proportion score or combined positive score [4][5].

Brain metastasis remains a major complication in NSCLC, contributing to morbidity and reduced overall survival [6]. Approximately 25% of patients with epidermal growth factor receptor – mutant NSCLC present with central nervous system involvement at diagnosis, and this rate exceeds 45% within three years despite treatment with epidermal growth factor receptor tyrosine kinase inhibitors [7]. Traditional management options for limited brain metastases have included surgical resection, whole-brain radiotherapy, and stereotactic radiosurgery [8]. However, the poor prognosis associated with central nervous system involvement has led to increased interest in systemic immunotherapy, particularly immune checkpoint inhibitors (ICIs) [8].

ICIs, alone or in combination with chemotherapy, have demonstrated efficacy in managing NSCLC with brain metastases [9]. Notably, the CheckMate 9LA trial showed that nivolumab plus ipilimumab, combined with a limited course of chemotherapy, provided a durable survival benefit across PD-L1 expression subgroups [10][11]. This regimen was well tolerated and has been approved as a first-line treatment for advanced NSCLC in multiple regions, including the United States and Europe. Age, however, remains a recognized negative prognostic factor in elderly patients with brain metastases, often influencing therapeutic decisions [10].

The aim of this case report is to highlight the successful management of stage IVB NSCLC with brain metastasis in elderly, comorbid patient, treated with nivolumab plus ipilimumab in combination with chemotherapy per the CheckMate 9LA protocol.

An 83-year-old woman, non-smoker with a medical history of hypertension, diabetes mellitus, and atrial fibrillation, was referred to the oncology clinic for the evaluation of a pulmonary lesion. In August 2021, following recovery from a COVID-19 infection, a chest computed tomography scan revealed a 3.2 cm mass in the left upper lobe apex, raising suspicion for malignancy (Fig. 1). This incidental finding prompted further oncological analysis. The patient reported symptoms of anxiety and depression. Upon physical examination, the patient’s temperature was 36.8 °C, heart rate 78 bpm, respiratory rate 19 bpm, blood pressure 163/94 mmHg, and oxygen saturation 92%. She experienced pleuritic chest pain (numeric pain rating score 4), shortness of breath, and easy fatigability. Her ECOG performance status was 1, primarily due to age and comorbidities. However, no problems with the central nervous system were observed.

Due to the patient’s low engagement in the treatment process, an active diagnostic approach was initiated only seven months after the initial detected abnormalities on computed tomography.

On March 24, 2022, a computed-tomography-guided percutaneous lung biopsy confirmed a diagnosis of poorly differentiated pulmonary adenocarcinoma. Molecular analysis was negative for actionable driver mutations. PD-L1 expression was detected in 40% of tumor cells. To evaluate for distant metastases, a positron emission tomography scan was performed on March 30, 2022 (part A of Fig. 2), and the disease was staged as IVB poorly differentiated non-small cell adenocarcinoma (T4N2M1c).

A contrast-enhanced brain magnetic resonance imaging (MRI) in April 2022 revealed a solitary ring-enhancing lesion in the left frontal lobe, considered consistent with cerebral metastasis (part A of Fig. 3). Despite the absence of neurologic symptoms, dexamethasone was administered for 14 days. No radiation therapy was initiated because of the patient’s asymptomatic status, advanced age, risk of toxicity, and emerging data supporting durable intracranial responses with immune checkpoint inhibitors.

Systemic therapy commenced in May 2022 with a regimen of carboplatin, pemetrexed, nivolumab, and ipilimumab, administered at a 50% dose reduction due to advanced age, in accordance with the CheckMate 9LA protocol. The second cycle was completed in June 2022. Brain MRI in August 2022 demonstrated an impressive reduction in the left frontal metastasis to 7 mm (part B of Fig. 3).

After ten cycles of immunotherapy, a positron emission tomography in July 2023 demonstrated marked reduction in both size and 18-fluorodeoxyglucose avidity of the left apical lung mass and right axillary nodes. Complete metabolic resolution was observed in the mediastinal and left hilar nodes, with near-complete resolution in the retroperitoneal nodes (Part B of Fig. 2).

By May 2024, complete resolution of both lung lesions was documented. Brain MRI showed almost complete response (part C of Fig. 3). Initial 18-fluorodeoxyglucose-avid lymphadenopathy (mediastinal, left hilar, right axillary, retroperitoneal) had fully or nearly resolved (part C of Fig. 2).

Clinical improvement paralleled the radiological response: the respiratory symptoms resolved, and the patient experienced substantial enhancement in energy, mobility, and independence. Psychological well-being also improved significantly, with restored social engagement and quality of life – key outcomes in elderly patients with multiple comorbidities. On physical examination after two years of treatment, the patient was afebrile (37.0 °C), with a heart rate of 72 bpm, respiratory rate 18 bpm, blood pressure 120/79 mmHg, and oxygen saturation of 96%. HbA1c was 6.7%. She reported minimal pain (numeric pain rating score 2), no dyspnea, and stable clinical status.

NSCLC accounts for approximately 85% of lung cancer cases and comprises several histologic subtypes, including adenocarcinoma, squamous cell carcinoma, and large cell carcinoma [12]. Each subtype differs in morphology, molecular profile, and therapeutic strategies [13]. Adenocarcinoma is the most common, especially in non-smokers, while squamous cell carcinoma is strongly associated with tobacco use2. Large cell carcinoma, though less prevalent, is typically poorly differentiated and aggressive. Advances in molecular diagnostics have facilitated the identification of targetable mutations and biomarkers, such as EGFR (epidermal growth factor receptor), ALK (anaplastic lymphoma kinase), and PD-L1, enabling individualized treatment approaches [14]. Management of NSCLC may include surgery, radiotherapy, chemotherapy, targeted agents, and ICIs, depending on disease stage and biomarker status [15].

This case report describes an elderly patient with stage IVB poorly differentiated lung adenocarcinoma and brain metastasis who achieved near-complete remission without brain surgery or radiotherapy. Historically, metastatic NSCLC has been associated with poor prognosis and with a median survival of around one year [16]. However, the advent of immune checkpoint inhibitors has ushered in a new era in lung cancer treatment, significantly improving overall survival [17].

Immunosenescence may attenuate immune responses in older adults, potentially reducing ICIs efficacy [18]. Nevertheless, analyses of clinical trial data by the U.S. Food and Drug Administration indicate that patients aged ≥65 years, including those ≥75, derive similar survival benefits from ICIs as younger patients [18]. This case confirms the superiority of ICI monotherapy or chemoimmunotherapy over chemotherapy alone in terms of both survival and toxicity.

The combination of nivolumab and ipilimumab with two cycles of chemotherapy, as in the CheckMate 9LA protocol, has demonstrated sustained survival benefit versus four cycles of chemotherapy, independent of PD-L1 expression or histology [11]. In patients with low PD-L1 expression or high disease burden, combining PD-L1 ICIs with platinum-based doublet chemotherapy has been particularly advantageous. Our patient, with PD-L1 expression <50% and brain metastasis, met the profile of a candidate likely to benefit from this combined regimen.

Although the blood-brain barrier limits systemic therapy efficacy in brain metastases, emerging evidence suggests that PD-1/PD-L1 blockade may yield intracranial responses via mechanisms not yet fully elucidated [19]. Clinical trials report that patients with asymptomatic brain metastases respond favorably to nivolumab–ipilimumab combinations, with 57% intracranial benefit and 71.9% 3-year overall survival [20][21]. While we could not assess PD-L1 expression in the brain lesion, the radiographic and clinical response suggests comparable or higher PD-L1 levels. Data from the CheckMate 9LA trial reinforce the role of immunotherapy in managing NSCLC with brain metastases, highlighting its potential to improve outcomes in complex clinical scenarios.

This case highlights the potential of combination immunotherapy and chemotherapy, per the CheckMate 9LA protocol, to achieve durable remission in advanced NSCLC with brain metastasis in elderly, comorbid patients. A personalized approach combining chemotherapy and ICIs, adjusted for age and clinical status, resulted in a near-complete response and significant improvement in quality of life. Further research and prospective clinical trials are essential to define optimal therapeutic strategies for similar high-risk patient populations.

Ashraf ALakkad made a major contribution to the development of the concept of the article with writing and editing the case report. Aref Chehal, Aly A. Razek and Yazan Z. Alabed contributed to the interpretation of clinical data, critically reviewed the manuscript, and approved the final version for publication. Hazem M. Almasarei was responsible for the radiological analysis and its interpretation in the article. Aref Chehal, and Hamda Alkaabi helped put the manuscript together. All the authors approved the final version of the article.

Ethics statements. Consent statement. The patient consented to the publication of the article “Complete remission in an elderly patient with non-small cell lung cancer and brain metastasis using immunotherapy plus chemotherapy: a clinical case” in the “Sechenov Medical Journal”.

Conflict of interests. The authors declare that there is no conflict of interests.

Financial support. The study was not sponsored (own resources).

1. Thoracic Tumours. WHO classification of tumours, 5th Edition, Volume 5. International Agency for Research on Cancer. 2021. ISBN 978-92-832-4506-3 2. Belloum Y. Circulating tumor cells (CTCs) and circulating cell-free tumor DNA (ctDNA) as blood-based biomarkers for managing non-small cell lung cancer patients [dissertation]. Hamburg: University of Hamburg; 2023. https://ediss.sub.uni-hamburg.de/handle/ediss/10671 (access date: 12.11.2024).