Efficacy and Safety of Initial Low‐Dose, Extended‐Interval Nivolumab Monotherapy in a 91‐Year‐Old Patient With Locally Advanced NSCLC and Poor Performance Status: A Case Report

ABSTRACT

The incidence of non‐small cell lung cancer (NSCLC) increases with age, with approximately half of the cases diagnosed in individuals aged 70 and older. In numerous clinical trials, immune checkpoint inhibitors (ICIs) have demonstrated significant efficacy in treating NSCLC without driver gene mutations. However, elderly lung cancer patients, particularly those aged 80 and above, are underrepresented in clinical trials, resulting in limited information on the efficacy and safety of ICIs in this population. This report details the clinical course of a 91‐year‐old patient with locally advanced NSCLC and an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 2. The patient received nivolumab monotherapy at a dose of 200 mg every 3 weeks for the first four cycles, and then the dose was adjusted to 240 mg every 3 weeks from the fifth cycle, with a total of 32 treatment cycles administered. Treatment was well‐tolerated without significant immune‐related adverse events (irAEs). A durable partial response (PR) was achieved, with progression‐free survival (PFS) exceeding 31 months. The patient maintained a favorable quality of life throughout the treatment period. This case suggests that initial low‐dose, extended‐interval individualized nivolumab therapy may serve as a treatment option for the oldest old patients with advanced NSCLC and poor PS.

Key Clinical Message

This 91‐year‐old patient with locally advanced NSCLC and poor PS had 32 cycles of nivolumab monotherapy, with no severe adverse events occurring, achieving sustained PR, a 31‐month PFS, no disease progression during a 7‐month follow‐up, and maintaining a good quality of life.

1. Introduction

Lung cancer, particularly non‐small cell lung cancer (NSCLC), which accounts for over 80% of all lung cancers, poses a significant global health issue and is a major cause of cancer‐related deaths [1, 2]. Age is a primary risk factor for NSCLC, with more than half of all patients being aged 70 or above, and 10% being aged 80 or above [3]. Compared to younger patients, elderly cancer patients with advanced age have more comorbidities and poorer performance status (PS), and they are underrepresented in clinical trials [1, 4]. Consequently, clinicians face challenges in selecting optimal treatment regimens for this patient population. Limited treatment options may lead to poorer survival outcomes for elderly cancer patients, as they may opt for less aggressive therapies to avoid potential drug toxicity and minimize the risk of surgical complications and mortality.

Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD‐1) and programmed cell death protein ligand 1 (PD‐L1) have revolutionized thoracic oncology treatment [5]. Nivolumab, a fully humanized immunoglobulin G4 monoclonal antibody, enhances T cell antitumor response by blocking PD‐1 receptor binding to PD‐L1 and programmed cell death protein ligand 2 (PD‐L2) [6]. In 2015, the US Food and Drug Administration (FDA) approved nivolumab for lung cancer treatment, with a recommended dose of 3 mg/kg or a fixed dose of 240 mg administered intravenously every 2 weeks [1]. In this case, we define “extended‐interval” as a treatment regimen in which the dosing interval is extended to every 3 weeks, compared with the standard every‐2‐week dosing schedule described above.

Here, we report the case of a 91‐year‐old patient diagnosed with locally advanced non‐small cell lung cancer and an Eastern Cooperative Oncology Group (ECOG) PS score of 2. The patient received a personalized regimen of 32 cycles of initial low‐dose, extended‐interval nivolumab monotherapy. No serious adverse events occurred throughout the treatment course. The patient achieved a partial response (PR) with a progression‐free survival (PFS) of 31 months while maintaining good quality of life.

2. Case History/Examination

In July 2022, a 91‐year‐old male patient with dyspnea, cough, and hemoptysis was admitted to the hospital. A previous chest computed tomography (CT) scan had revealed progressive enlargement of pulmonary nodules over a 2‐year period, but he had not sought any diagnosis or treatment. He has a 40‐year history of hypertension and a 10‐year history of hyperlipidemia, with no reported family history of genetic disorders. His smoking index is 60 pack‐years. On admission physical examination, his weight was 83.5 kg, with decreased breath sounds in the left lung and no other positive findings. His functional status score at admission was 2.

3. Methods (Differential Diagnosis, Investigations, and Treatment)

A chest CT scan revealed a large mass near the left hilum (Figure 1A). A positron emission tomography (PET)/computed tomography (CT) scan revealed irregular masses (7.5 cm × 5.6 cm × 6.2 cm) in the upper lobe of the left lung and adjacent hilum, with abnormally elevated radioactive uptake (Figure 2A). The scan also revealed stenosis and occlusion of the corresponding segment of bronchi. Notably, there was no evidence of distant metastasis on the PET/CT scan. Subsequently, the patient underwent a CT‐guided percutaneous lung aspiration biopsy, and histopathological examination confirmed squamous cell carcinoma. PD‐L1 expression was evaluated by immunohistochemistry (IHC) on formalin‐fixed paraffin‐embedded (FFPE) biopsy specimens using the commercial antibody clones 22C3 and SP263. Results were interpreted according to the Tumor Proportion Score (TPS), which was ≥ 50% in this case, indicating high PD‐L1 expression. Molecular subtyping was performed on paraffin‐embedded percutaneous lung biopsy specimens using the Lung Cancer 10‐Gene Targeted Combined Detection Kit (referred to as the LMG kit) based on multiplex polymerase chain reaction (PCR). This platform is a site‐specific targeted assay without employing next‐generation sequencing (NGS). The panel covers 10 core driver genes of lung cancer, including anaplastic lymphoma kinase (ALK), c‐ros oncogene 1 (ROS1), rearranged during transfection (RET), epidermal growth factor receptor (EGFR), KRAS proto‐oncogene (KRAS), B‐Raf proto‐oncogene (BRAF), human epidermal growth factor receptor 2 (HER2), neuroblastoma RAS (NRAS), phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit alpha (PIK3CA), and MET proto‐oncogene (MET). It is capable of detecting common fusion variants, hotspot point mutations in exons, insertions and deletions (indels) of the above genes, as well as MET exon 14 skipping mutations. No mutations that are known to respond favorably to targeted therapies were detected in the tested genes. Blood tests revealed a cytokeratin 19 fragment level of 8.07 ng/mL (reference range: 0–3.30 ng/mL), with all other blood test results within normal limits. PET/CT revealed the primary left lung tumor with a maximum diameter exceeding 7 cm, corresponding to T4 disease according to the 8th edition of the Tumor‐Node‐Metastasis (TNM) staging system for lung cancer. Whole‐body imaging showed no hilar or mediastinal lymphadenopathy with abnormal radiotracer uptake. As lymph node biopsy was not performed, cN0 was assigned solely based on imaging findings. No distant metastatic lesions were identified in the bones, abdomen, brain, or other systemic regions, consistent with M0. In summary, the patient was diagnosed with locally advanced squamous cell carcinoma of the left lung, and the clinical stage was confirmed as cT4N0M0.

FIGURE 1.

Chest CT scan in August 2022 revealed that, prior to nivolumab treatment, the lung tumor was located in the left upper lobe and the adjacent hilar region, with corresponding segmental bronchial stenosis and occlusion (A). The follow‐up chest CT scan after the third treatment cycle showed a reduction in tumor size (B). The follow‐up chest CT scan after the eighth treatment cycle indicated that the lung tumor continued to shrink, and the patient achieved PR (C). The follow‐up chest CT scan conducted 7 months after treatment cessation demonstrated that the lung tumor remained stable (D). The red arrows indicate the pulmonary lesions.

FIGURE 2.

Prior to nivolumab treatment, a PET/CT scan revealed a large pulmonary tumor in the left upper lobe and the adjacent hilar region, with a markedly elevated abnormal radioactive uptake (A). A follow‐up PET/CT scan conducted after the completion of the 23rd cycle of immunotherapy showed a significant reduction in the size of the pulmonary tumor, along with a substantial decrease in abnormal radioactive uptake (B). The red arrows indicate the pulmonary lesions.

During Multidisciplinary Team (MDT) deliberation, multiple therapeutic options were systematically evaluated. Comprehensive geriatric assessment (CGA) demonstrated stable physical function, preserved cognitive and emotional status, and effective family and social support. The patient and his family expressed a strong preference for antitumor therapy and declined exclusive best supportive care (BSC). However, given the patient's extremely advanced age of 91 years, age‐related physiological decline in hepatic and renal functional reserve, and bulky hilar‐proximal tumor burden, the MDT panel raised concerns and estimated that the patient would face substantial risks of treatment intolerance if any of the curative radical strategies under evaluation were implemented. Surgical resection could bring markedly elevated risks of perioperative visceral injury; definitive thoracic radiotherapy alone might induce radiation pneumonitis and myelosuppression, and the patient would be unlikely to tolerate the relevant toxicities owing to limited visceral compensatory reserve. Concurrent chemoradiotherapy incorporates cytotoxic agents cleared via hepatic and renal metabolism, and the patient's diminished organ reserve would markedly raise the incidence of severe myelosuppression, acute hepatorenal injury, and life‐threatening treatment‐related adverse events (TRAEs). Notably, the patient had a PD‐L1 TPS of ≥ 50%, identifying him as a favorable candidate for immunotherapy. Individualized monotherapy with an ICI was expected to balance tumor control with quality of life preservation. Taking all the above factors into account, along with drug availability at our institution, individualized nivolumab monotherapy was ultimately selected.

The patient initiated nivolumab monotherapy in August 2022. To minimize potential adverse effects, he initially received a reduced dose of nivolumab (200 mg) every 3 weeks. Within 1–2 days of administration, he experienced side effects such as decreased appetite, fatigue, and muscle pain, which gradually subsided over time. Follow‐up chest CT scan after the third cycle of treatment showed tumor shrinkage to 5.8 × 4.4 × 4.7 cm (Figure 1B). After four cycles of treatment, the patient's symptoms such as dyspnea improved, and the PS score increased to 1, with no serious adverse reactions observed. Given the efficacy and safety of the treatment, starting from the fifth treatment cycle, the dose of nivolumab was adjusted to the recommended level of 240 mg while maintaining the 3‐week dosing interval. At this time, thyroid function tests indicated Grade 2 immune‐related thyroiditis with concurrent hypothyroidism. The patient developed no other immune‐related adverse events (irAEs), such as rash, immune‐related pneumonitis, immune‐related colitis, or hypophysitis and others. Levothyroxine sodium was initiated for hormone replacement, and nivolumab immunotherapy was maintained throughout treatment without glucocorticoid administration. Following replacement therapy, thyroid function indices gradually normalized. After eight cycles of treatment, follow‐up chest CT revealed a 37.6% reduction in the total diameter of target lesions. According to the Response Evaluation Criteria in Solid Tumors (RECIST), the response was assessed as PR (Figure 1C). At this point, the patient's PS score recovered to 0. Following 23 cycles of nivolumab therapy, follow‐up PET/CT scans revealed the pulmonary tumor had shrunk to 3.6 cm × 2.4 cm × 3.7 cm with significantly reduced abnormal radioactive uptake (Figure 2B). No new lesions or metastatic disease were detected in other sites.

4. Conclusion and Results (Outcome and Follow‐Up)

Within 2 years, the patient successfully completed 32 cycles of immunotherapy (Figure 3). Following treatment completion, the patient returned home and adhered to scheduled hospital follow‐up appointments. After 7 months of follow‐up, a chest CT scan revealed stable disease in the left lung tumor (Figure 1D). The patient remained in PR, achieving a PFS of 31 months and maintaining good quality of life.

FIGURE 3.

Timeline of changes in patients' PS and tumor imaging responses after nivolumab treatment. C, cycle; CT, computed tomography; PET/CT, positron emission tomography/computed tomography; PR, partial response; PS, performance status; SD, stable disease.

Written informed consent was obtained from the patient for publication of this case report and associated clinical images. All identifying personal information has been de‐identified to protect patient privacy.

5. Discussion

Driven by both population aging and demographic growth, the number of patients with advanced‐age cancer will experience unprecedented growth in the future, necessitating greater attention to cancer treatment for this demographic [7]. Although age is not an absolute contraindication for chemotherapy and radiotherapy, the functional decline, comorbidities, cognitive impairment, malnutrition, and polypharmacy common in the oldest old reduce their tolerance to cancer treatments, increasing the complexity of cancer care [8]. Therefore, it warrants further exploration of effective treatment approaches for cancer patients in this demographic. In recent years, immunotherapy has garnered significant attention as a highly promising treatment option in solid tumor research, with related studies advancing rapidly. A total of 272 patients with advanced squamous cell non‐small cell lung cancer were enrolled in the CheckMate 017 trial [9]. The results demonstrated that the median overall survival (mOS) was prolonged by 3.2 months in the nivolumab group compared with the docetaxel group (9.2 months vs. 6.0 months), representing a 41% reduction in the risk of death. The objective response rate (ORR) was also superior in the nivolumab arm (20% vs. 9%). Nivolumab yielded statistically significant improvements in OS, ORR, and PFS versus docetaxel. Research on safety aspects indicates that immunotherapy not only has fewer adverse reactions than chemotherapy, but also reduces the risk of death by 34% in patients aged 65 and older [10, 11]. Further exploration is needed regarding the application of immunotherapy in specific patient populations. Limited data exist on the safety and efficacy of immunotherapy in patients with poor ECOG PS. While multiple studies suggest no significant difference in the incidence of serious adverse events between patients with PS ≥ 2 and those with ECOG PS 0–1, the therapeutic outcomes (e.g., OS and PFS) are inferior in the former group [12, 13, 14]. Therefore, key reference indicators are also required for selecting patients suitable for immunotherapy. Currently, PD‐L1 TPS remains the primary predictive biomarker for identifying patients responsive to ICIs [15]. Additionally, smoking history in NSCLC patients is associated with higher PD‐L1 tumor proportion scores and better ORR to immunotherapy compared to non‐smokers, suggesting smoking history may be another factor predicting immunotherapy response [16]. Based on these findings, our patient benefited from nivolumab monotherapy despite poor PS, owing to high PD‐L1 expression, smoking history, and absence of driver gene mutations.

Another study observed that low‐dose fixed‐dose nivolumab (10 mg every 2 weeks, equivalent to 0.1 mg/kg in a 100 kg patient) demonstrated relevant biological activity in clinical settings, achieving an ORR of 22% across various malignancies and a clinical benefit rate of 50% [17]. A Japanese study evaluated the pharmacokinetics and clinical outcomes of a 3 mg/kg every‐four‐weeks nivolumab regimen in patients with advanced NSCLC, finding sustained efficacy even at a lower dosing frequency than the standard regimen [18]. Bellesoeur et al. [19] also demonstrated that extending dosing intervals improves the safety profile of nivolumab without compromising its efficacy. These studies suggest that reduced doses and dosing frequencies below standard protocols may still offer advantages in certain specific patient populations. Our patient initially received a low‐dose, extended‐interval nivolumab regimen (200 mg every 3 weeks for the first four cycles; then 240 mg every 3 weeks starting from Cycle 5). Encouragingly, this regimen demonstrated significant efficacy: the patient's pulmonary tumor began shrinking after Cycle 3, achieved radiographic PR after Cycle 8, and maintained PR 7 months after completing 32 cycles of treatment.

Regarding irAEs associated with immunotherapy, results from an international cohort study indicate that irAE‐induced discontinuation of ICIs becomes more frequent with increasing age [20]. The patient in this case developed Grade 2 immune‐related hypothyroidism during treatment, requiring thyroid hormone supplementation. However, this did not necessitate discontinuation of therapy. The individualized treatment regimen—initiated with low‐dose nivolumab monotherapy at extended intervals—effectively reduced the risk of treatment‐related adverse events and enhanced treatment safety. Notably, research by Dr. Koji Haratani [21] suggests that irAEs are closely associated with the efficacy of nivolumab in patients with NSCLC. Some studies indicate that irAEs correlate positively with ORR, PFS, and OS, with endocrine toxicity showing a significant association with improved OS [22, 23, 24]. This suggests that mild irAEs may not be entirely negative.

In conclusion, this case suggests that initial low‐dose, extended‐interval individualized nivolumab therapy may serve as a treatment option for the oldest old patients with advanced NSCLC and poor PS. Further larger‐scale studies are needed to validate these findings, and rigorous patient selection should be emphasized in future clinical practice.

Author Contributions

Dan Kou: data curation, investigation, writing – original draft. Xiang Yan: data curation, investigation, visualization. Qi Huang: methodology, project administration. Jingye Zhong: validation, visualization. Qiongcheng Chen: methodology, project administration. Tao Zhao: formal analysis. Xianhua Xu: data curation, investigation, writing – review and editing.

Funding

The authors have nothing to report.

Ethics Statement

The authors declare that appropriate written informed consent was obtained for the publication of this manuscript and accompanying images.

Consent

Written informed consent was obtained from the patient for publication of this case report and accompanying images.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.