Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder of the neuromuscular junction that primarily targets voltage-gated calcium channels on the presynaptic membrane, resulting in reduced acetylcholine release and impaired neuromuscular transmission [1]. Clinically, it is characterized by proximal muscle weakness, diminished or absent deep tendon reflexes, and autonomic symptoms such as dry mouth, constipation, and erectile dysfunction. These manifestations can markedly impair patients’ quality of life, leading to difficulties in walking, dysphagia, and, in severe cases, respiratory failure due to diaphragmatic involvement, thereby increasing morbidity and mortality [2].

LEMS often occurs as a paraneoplastic neurological syndrome and is strongly associated with malignancy, with approximately 50–60% of cases linked to small-cell lung cancer (SCLC) [3]. SCLC is a highly aggressive neuroendocrine carcinoma. When LEMS coexists with SCLC, it typically reflects a neuroendocrine tumor phenotype in which cross-reactive antibodies—such as anti-P/Q-type voltage-gated calcium channel antibodies—trigger autoimmune attacks. This paraneoplastic association complicates cancer management and may delay tumor diagnosis, as LEMS symptoms can precede tumor detection by several months [4, 5, 6].

Immune checkpoint inhibitors (ICIs) have become a cornerstone of SCLC treatment. By blocking the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) pathway, ICIs enhance T-cell-mediated antitumor immunity and significantly improve objective response rates and progression-free survival [7]. For example, durvalumab, a PD-L1 inhibitor, combined with chemotherapy, has demonstrated improved survival outcomes in patients with advanced SCLC [8]. However, while ICIs potentiate antitumor immunity, they may also provoke excessive immune activation, resulting in immune-mediated adverse events (imAEs) that can affect nearly all organ systems [9]. Common imAEs include dermatitis, colitis, hepatitis, pneumonitis, and endocrine disorders such as thyroiditis and hypophysitis, which can be life-threatening in severe cases [10]. Therefore, early recognition, accurate diagnosis, and standardized management of imAEs are critical during immune checkpoint inhibitor (ICI) therapy.

We report the case of a 76-year-old man with extensive-stage SCLC who developed LEMS during durvalumab immunotherapy. He presented with progressive limb weakness and reduced reflexes, and was diagnosed with LEMS based on electrophysiological testing, elevated inflammatory markers, and increased serum pro-gastrin-releasing peptide levels. Following treatment with intravenous immunoglobulin and pyridostigmine, his muscle strength improved to grade 5. He subsequently received three cycles of lurbinectedin chemotherapy, achieving partial remission of inflammation and tumor burden. The distinctive feature of this case is that LEMS partially improved after initial antitumor therapy but continued to relapse after discharge; however, following lurbinectedin treatment, the lung cancer did not recur, suggesting that lurbinectedin demonstrated good tumor control in this case of small-cell lung cancer complicated by LEMS. The case underscores the importance of early detection and appropriate management of LEMS to optimize functional recovery and maintain continuity of oncologic therapy. The report follows the case report (CARE) guidelines to ensure completeness and transparency; the corresponding checklist is provided as Supplementary Material [11].

LEMS is a rare autoimmune disorder of the neuromuscular junction, characterized by autoantibodies targeting presynaptic P/Q-type VGCCs, resulting in reduced acetylcholine release and impaired neuromuscular transmission [14]. Clinically, patients typically present with proximal lower-limb weakness, diminished or absent deep tendon reflexes, and autonomic symptoms such as dry mouth, constipation, and erectile dysfunction. Respiratory muscle involvement may lead to life-threatening respiratory failure, representing one of the most severe complications [15, 16]. Several case reports have documented the coexistence of LEMS and SCLC, underscoring their clinical complexity and prognostic implications. According to a European multicenter study, approximately half of patients with LEMS are ultimately diagnosed with SCLC, with older age, male sex, and smoking being common risk factors [4]. In some patients, neurological symptoms may appear several months before the tumor is detected, serving as a potential early clinical indicator of malignancy [17]. In addition to this classic paraneoplastic association, recent evidence has identified immune checkpoint inhibitors (ICIs) as potential triggers or amplifiers of LEMS. The current case contributes to this emerging evidence by describing LEMS onset during durvalumab maintenance therapy [18].

One report described a 74-year-old man with extensive-stage SCLC who developed muscle weakness and fatigue after 13 cycles of atezolizumab maintenance therapy; diagnostic workup confirmed ICI-induced LEMS, highlighting neuroimmunologic adverse events related to ICI therapy [19]. Similarly, another case described a 70-year-old man with extensive-stage SCLC who developed LEMS after five cycles of atezolizumab maintenance therapy; cessation of the drug and administration of corticosteroid pulse therapy plus IVIG resulted in marked neurological improvement [20].

The advent of ICIs has revolutionized the treatment of SCLC but has also introduced new challenges. Beyond atezolizumab, other PD-L1 inhibitors may elicit similar immune-mediated complications. For example, a 62-year-old woman with extensive-stage SCLC and pre-existing paraneoplastic LEMS received durvalumab with chemotherapy followed by maintenance therapy, which did not exacerbate LEMS; antibody titers decreased substantially, but brain metastases later developed, underscoring the need for vigilant monitoring [21]. Another report described a 73-year-old woman who had achieved long-term remission of LEMS after limited-stage SCLC therapy 22 years earlier; upon later diagnosis of non-small-cell lung cancer (NSCLC) treated with pembrolizumab plus chemotherapy, she experienced recurrent muscle weakness and ptosis, with elevated anti-VGCC antibody titers confirming LEMS relapse—providing key evidence that ICIs can reactivate prior LEMS [22].

In our case, the patient developed LEMS during durvalumab maintenance therapy, suggesting that ICIs may act as either precipitating or aggravating factors. Durvalumab was promptly discontinued following LEMS confirmation. Subsequent treatment with IVIG and pyridostigmine led to rapid neurological improvement, and subsequent chemotherapy with lurbinectedin plus supportive care achieved both symptomatic relief and partial tumor response. These findings are consistent with previous reports, demonstrating that individualized sequential therapy can effectively balance tumor control and neuromuscular recovery in complex clinical settings.

Diagnostic confirmation relies on the integration of clinical manifestations, electrophysiological findings, and serologic testing. Repetitive nerve stimulation (RNS) typically demonstrates low-frequency decremental and high-frequency incremental responses that are characteristic of LEMS, while the detection of anti-VGCC antibodies provides valuable supportive evidence [23]. Early recognition and timely initiation of treatment are essential for optimizing patient outcomes.

LEMS management generally involves two main strategies: (1) symptomatic treatment to enhance neuromuscular transmission and (2) antitumor therapy to control the underlying malignancy [24]. Among symptomatic agents, 3,4-diaminopyridine remains the first-line therapy, as it prolongs presynaptic action potentials and promotes acetylcholine release, thereby improving muscle strength [25]. Pyridostigmine, an acetylcholinesterase inhibitor, may be used as an adjunct but often provides limited efficacy [15]. IVIG and corticosteroids play pivotal roles in immunomodulation by reducing autoantibody levels and suppressing immune responses [26, 27].

Lurbinectedin has been supported by studies for the treatment of relapsed small-cell lung cancer. A phase II clinical trial showed that in patients with disease progression after platinum-based chemotherapy, the objective response rate reached 35.2%, with a median progression-free survival of 3.5 months [28]. Another study targeting relapsed patients also suggested that the drug can provide stable disease control, consistent with the observed tumor stabilization and reduction in inflammatory markers in this case [29].

The fluctuating muscle weakness observed in this case may have been driven by multiple factors. The initial IVIG treatment administered in February 2025 produced marked improvement, whereas the second course in May yielded only limited benefit, suggesting potential IVIG tolerance or resistance. Furthermore, the patient’s fluctuating muscle strength and concomitant diabetes during durvalumab therapy raise the possibility that checkpoint inhibition disrupted immune homeostasis, exacerbating LEMS symptoms [30]. Although causality cannot be definitively established, these observations suggest that variations in IVIG responsiveness, corticosteroid effects, and ICI-induced immune remodeling likely acted synergistically, underscoring the multifactorial nature of neuromuscular instability in patients treated with ICIs.

This case presents several notable strengths. Early recognition and electrophysiological confirmation of LEMS during ICI therapy prevented misdiagnosis and treatment delays. The combined use of IVIG and pyridostigmine facilitated rapid neurological recovery and enabled continuation of antitumor therapy. Additionally, proactive monitoring and management of complications—such as inflammation, anemia, and venous thrombosis—illustrate the importance of multidisciplinary care. However, the study is limited by a relatively short follow-up period and the inability to assess long-term prognosis or recurrence risk. As a single-case observation, the findings cannot be generalized but provide valuable clinical insight, warranting further investigation.

This case underscores the importance of early detection and standardized management of paraneoplastic LEMS in patients with SCLC. Prompt initiation of immunomodulatory therapy not only improves functional outcomes but also allows uninterrupted oncologic treatment. While ICIs have significantly improved survival in SCLC, their immune-activating mechanisms may also induce or exacerbate neuroimmunologic adverse events. Therefore, vigilance for neuromuscular symptoms during immunotherapy is essential, as such manifestations should not be attributed solely to tumor progression or chemotherapy toxicity. A multidisciplinary approach integrating oncology and neurology expertise is crucial for optimizing patient outcomes. As ICI use continues to expand, the establishment of comprehensive monitoring and management systems for neuroimmune toxicity is urgently needed. Continued accumulation of clinical evidence will help refine therapeutic strategies and improve long-term prognosis.

This case reports worsening of LEMS during durvalumab maintenance immunotherapy. Following discontinuation of the drug, treatment with IVIG combined with pyridostigmine was administered, and immune checkpoint inhibitors were not reintroduced, resulting in rapid neurological recovery. Subsequently, lurbinectedin was used as second-line chemotherapy to further improve the patient’s condition. During immunotherapy, monitoring for neurological complications and early recognition and management are of critical importance.

• Even in patients with a prior diagnosis of small-cell lung cancer, LEMS may worsen during treatment with immune checkpoint inhibitors such as durvalumab.

• The close temporal association between durvalumab maintenance and the onset of LEMS, along with improvement after drug withdrawal, possibly supports an ICI-related mechanism.

• This case adds to the limited literature describing immune-related neuroimmunologic complications in small-cell lung cancer, highlighting the need for increased clinical awareness and early diagnostic evaluation.

• Early recognition and treatment with intravenous immunoglobulin and corticosteroids can achieve rapid neurological recovery and allow continuation of antitumor therapy, laying the foundation for second-line lurbinectedin chemotherapy.

• Multidisciplinary collaboration between oncologists and neurologists is essential for optimizing outcomes and ensuring the safe administration of immunotherapy in patients at risk for neuroimmune adverse events.

The data and materials in the current study are available from the corresponding author on reasonable request.

YYF, YY, and LRD contributed to the study design. YY conducted the literature search. YYF and LRD acquired the data. YYF and YY wrote the article. LRD performed data analysis. All authors contributed to revising the manuscript critically for important intellectual content. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

This study was approved by the Ethics Committee of the Second Affiliated Hospital, Zhejiang University School of Medicine (Approval No. 2025-1574). The study was conducted in accordance with the principles of the Declaration of Helsinki. Written informed consent for participation and publication of clinical details and accompanying images was obtained from the patient.

Not applicable.

This research received no external funding.

The authors declare no conflict of interest.

Supplementary material associated with this article can be found, in the online version, at https://doi.org/10.31083/BJHM53025.