Significant Intracranial Response and Long-term Survival after Pembrolizumab in Non-small Cell Lung Cancer Brain Metastases Resistant to Stereotactic Radiotherapy

Ryuichi NODA; Atsuya AKABANE; Mariko KAWASHIMA; Masafumi SEGAWA; Akihiro SHIMOI; Yoshio MASUDA; Teppei MORIKAWA; Kazuhiro USUI; Tomohiro INOUE

doi:10.2176/jns-nmc.2026-0128

Abstract

Brain metastases from non-small cell lung cancer are typically managed with local therapies, such as surgery and radiotherapy, whereas systemic treatments have historically demonstrated limited efficacy in the intracranial setting. Immune checkpoint inhibitors, particularly programmed cell death-1 inhibitors, have recently demonstrated potential in this context. We report a case of a 48-year-old man with lung adenocarcinoma who developed a radiation-resistant brain metastasis with postoperative recurrence and severe neurological deterioration. Despite multiple courses of stereotactic radiosurgery and surgical resection, the lesion progressed, accompanied by seizures, impaired consciousness, and poor performance status.

Pembrolizumab monotherapy was initiated as salvage treatment. Although initial clinical and radiological worsening, rapid tumor regression was observed within 1 month, along with marked neurological recovery. Notably, the patient achieved sustained complete remission without additional systemic therapy and remained alive for more than 7 years after treatment.

Histopathological evaluation revealed increased programmed cell death-ligand 1 expression in brain metastasis compared to that in the primary tumor, possibly influenced by prior radiotherapy. This case highlights the potential synergy between radiotherapy and immune checkpoint inhibitors. Even in patients with poor performance status and refractory intracranial disease, programmed cell death-1 blockade may provide durable clinical benefits in selected patients.

Introduction

Brain metastases pose a significant clinical challenge in advanced malignancies. Local treatments, such as surgical resection, whole-brain radiotherapy, and stereotactic radiosurgery (SRS), are standard approaches for intracranial disease control.¹⁾

Pembrolizumab, a programmed cell death 1 (PD-1) inhibitor, has significantly improved survival in advanced non-small cell lung cancer (NSCLC), particularly in tumors with high programmed cell death-ligand 1 (PD-L1) expression.²⁾ Historically, systemic therapies have been considered less effective for treating brain metastases because of the blood–brain barrier. However, recent evidence suggests that immune checkpoint inhibitors (ICIs) may also have intracranial efficacy.³⁾

Here, we report a case of radiation-resistant recurrent brain metastasis from NSCLC showing a marked and durable response to pembrolizumab.

Case Report

A 48-year-old man was diagnosed with an apical pulmonary mass. Computed Tomography (CT)-guided biopsy revealed poorly differentiated lung adenocarcinoma with focal Thyroid transcription factor (TTF)-1 positivity and p63 negativity. Molecular testing showed no Epidermal Growth Factor Receptor (EGFR) mutation, Anaplastic Lymphoma Kinase (ALK) negativity, and a PD-L1 tumor proportion score (TPS) of 25%-49%. Staging Positron Emission Tomography (PET)/CT revealed mediastinal and supraclavicular lymph node metastases. The patient received platinum-based chemotherapy and thoracic radiotherapy (60 Gy/30 fr). No recurrence of primary lung cancer was observed after initial chemoradiotherapy. Seven months later, he developed left facial spasms and dysarthria. Magnetic resonance imaging (MRI) revealed a right frontal brain metastasis adjacent to the motor cortex. Owing to the eloquent location, two-staged Gamma Knife radiosurgery was performed (first session: marginal dose, 13 Gy; maximum dose, 20.1 Gy; target volume, 4.6 mL; second session: marginal dose, 14 Gy; maximum dose, 21.2 Gy; target volume, 4.1 mL) (Figure 1A). Three months after the first Gamma Knife radiosurgery, 5 courses of bevacizumab were administered for radiation-induced brain edema. However, the treated lesion recurred 6 months after the initial Gamma Knife radiosurgery. Considering the risk of neurological symptoms and the patient's preference, repeat fractionated Gamma Knife radiotherapy was performed (marginal dose, 40 Gy in 10 fractions; maximum dose, 61.5 Gy; target volume, 22.3 mL) (Figure 1B). Tegafur/Gimeracil/Oteracil (TS-1) was selected for concurrent systemic therapy. Four months after the second Gamma Knife radiosurgery, the lesion recurred again, and was treated with another course of fractionated Gamma Knife radiotherapy (marginal dose, 35 Gy in 10 fractions; maximum dose, 46.7 Gy; target volume, 7.3 mL) (Figure 1C). Four months after the third Gamma Knife radiosurgery, the lesion recurred despite repeated SRS (Figure 1D). As further radiotherapy was considered unlikely to be effective based on prior treatment responses, surgical resection was performed. TS-1 was discontinued (Figure 1E). Histological examination revealed highly atypical spindle-shaped sarcomatoid tumor cells with the loss of TTF-1 and focal cytokeratin positivity, consistent with metastatic lung cancer showing histologic transformation. The PD-L1 TPS increased to 50%-75% (Figure 2). The patient was readmitted with seizures 3 weeks after the surgery. MRI revealed recurrence in the resection cavity with severe edema, midline shift, and hydrocephalus (Figure 1F). His condition deteriorated to status epilepticus and impaired consciousness, with a Karnofsky Performance Status (KPS) score of 10-20. Considering disease progression despite surgery and radiotherapy, systemic therapy was prioritized over other treatment options. Since histopathological examination revealed histological transformation and an increase in the PD-L1 TPS to 50%-75%, treatment with pembrolizumab (200 mg) was initiated. Pembrolizumab monotherapy was selected because the patient was considered unable to tolerate cytotoxic chemotherapy. Corticosteroid treatment was tapered from 4 mg/day to 0.5 mg/day 1 week before initiating pembrolizumab. One week later, MRI revealed apparent tumor enlargement and worsening edema. However, at 2 weeks, tumor growth slowed, and by 3 weeks, a marked tumor regression was observed. A second dose was administered at 3 weeks, resulting in further shrinkage, resolution of edema, and neurological improvement. Despite the planned continuation of treatment, the patient chose to transfer to palliative care. Consequently, the dexamethasone dose was increased to 2 mg/day. Follow-up MRI at 2, 3, and 6 months showed a complete response with no recurrence. He regained full consciousness and was discharged with mild hemiparesis. Remarkably, no intracranial recurrence was observed over 5 years, and the patient remained alive for 7 years after pembrolizumab treatment without additional systemic therapy (Figure 3). The patient remained free of disease, except for a metastatic lesion at the T2 vertebra, which was treated with radiotherapy. No immune-related adverse events were observed.

Figure 1

Serial MRI of initial and recurrent brain metastases.

Contrast-enhanced T1-weighted MRI (upper row: axial; lower row: coronal) showing the initial and recurrent brain metastases in the right frontal lobe. The initial lesion (tumor volume, 4.6 mL) was treated with staged GKS (first session: 13 Gy, yellow line; maximum dose, 20.1 Gy; second session: 14 Gy; maximum dose, 21.2 Gy) (A). The recurrent lesion was treated with fractionated GKS 6 months after the first GKS (tumor volume, 22.3 mL; 40 Gy in 10 fractions; maximum dose, 61.5 Gy; yellow line indicates the prescription isodose) (B). The second recurrence occurred 4 months after the second GKS and was treated with fractionated GKS (tumor volume, 7.3 mL; 35 Gy in 10 fractions; maximum dose, 46.7 Gy; yellow line indicates the prescription isodose) (C). However, over the subsequent 4 months, the lesion enlarged, necessitating surgical resection (D). Postoperative MRI demonstrated complete tumor resection (E). One month later, MRI revealed the regrowth of contrast-enhancing tissue within the surgical cavity (F).

MRI: magnetic resonance imaging; GKS: Gamma Knife radiosurgery; TS-1: Tegafur/Gimeracil/Oteracil

Figure 2

Histopathology and PD-L1 immunohistochemistry of the primary lung tumor and brain metastasis.

H&E staining of the primary lung lesion showing nest-like proliferation of carcinoma cells, consistent with poorly differentiated lung adenocarcinoma (A). PD-L1 (22C3) immunohistochemistry of the primary lung tumor showing a TPS of 25%-49% (B). H&E staining of the resected brain metastasis showing diffuse proliferation of markedly atypical spindle-shaped tumor cells (C). PD-L1 (22C3) immunohistochemistry of the brain metastasis demonstrating a TPS of 50%-75% (D).

PD-L1: programmed cell death-ligand 1; H&E: Hematoxylin and eosin; TPS: tumor proportion score

Figure 3

Clinical course and radiological response after ICI therapy.

Serial MRI findings after ICI administration showing the recurrent tumor (upper row: contrast-enhanced T1-weighted coronal images) and peritumoral edema (lower row: axial FLAIR images). Both tumor size and edema worsened during the first 2 weeks after ICI initiation, followed by a marked improvement after 3 weeks. This therapeutic response was sustained for 7 years.

ADL: Activities of Daily Living; FLAIR: Fluid-Attenuated Inversion Recovery; ICI: immune checkpoint inhibitor; MRI: magnetic resonance imaging; w: week; y: year

Discussion

During the 2-year interval between tissue sampling of the primary lung lesion and brain metastasis, biological changes may have occurred in the tumor, possibly associated with repeated radiotherapy. These changes may have contributed to the observed response to ICI therapy. The primary tumor was pathologically diagnosed as lung adenocarcinoma with positive TTF-1 expression. In contrast, the recurrent brain tumor demonstrated increased cytological atypia and was predominantly composed of spindle-shaped sarcomatoid cells. Immunohistochemically, the tumor cells were negative for TTF-1 but showed focal positivity for cytokeratin (Anion Exchanger (AE) 1/AE3), supporting an epithelial origin. These findings suggest histological transformation from the original lung adenocarcinoma to a sarcomatoid carcinoma–like phenotype during the clinical course. Sarcomatoid transformation may be driven by epithelial–mesenchymal transition.⁴⁾

PD-L1 expression is a predictive marker of response to pembrolizumab in NSCLC, particularly when TPS exceeds 50%.⁵⁾ In this case, the PD-L1 TPS was 25%-49%, just below the high-expression threshold at the time of lung cancer diagnosis. However, the PD-L1 TPS in the resected brain metastasis was higher (50%-75%). Between the diagnosis of the primary lung lesion and surgical resection of the brain metastasis, the patient underwent radiotherapy for the primary lung lesion and multiple sessions of stereotactic radiotherapy for brain metastasis. PD-L1 expression increases after radiotherapy. Radiation induces the release of inflammatory cytokines, enhances antigen presentation, and may upregulate PD-L1 expression on tumor cells, potentially augmenting synergy with ICIs.⁶⁾ In addition, lung adenocarcinoma with sarcomatoid transformation has been reported to be frequently associated with PD-L1 overexpression.⁷⁾ Another important aspect is corticosteroid administration. Corticosteroids provide rapid relief of symptoms associated with tumor-related edema; however, they may attenuate the effects of ICIs. One study reported decreased treatment response and progression-free survival in patients with NSCLC receiving ≥10 mg prednisone equivalent at ICI initiation.⁸⁾ Our patient continued low-dose dexamethasone (0.5 mg/day), despite symptom progression, to avoid compromising the efficacy of pembrolizumab. Strict monitoring was conducted to prevent severe brain damage resulting from the worsening brain edema. Although this allowed for temporary deterioration, it may have contributed to the ultimately favorable outcome. A previous study described worsening neurological symptoms and MRI enhancement 11 days after pembrolizumab administration for metastatic melanoma, followed by rapid improvement by day 21.⁹⁾ In this case, both clinical and MRI findings worsened during the first 2 weeks, followed by substantial tumor shrinkage at 3 weeks. Avoiding high-dose corticosteroids during this period could have been key to preserving ICI efficacy. However, the impact of corticosteroids on ICI therapy remains controversial, as they may be beneficial in certain contexts.¹⁰⁾

A long-term treatment effect was also observed, persisting for 7 years after the final pembrolizumab infusion. PD-1 blockade is believed to "reset" the equilibrium between tumor cells and host immunity, potentially enabling a sustained antitumor response even after treatment discontinuation. One study reported that approximately half of patients with NSCLC treated with PD-1 inhibitors remained progression-free for 9 months following final treatment.¹¹⁾ However, a systematic review and meta-analysis of 36 studies reported that among patients who discontinued ICIs for reasons other than progressive disease, progression-free survival after treatment discontinuation was shorter in patients with NSCLC.¹²⁾ Therefore, the durability of the treatment response after ICI discontinuation remains controversial.

Finally, it is noteworthy that, in our case, the patient recovered from a critical condition, characterized by a KPS of 10-20, which is typically considered an indicator of poor response to ICIs and had previously necessitated referral to palliative care prior to pembrolizumab initiation. Some reports have suggested that pembrolizumab provides limited benefit in frail patients with a performance status >2 or symptomatic brain metastasis.¹³^,¹⁴⁾ Our case is a notable exception to these previously reported findings. From an evidence-based perspective, a poor performance status is generally associated with a poor prognosis, and not all patients with high PD-L1 expression respond to treatment. However, some patients, including the patient in this case, exhibit a dramatic response to ICIs, and identifying this subgroup remains an important challenge for future research. Because of the patient's poor KPS, ICI monotherapy was selected instead of combination chemotherapy.

In clinical practice, neurosurgeons and oncologists frequently encounter patients with refractory brain metastases for whom no effective treatment options are available. In this context, ICIs may be an important component of salvage therapeutic strategies.

Limitations

This report has some limitations. The initial diagnosis was based on needle biopsy, which may not fully reflect tumor heterogeneity, particularly in PD-L1 expression. Additionally, this was a single case report, and causal relationships between radiotherapy, PD-L1 upregulation, and ICI response could not be definitively established.

Conclusion

We report a case of recurrent brain metastasis from NSCLC that was refractory to repeated radiotherapy, but achieved a complete and durable response to pembrolizumab. Even in patients with poor performance status and severe neurological deficits, PD-1 blockade may provide substantial clinical benefits, particularly in tumors with high PD-L1 expression.

Conflicts of Interest Disclosure

All authors have no conflict of interest.

Ethics Statement

Written informed consent was obtained from the patient for publication of this case report and the accompanying images. This study was approved by the Institutional Review Board of our institution (Approval No. 000200033255-01).

References

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