Remarkable response to pembrolizumab in PD-L1 overexpressing (≥ 50%) NSCLC and extracranial abscopal effect induced by brain radiotherapy: a case report.

1
Introduction
Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality worldwide and poses a particular challenge in patients who develop brain metastases (BMs) (1, 2). Approximately 20%–60% of individuals with advanced NSCLC will eventually develop BMs, and 7%–10% of cases present with intracranial involvement at the time of initial diagnosis. Without treatment, brain metastases are associated with a dismal prognosis, often leading to death within 1–2 months (3). In recent years, advances in radiotherapy, surgery, molecularly targeted therapies, and immune checkpoint inhibitors (ICIs) have significantly expanded treatment options for lung adenocarcinoma with brain metastases. Among these, ICIs are particularly noteworthy because they can cross the blood–brain barrier and demonstrate antitumor activity within the central nervous system. Compared with palliative chemotherapy, pembrolizumab has been shown to prolong both progression-free survival (PFS) and overall survival (OS) in NSCLC patients with or without brain metastases who express programmed cell death ligand 1 (PD-L1) with tumor proportion score (TPS) ≥1%, achieving an intracranial response rate of 20%–30% (4, 5).
For patients with NSCLC who present with symptomatic brain metastases, timely and active local treatment is essential. When the number of brain lesions is ≤3, several options are available: (1) surgical resection, (2) stereotactic radiotherapy (SRT), or (3) SRT in combination with whole-brain radiotherapy (WBRT). For patients with >3 brain metastases, WBRT or SRT may be considered as appropriate strategies.
The abscopal effect describes a unique phenomenon in which local treatment, most commonly radiotherapy, exerts systemic antitumor activity. Beyond its direct cytotoxic effect on the irradiated lesions, radiotherapy may stimulate the immune system to mount an antitumor response against distant, untreated tumor sites. The occurrence of an extracranial abscopal effect following brain-directed radiotherapy alone is exceedingly rare, likely due to the specialized immune microenvironment of the brain (6, 7).
In the present study, we describe a rare case of lung adenocarcinoma with PD-L1 TPS ≥50% in which an extracranial abscopal effect was observed following brain radiotherapy alone, accompanied by a striking and durable response to subsequent pembrolizumab therapy.

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Case report
On May 5, 2023, a 64-year-old Chinese male presented to the Biotherapy Center of Shanghai Mengchao Cancer Hospital with complaints of “right-sided hemiplegia, decreased muscle strength, inability to ambulate, headache, projectile vomiting, and fatigue for five days”. Positron emission tomography–computed tomography (PET-CT) revealed a malignant lesion in the lower lobe of the left lung, accompanied by multiple metastatic deposits in the bilateral lungs, left hilar and mediastinal lymph nodes, bilateral supraclavicular lymph nodes, as well as numerous intracranial and osseous metastases (Supplementary Figure S1). Given the extensive tumor burden, the patient’s initial prognosis was considered poor.
Furthermore, his medical history was notable for hepatocellular carcinoma, for which he underwent radical hepatectomy in May 2012, with postoperative pathology confirming the diagnosis. To date, no evidence of recurrence has been observed. The patient reported a long-term history of tobacco use (20 cigarettes daily for approximately 30 years) and alcohol consumption (beer, three times per week, ~400 mL per occasion). He denied a history of diabetes, hypertension, autoimmune disorders, or other chronic medical conditions.
Following multidisciplinary consultation with the radiotherapy department, palliative radiotherapy was initiated to alleviate hemiplegia, targeting metastatic lesions in the left frontal lobe and the posterior horn of the right lateral ventricle (Intensity-Modulated Radiation Therapy [IMRT]: 2 Gy × 14 fractions). On May 18, 2023, a core needle biopsy of the right supraclavicular lymph node mass was performed. Histopathological evaluation confirmed metastatic lung adenocarcinoma. Immunohistochemical analysis demonstrated the following profile: CK7 (+), TTF-1 (+), Napsin A (+), P40 (–), MET (90%), CK20 (–), ALK (–), PAX-8 (–), WT-1 (–), Ki-67 (+, ~30%), and PD-L1 (TPS = 60%) (Figure 1).
Remarkably, before the initiation of systemic therapy, chest CT performed on June 5, 2023, revealed an extracranial abscopal effect, with regression of extracranial pulmonary lesions and metastatic lymph nodes exceeding 20% relative to baseline (Figure 2, Supplementary Table S1). Similarly, neurological symptoms, including right hemiplegia, headache, and projectile vomiting, showed significant improvement.
The supraclavicular lymph node specimen was subsequently submitted for genetic sequencing, which identified a KRAS G12C mutation, while EGFR, ALK, and ROS1 mutations were absent. Based on the molecular and immunohistochemical findings (PD-L1 TPS = 60%), pembrolizumab monotherapy was recommended in accordance with NCCN guidelines. Treatment with pembrolizumab (200 mg every 3 weeks) commenced in June 2023 and was continued until June 2025. The patient achieved a durable partial response both intracranially and extracranially, sustained for up to 24 months (Figures 3, 4). During the course of pembrolizumab therapy, serum tumor markers carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA21-1) demonstrated a mild decline (Supplementary Figure S2) (Supplementary Figure S3).

3
Discussion
In this report, we describe a patient with advanced primary lung adenocarcinoma harboring a KRAS G12C mutation and high PD-L1 expression (TPS ≥50%) who underwent palliative brain radiotherapy followed by PD-1 antibody therapy. The patient achieved a durable partial response (PR) lasting over 24 months, experienced an extracranial abscopal effect, and did not develop severe systemic adverse events. These findings suggest that PD-1 blockade may play a pivotal role in sustaining antitumor immunity.
The abscopal effect is generally believed to be mediated through immune system activation (8). Radiotherapy can induce immunogenic cell death, resulting in the release of tumor-associated antigens. These antigens are subsequently processed by antigen-presenting cells (APCs), which activate cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, capable of eradicating distant tumor cells (9, 10). However, the extracranial abscopal effect following brain-directed radiotherapy remains exceedingly rare. This rarity is thought to be linked to the restrictive nature of the blood–brain barrier, which both limits the release of tumor antigens into the periphery and restricts APC infiltration into the brain parenchyma (6). Studies have shown the radiation fractionation is related to the occurrence of abscopal effect. Hypofractionated Radiotherapy schedules, especially single high dose(>3 Gy), seem the most effective regimen for inducing an abscopal effect (11, 12). High PD-L1 expression in tumor cells has been shown to drive immune evasion by inducing apoptosis of activated T cells, suppressing T-cell proliferation, and inhibiting effector functions within the tumor microenvironment (13, 14). Despite these mechanisms of immune suppression, our report is the first to demonstrate that an extracranial abscopal effect can still be elicited by brain radiotherapy alone in a patient with lung adenocarcinoma and PD-L1 TPS ≥50%, even before systemic immunotherapy was initiated.
Pembrolizumab remains the standard of care for NSCLC with PD-L1 overexpression (TPS ≥50%), with reported median objective response rates, progression-free survival, and overall survival of 44.8%, 10.3 months, and 26.3 months, respectively (15). Patients with symptomatic brain metastases requiring immediate radiotherapy often show significantly reduced survival outcomes (16). In this case, radiotherapy likely initiated an endogenous antitumor immune response, characterized by increased activation of effector and memory T-cell subsets (Tcm and Tem). Subsequent administration of pembrolizumab appeared to sustain and amplify this response, enabling durable disease control and maintaining partial response for 24 months despite the presence of brain metastases.
In conclusion, this case demonstrates that even within an immunosuppressive tumor microenvironment characterized by high PD-L1 expression (TPS ≥50%), brain radiotherapy alone has the potential to induce an abscopal effect. Further prospective studies are warranted to validate and expand upon these preliminary observations.

Patient perspective
I was admitted to the hospital for treatment due to right-sided hemiplegia and inability to take care of myself in daily life. After undergoing brain radiotherapy and systemic immunotherapy, my symptoms have improved significantly, and the adverse reactions of the treatment are tolerable.