Pembrolizumab in brain metastases of diverse histologies: phase 2 trial results

Brastianos, Priscilla K.; Kim, Albert E.; Giobbie-Hurder, Anita; Lee, Eudocia Q.; Lin, Nancy U.; Overmoyer, Beth; Wen, Patrick Y.; Nayak, Lakshmi; Cohen, Justine V.; Dietrich, Jorg; Eichler, April; Heist, Rebecca S.; Krop, Ian; Lawrence, Donald; Ligibel, Jennifer; Tolaney, Sara; Mayer, Erica; Winer, Eric; Bent, Brittany; de Sauvage, Magali A.; Ijad, Nazanin; Larson, Juliana M.; Marion, Braxton; Nason, Sally; Murthy, Naina; Ratcliff, Sherry; Summers, Elizabeth J.; Mahar, Maura; Shih, Helen A.; Oh, Kevin; Cahill, Daniel P.; Gerstner, Elizabeth R.; Sullivan, Ryan J.

doi:10.1038/s41591-023-02392-7

Cited by 9 publications

(3 citation statements)

References 35 publications

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“…These real-world data are consistent with those from prospective studies. In a histology-agnostic phase 2 trial of patients with BM, including seven with NSCLC (of whom two had EGFR mutations and one had an ALK rearrangement), the overall intracranial benefit rate of pembrolizumab was 42.1%, and 43% of patients with NSCLC had an intracranial response, which is consistent with our results [ 18 ]. Moreover, the ATEZO-Brain trial reported similar systemic and cerebral efficacy of the addition of immunotherapy to chemotherapy.…”

Section: Discussionsupporting

confidence: 89%

“…In recent translational studies performing RNA sequencing, advanced metastatic lung cancer seems to present distinct molecular and cellular features from those of the early stage, with sustained reprogramming of the tumor microenvironment (TME) [ 22 ]. In the case of BM, the intracranial TME seems to be more immunosuppressive than the extracranial TME is, with a growing interest in immune-based strategies that promote antitumoral T-cell activity [ 18 , 22 , 23 , 24 , 25 ].…”

Section: Discussionmentioning

confidence: 99%

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Outcomes of Patients with Non-Small Cell Lung Cancer and Brain Metastases Treated with the Upfront Single Agent Pembrolizumab: A Retrospective and Multicentric Study of the ESCKEYP GFPC Cohort

Nannini,

Guisier,

Curcio

et al. 2024

Current Oncology

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Non-small cell lung cancer (NSCLC) is the most common cause of brain metastasis (BM). Little is known about immune checkpoint inhibitor activity in the central nervous system, especially in patients receiving monotherapy for tumors with a tumor proportion score (TPS) ≥ 50%. This noninterventional, retrospective, multicenter study, conducted with the GFPC, included treatment-naïve patients strongly positive for PD-L1 (TPS ≥ 50%) with BM receiving first-line single-agent pembrolizumab treatment between May 2017 and November 2019. The primary endpoints were centrally reviewed intracranial overall response rates (ORRs), centrally reviewed intracranial progression-free survival (cPFS), extracranial PFS, and overall survival were secondary endpoints. Forty-three patients from five centers were included. Surgical or local radiation therapy was administered to 31 (72%) patients, mostly before initiating ICI therapy (25/31). Among 38/43 (88.4%) evaluable patients, the intracranial ORR was 73%. The median PFS was 8.3 months. The cerebral and extracerebral median PFS times were 9.2 and 5.3 months, respectively. The median OS was 25.5 months. According to multivariate analysis, BM surgery before ICI therapy was the only factor significantly associated with both improved PFS (HR = 0.44) and OS (HR = 0.45). This study revealed the feasibility and outcome of front-line pembrolizumab treatment in this population with BM.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Outcomes of Patients with Non-Small Cell Lung Cancer and Brain Metastases Treated with the Upfront Single Agent Pembrolizumab: A Retrospective and Multicentric Study of the ESCKEYP GFPC Cohort

Nannini,

Guisier,

Curcio

et al. 2024

Current Oncology

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“…Furthermore, no new and more effective therapies have been found in the past years to treat brain tumors [3]. Recently, immunotherapy has shown promising results for patients with metastatic brain lesions from melanoma and lung cancer [4][5][6]. However, the overall survival of patients with malignant brain tumors, particularly GB and BM, remains poor despite decades of research and clinical trial development [3].…”

Section: Introductionmentioning

confidence: 99%

Role of UBE2C in Brain Cancer Invasion and Dissemination

Domentean,

Paisana,

Cascão

et al. 2023

IJMS

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Glioblastoma (GB) and brain metastases (BM) are the most common brain tumors in adults and are invariably associated with a dismal outcome. These highly malignant tumors share common features including increased invasion and migration of the primary or metastatic brain cancer cells, whose triggering mechanisms are largely unknown. Emerging evidence has suggested that the ubiquitin-conjugating enzyme E2C (UBE2C), essential for controlling cell cycle progression, is overexpressed in diverse malignancies, including brain cancer. This review highlights the crucial role of UBE2C in brain tumorigenesis and its association with higher proliferative phenotype and histopathological grade, with autophagy and apoptosis suppression, epithelial-to-mesenchymal transition (EMT), invasion, migration, and dissemination. High expression of UBE2C has been associated with patients’ poor prognosis and drug resistance. UBE2C has also been proven as a promising therapeutic target, despite the lack of specific inhibitors. Thus, there is a need to further explore the role of UBE2C in malignant brain cancer and to develop effective targeted therapies for patients with this deadly disease.

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Predictive role of intracranial PD-L1 expression in a real-world cohort of NSCLC patients treated with immune checkpoint inhibition following brain metastasis resection

Wasilewski,

Onken,

Höricke

et al. 2024

J Neurooncol

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Background Emerging evidence suggests that treatment of NSCLC brain metastases with immune checkpoint inhibitors (ICIs) is associated with response rates similar to those of extracranial disease. Programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) serves as a predictive biomarker for ICI response. However, the predictive value of brain metastasis-specific (intracranial) PD-L1 TPS is not established. We investigated the role of intra- and extracranial PD-L1 TPS in NSCLC patients treated with ICI following brain metastasis resection. Methods Clinical data from NSCLC patients treated with ICI following brain metastasis resection (n = 64) were analyzed. PD-L1 TPS of brain metastases (n = 64) and available matched extracranial tumor tissue (n = 44) were assessed via immunohistochemistry. Statistical analyses included cut point estimation via maximally selected rank statistics, Kaplan–Meier estimates, and multivariable Cox regression analysis for intracranial progression-free survival (icPFS), extracranial progression-free survival (ecPFS), and overall survival (OS). Results PD-L1 expression was found in 54.7% of brain metastases and 68.2% of extracranial tumor tissues, with a median intra- and extracranial PD-L1 TPS of 7.5% (0 – 50%, IQR) and 15.0% (0 – 80%, IQR), respectively. In matched tissue samples, extracranial PD-L1 TPS was significantly higher than intracranial PD-L1 TPS (p = 0.013). Optimal cut points for intracranial and extracranial PD-L1 TPS varied according to outcome parameter assessed. Notably, patients with a high intracranial PD-L1 TPS (> 40%) exhibited significantly longer icPFS as compared to patients with a low intracranial PD-L1 TPS (≤ 40%). The cut point of 40% for intracranial PD-L1 TPS was independently associated with OS, icPFS and ecPFS in multivariable analyses. Conclusion Our study highlights the potential role of intracranial PD-L1 TPS in NSCLC, which could be used to predict ICI response in cases where extracranial tissue is not available for PD-L1 assessment as well as to specifically predict intracranial response.

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Pembrolizumab in brain metastases of diverse histologies: phase 2 trial results

Cited by 9 publications

References 35 publications

Outcomes of Patients with Non-Small Cell Lung Cancer and Brain Metastases Treated with the Upfront Single Agent Pembrolizumab: A Retrospective and Multicentric Study of the ESCKEYP GFPC Cohort

Outcomes of Patients with Non-Small Cell Lung Cancer and Brain Metastases Treated with the Upfront Single Agent Pembrolizumab: A Retrospective and Multicentric Study of the ESCKEYP GFPC Cohort

Role of UBE2C in Brain Cancer Invasion and Dissemination

Predictive role of intracranial PD-L1 expression in a real-world cohort of NSCLC patients treated with immune checkpoint inhibition following brain metastasis resection

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