Intracranial Progression Research Articles

IMMU-02. INTRACRANIAL PROGRESSION IS LESS COMMON IN PATIENTS WITH ADVANCED NSCLC RECEIVING CANCER IMMUNOTHERAPY

Abstract BACKGROUND Intracranial metastases are common in patients with non-small cell lung cancer (NSCLC) and their prognosis is very poor. Furthermore, intracranial progression is common during systemic therapy due to the inability to cross the blood brain barrier, but the impact of cancer immunotherapy on intracranial progression remains unclear. METHODS We analyzed clinical data to evaluate the frequency of intracranial progression in patients with advanced NSCLC treated with PD-1 blockade therapies compared to patients not treated with PD-1 blockade therapies (Approval number: 2201-022). We also evaluated durable responses to PD-1 blockade and analyzed tumor-infiltrating lymphocytes using tumor-rechallenging murine models. RESULTS The clinical data analysis showed that the frequency of intracranial progression was significantly lower in patients with advanced NSCLC treated with PD-1 blockade than in patients treated with cytotoxic chemotherapy. In murine models, intracranial rechallenged tumors after initial rejection by PD-1 blockade therapy were suppressed, as observed for subcutaneous tumors. Accordingly, PD-1 blockade increased long-lived memory precursor effector T cells and antigen-specific T cells in intracranial lesions. In contrast, intracranial rechallenged different tumors were not suppressed. CONCLUSIONS The CNS has been considered a site in which cancer patients tend to experience progression during systemic therapies, however our results indicate that cancer immunotherapies can prevent intracranial progression, maintaining long-term effects intracranially as well as systemically. (Kemmotsu N. et. al., Int J Cancer, 2024)

PATH-43. MALIGNANT TRANSFORMATION OF MENINGEAL MELANOCYTOMA - GENETIC ALTERATIONS AND RESPONSE TO CHECKPOINT BLOCKADE IMMUNOTHERAPY

Abstract INTRODUCTION Meningeal melanocytomas are uncommon tumors that develop from leptomeningeal melanocytes. These tumors can exhibit aggressive behavior, leading to symptoms due to compression and potential invasion of nearby central nervous tissue. Case: In this report, we discuss the case of a 45-year-old man who was diagnosed 18 years ago with a meningeal melanocytoma in the right temporal region. He underwent complete resection with each recurrence and received focal intensity-modulated radiation therapy after a third recurrence in 2013. In May 2022, he developed progressive headaches and diplopia secondary to tumor recurrence on the right temporal region. Resection revealed that the tumor had progressed to malignant meningeal melanoma with 34 mitoses per 10 high-power fields. Next-generation sequencing (NGS) showed GNAQ mutation confirming tumor of central nervous system (CNS) origin, and also showed an SF3B1 mutation, indicating aggressive behavior. Several chromosomal abnormalities were also detected. Systemic workup revealed liver, lung, and bone metastasis. Liver biopsy confirmed meningeal melanoma of central origin. The patient received radiosurgery with a total of 30Gy over five fractions to intracranial surgical cavity, followed by three cycles of nivolumab and relatlimab. Unfortunately, the patient experienced severe intracranial and systemic progression, leading to his death six months after the malignant transformation. DISCUSSION Meningeal melanocytomas are rare however these tumors have a high recurrence rate with potential malignant transformation over time. NGS is a valuable tool for confirming the CNS origin of the tumor and predicting its aggressive behavior. Despite microscopic similarity with cutaneous melanomas, meningeal melanocytomas have different pathogenesis and do not seem to respond to immunotherapy, as observed in this case.

EXTH-66. ONCOLYTIC ADENOVIRAL INFECTION SYNERGIZES WITH IMMUNE CHECKPOINT INHIBITION TO MEDIATE INTRACRANIAL TUMOR CONTROL IN DISPARATE MODELS OF MELANOMA BRAIN METASTASES

Abstract Amongst all solid cancers, melanoma brain metastases (MBM) have the highest likelihood of metastasizing to the brain. The emergence of immune checkpoint inhibitors (ICI) for metastatic melanoma have demonstrated increasingly promising results; however, intracranial progression remains a challenging obstacle. Oncolytic viral (OV) therapy leverages tumor cell replication machinery to selectively replicate and kill tumor cells and promote anti-tumor immunity. We propose this OV strategy can be applied to MBM through direct tumor infection that simultaneously sustains a distant antitumor immune response. To counteract immunosuppressive features of the tumor microenvironment (TME), a third-generation oncolytic adenovirus (Delta-24-RGDOX) has been developed which expresses the immune stimulatory OX40 ligand (OX40L). We quantified the cytotoxic capacity of Delta-24-RGDOX and its ability to achieve immunogenic cell death (ICD) in vitro along with cerebral organoid co-culture models. Additionally, we used a series of syngeneic murine melanoma models to explore local and systemic antitumor immunity following Delta-24-RGDOX infection. Delta-24-RGDOX inoculation achieved viral infection, OX40L cell surface expression, tumor cell cytotoxicity, and ICD in vitro. Viral oncolysis was recapitulated in a cerebral organoid melanoma co-culture model with concomitant alterations in microglia activation and detection of viral transcripts within microglia using single cell RNA sequencing, suggesting a viral-clearing role of microglia within the TME. Local tumor clearance was achieved in orthotopic intracranial models following direct intracranial viral inoculation alone, and in combination with ICI. Lastly, we demonstrated improvement in overall survival in a synchronous subcutaneous/intracranial B16F10 model where the subcutaneous tumor was treated with Delta-24-RGDOX in combination with ICI. In summary, Delta-24-RGDOX achieves viral infection, oncolysis, and ICD following infection of melanoma cell lines. These findings translated in multiple in vivo models including immune cell activation and systemic antitumor immunity against uninfected MBM. Future studies are needed to explore the role of immune cell trafficking, myeloid cell modulation, T cell priming, and clonal expansion withing locally infected and the distant melanoma TME.

Quality of life after stereotactic radiosurgery for brain metastasis: an assessment from a prospective national registry.

Stereotactic radiosurgery (SRS) is frequently used in the management of brain metastasis patients. However, there is an urgent need to evaluate post-treatment outcomes and quality of life metrics for patients undergoing SRS for brain metastases. The NeuroPoint Alliance (NPA) SRS Quality Registry conducted prospective enrollment of patients undergoing SRS from 2017 to 2024. Patients with brain metastases from lung cancer, breast cancer, and melanoma were included in the analysis. Outcomes of interest included quality of life metrics, as captured by the five-dimension Euro-QOL (EQ-5D) at 6-12 months and last record follow-up, overall survival, local progression, out-of-field progression, and overall intracranial progression. 522 patients comprised our analytic cohort, and 315 patients had available EQ-5D data at the time of SRS and final follow-up. 264 (47.8%), 197 (35.7%), and 91 (16.5%) patients had 1, 2-4, and 5-14 lesions pre-SRS, respectively. The median overall survival time from diagnosis was 27.3 months. The median time-to-local progression was not reached. At final follow-up, 107 (34.0%) patients had improvement, 51 (16.2%) patients had stable, and 113 patients (35.9%) had worsening EQ-5D scores when compared to baseline. For 44 (13.9%) patients mixed responses across the EQ-5D indices were reported. Linear regression analysis showed that male sex, smoking status, primary tumor type, time-to-overall progression, cumulative intracranial tumor volume (CITV), and baseline EQ-5D were statistically significantly associated with EQ-5D single index at the final follow-up. Real-world data from the SRS NPA Registry demonstrated that most patients with brain metastasis had no change or improvement in quality of life after SRS. Baseline EQ-5D was predictive of EQ-5D single index at final follow-up, and, as such, EQ-5D at baseline would be a valuable assessment measure for brain metastasis patients undergoing SRS.

Site-specific m6A-miR-494-3p, not unmethylated miR-494-3p, compromises blood brain barrier by targeting tight junction protein 1 in intracranial atherosclerosis.

Intracranial atherosclerosis is one of the most common causes of ischaemic stroke. However, there is a substantial knowledge gap on the development of intracranial atherosclerosis. Intracranial arteries are characterized by an upregulation of tight junctions between endothelial cells, which control endothelial permeability. We investigated the role of N6-methyladenosine (m6A), a common RNA modification, on endothelial integrity, focusing on the pro-atherogenic microRNA miR-494-3p and tight junction proteins TJP1 and PECAM1. We assessed the m6A landscape, along with the expression of miR-494-3p, TJP1 and PECAM1 in postmortem human vertebral arteries (VA), internal carotid arteries (ICA), and middle cerebral arteries (MCA) with various stages of intimal thickening and plaque formation. The interactions between m6A-modified miR-494-3p mimics, TJP1 and PECAM1, were investigated in vitro using primary human (brain) endothelial cells. Increased m6A expression was observed in the luminal lining of atherosclerosis-affected VAs, accompanied by reduced TJP1 and PECAM1, but not VE-cadherin, expression. Colocalization of m6A and miR-494-3p in the luminal lining of VA plaques was confirmed, indicating m6A methylation of miR-494-3p in intracranial atherosclerosis. Moreover, site-specific m6A-modification of miR-494-3p led to repression specifically of TJP1 protein expression at cell-cell junctions of brain microvascular endothelial cells, while unmodified miR-494-3p showed no effect. This study highlights increasing m6A levels during intracranial atherogenesis. Increases in m6A-miR-494-3p contribute to the observed decreased TJP1 expression in endothelial cell-cell junctions. This is likely to have a negative effect on endothelial integrity and may thus accelerate intracranial atherosclerosis progression.

Glioblastoma multiforme recurrence on skin and subcutaneous tissue: a case report

Glioblastoma multiforme (GBM) is the most common malignant primary central nervous system (CNS) tumor. It presents an aggressive pattern, with a tendency for intracranial progression despite optimal treatment. On the other hand, metastases and manifestations outside the CNS are exceptional, and very few cases have been described. The authors submitted a case of a 48-year-old male diagnosed with a left parietooccipital GBM isocitrate dehydrogenase (IDH) wild-type, non-methylated O6-methylguanine-DNA methyltransferase (MGMT). Six months after surgical treatment, followed by a chemotherapy (CT) and radiotherapy scheme, he developed a few subcutaneous erythematous nodules within the surgical scar. A punch biopsy confirmed the histopathology of GBM. The CT scan showed concomitant intracranial progression. We ruled out systemic metastases. As the performance status was good [Karnofsky Performance Status 90 (KPS 90)] and the subcutaneous implants were growing rapidly, limiting the quality of life, we decided to perform palliative surgery to remove the implants. The result was good. Unfortunately, the patient worsened during the following week, after ruling out medical complications, we attributed the worsening to cerebral tumor swelling, revealed in the CT scan, as unresponsive to steroids. He passed away a few days later. Based on the analysis of our case, we intend to provide useful information for the approach to this peculiar manifestation of GBM.

Role of osimertinib plus brain radiotherapy versus osimertinib single therapy in EGFR-mutated Non-Small-Cell Lung Cancer with brain metastases: a meta-analysis and systematic review.

Single-agent osimertinib has improved outcomes in EGFR-mutated lung cancer patients with brain metastases (BMs), but still, 40% of them will experience an intracranial progression. We performed a systematic review to evaluate the role of brain radiotherapy upfront plus osimertinib. We evaluated articles comparing the use of osimertinib versus osimertinib plus brain radiotherapy. We included 897 patients from nine retrospective studies. Patients treated with combination therapy had an improvement in intracranial progression-free survival (HR 0.76; 95% CI 0.61-0.94) and overall survival (HR 0.56; 95% CI 0.36-0.87) with an acceptable safety profile. Osimertinib with upfront brain radiotherapy may be a suitable first-line treatment option for EGFR mutated patients with BMs at diagnosis. The main limitations of this analysis are the retrospective nature and the inability to control for a single variable of interest. Despite that, the combination of osimertinib and upfront brain radiotherapy is a treatment strategy that deserves further prospective trials.

Pyrotinib plus capecitabine for patients with HER2-positive metastatic breast cancer and brain metastases (PERMEATE trial): overall survival results from a multicenter, single-arm, two-cohort, phase 2 trial

The phase 2 PERMEATE study has shown the antitumor activity and safety of pyrotinib plus capecitabine in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer and brain metastases. In this report, survival results were updated with extended follow-up. Between January 29, 2019 and July 10, 2020, adult patients with HER2-positive metastatic breast cancer who had radiotherapy-naïve brain metastases (cohort A, n=59) or progressive disease after radiotherapy (cohort B, n=19) were enrolled and received pyrotinib (400mg once daily) and capecitabine (1000mg/m2 twice daily on days 1-14 of each 21-day cycle) until disease progression or unacceptable toxicity. Secondary endpoints progression-free survival (PFS) and overall survival (OS) were updated, and post-hoc central nervous system (CNS)-PFS was analyzed. This study is registered with ClinicalTrials.gov (NCT03691051). As of February 2, 2023, the median follow-up duration was 30.9 months (interquartile range, 16.1-39.8). Median PFS was 10.9 months (95% confidence interval [CI], 7.6-14.6) in cohort A and 5.7 months (95% CI, 3.4-11.5) in cohort B. Median OS was 35.9 months (95% CI, 24.4-not reached) in cohort A and 30.6 months (95% CI, 12.6-33.3) in cohort B. Median CNS-PFS was 13.6 months (95% CI, 9.0-15.8) in cohort A and 5.7 months (95% CI, 3.4-11.5) in cohort B. Median OS was 34.1 months (95% CI, 21.7-not reached) for 14 patients with intracranial progression only in cohort A who restarted pyrotinib plus capecitabine after local radiotherapy. These data support further validation in a randomized controlled trial for the assessment of pyrotinib in combination with capecitabine as systemic therapy for patients with HER2-positive breast cancer and brain metastases. National Cancer Center Climbing Foundation Key Project of China, Jiangsu Hengrui Pharmaceuticals.

Phosphorylated NPY1R regulates phenotypic transition of vascular smooth muscle cells, inflammatory response and macrophage infiltration to promote intracranial aneurysm progression

BackgroundRupture of intracranial aneurysm (IA) could give rise to spontaneous subarachnoid hemorrhage, leading to a high disability rate and even death. NPY1R expression was upregulated in aneurysm tissues of IA patients. However, the role and underlying mechanism of NPY1R remains unknown. MethodsThe IA model of mice was established using inducing systemic hypertension and injecting elastase. The expression of genes and proteins was detected by RT-qPCR and western blot. The number of T cells, macrophages, and neutrophils in IA mice was detected using flow cytometry and IF assay. The levels of inflammatory factors were measured using ELISA. Patho-morphology and inflammatory cells in aneurysm tissues were evaluated by HE staining. The interaction between TK and NPY1R was validated using Co-IP. ResultsNPY1R expression was greatly elevated in aneurysm tissues in IA patients and mice, which were positively related to macrophage infiltration. Besides, exogenous overexpression of NPY1R resulted in the promotion of contractile phenotype to the synthetic phenotype of vascular smooth muscle cells (VSMCs), inflammatory response and M1 macrophage polarization. In terms of the underlying mechanism, NPY1R protein could be modified by TK-mediated phosphorylation and TKI could decrease IA formation and suppresse contractile phenotype to synthetic phenotype of VSMCs, inflammatory response and M1 macrophage polarization in IA mice. Furthermore, ablating mouse macrophages abolished NPY1R overexpression-mediated promotion of IA formation and rupture in mice. ConclusionPhosphorylated NPY1R contributed to IA progression through promoting contractile phenotype to synthetic phenotype of VSMCs, inflammatory response and M1 macrophage polarization in IA.

The DEBBRAH trial: Trastuzumab deruxtecan in HER2-positive and HER2-low breast cancer patients with leptomeningeal carcinomatosis.

Leptomeningeal disease (LMD) is associated with poor survival and diminished quality of life. Trastuzumab deruxtecan (T-DXd) has shown remarkable intracranial and extracranial activity in human epidermal growth factor receptor 2 (HER2)-positive and HER2-low advanced breast cancer (ABC). The DEBBRAH trial was designed to evaluate its efficacy and safety in patients with HER2-positive and HER2-low ABC with a history of brain metastases (BMs) and/or LMD. Here, we report results from cohort 5, which specifically included patients with pathologically confirmed LMD. This single-arm, open-label, five-cohort, phase 2 trial enrolled seven patients in cohort 5 who received 5.4mg/kg T-DXd intravenously every 21days until disease progression or unacceptable toxicity. The primary endpoint was overall survival (OS). Key secondary endpoints included progression-free survival (PFS) and safety profile. At data cutoff (April 4, 2023), the median duration of follow-up was 12.0months (range, 2.5-18.6). The median OS was 13.3months (95% confidence interval [CI], 5.7-NA, p<0.001), meeting the primary endpoint. The median PFS was 8.9months (95% CI, 2.1-NA). Two (28.6%) of seven patients remained on treatment after 18.6 and 11.9months, respectively. Of the five patients who progressed and died, none had intracranial progression or clinical worsening of leptomeningeal symptoms. Notably, 71.4% (95% CI, 29.0-96.3) achieved prolonged stabilization (≥24weeks) by response evaluation criteria in solid tumors (RECIST) v.1.1. No unexpected safety signals and no treatment-related deaths were observed. T-DXd showed promising antitumor activity in patients with HER2-positive and HER2-low ABC with previously untreated, pathologically confirmed LMD. These encouraging data warrant further investigation to address the unmet need in this difficult-to-treat condition. This work was funded by Daiichi Sankyo/AstraZeneca. This trial is registered with ClinicalTrials.gov: NCT04420598.

Outcome of whole brain irradiation with a dose-escalated simultaneous-integrated boost in patients with multiple large and/or diffuse brain metastases: real live data and review of the literature

BackgroundWe retrospectively investigate feasibility and safety of whole brain radiotherapy (WBRT) including a simultaneous-integrated boost technique (WBRT-SIB) in a cohort of patients with a very poor prognosis suffering from multiple and/or large brain metastases, unfavorable primary histology, poor performance status and/or symptomatic BMs.Materials and MethodsThirty-five patients with high brain tumor burden, extracranial metastases and low life-expectancy were treated with WBRT-SIB mostly with 35-42 Gy/14 fractions. All metastases were boosted in patients with up to 12 BMs. In patients with > 12 BM, large and/or small metastases in critical brain regions were boosted up to a maximum of 12 SIB volumes.ResultsThe median number of BM was 8 (range 2–45) and the median BM diameter was 12 mm (range 4–90 mm). Fifteen (43%) patients had ≥ 10 BMs and 25 patients presented with a Karnofski index ≤ 80%. Primary tumor histology was NSCLC (n = 13), SCLC (n = 11), breast cancer (n = 7), melanoma (n = 2), other (n = 2). The median iPFS was not reached, and 12- and 18-months iPFS were 75% and 50%, respectively. Overall, seven patients had intracranial progression: two patients within the SIB and WBRT area, one patient only within the SIB region and four patients had new BMs in the WBRT volume alone. The median iPFS for non-SCLC patients was 17 months and the 12- and 18-month iPFS were 56.8% and 28.4%, respectively. There was no significant OS difference between SCLC-group and non-SCLC patients (p = 0.38). Overall, median OS was 8.7 months and 1-year OS was 25%. The treatment was generally well-tolerated with no observed cases of radionecrosis.ConclusionOur WBRT-SIB approach involves a combination of whole brain radiotherapy and a simultaneous integrated boost to specific tumor volumes, and its effectiveness is compared with other treatment modalities in the literature. Further research, including prospective studies with larger patient cohorts, is necessary to validate and refine the findings.

Clinicogenomic predictors of survival and intracranial progression after stereotactic radiosurgery for colorectal cancer brain metastases.

Brain metastases (BM) from colorectal cancer (CRC) are associated with dismal prognosis. When BM-directed therapy is considered, better methods are needed to identify patients at risk of poor oncological outcomes in order to optimize patient selection for closer surveillance or escalated therapy. The authors sought to identify clinicogenomic predictors of survival and intracranial disease progression after CRC BM have been treated with stereotactic radiosurgery (SRS). Patients with newly diagnosed CRC BM treated with SRS between 2009 and 2022 who had next-generation genomic sequencing data available were included. Frameless SRS was delivered in 1-5 fractions, alone or after neurosurgical resection. Outcomes included overall survival (OS) and intracranial progression (IP), evaluated per patient treated with SRS, and local progression (LP), evaluated per BM. Associations between baseline clinicogenomic features and outcomes were evaluated with Cox regression and competing risk regression, with death as a competing risk. This analysis included 123 patients with 299 BM. At BM diagnosis, 111 patients (90%) had progressive extracranial disease, and 79 patients (64%) had ≥ 3 sites of extracranial metastasis. The median (IQR) number of BM was 2 (1-3) per patient. The median (IQR) biologically effective dose (BED) was 51.3 (51.3-65.1) Gy, corresponding to a prescription of 27 Gy in 3 fractions. OS, IP, and LP estimates at 1 year after SRS were 36%, 55%, and 12%, respectively. OS was independently associated with progressive extracranial disease (HR 4.26, 95% CI 1.63-11.2, p = 0.003) and ≥ 3 extracranial metastatic sites (HR 1.84, 95% CI 1.12-3.01, p = 0.02). LP was less likely when BM received BED ≥ 51.3 Gy (HR 0.24, 95% CI 0.07-0.78, p = 0.02), independent of BM diameter (HR 1.21/cm, 95% CI 0.8-1.84, p = 0.4). IP was independently associated with genomic alterations; TP53 driver alterations were associated with higher risk of IP (HR 2.71, 95% CI 1.26-5.79, p = 0.01), whereas MYC pathway alterations were associated with lower risk (HR 0.15, 95% CI 0.03-0.68, p = 0.01). The authors identified clinicogenomic features associated with adverse outcomes after SRS for CRC BM. Progressive and extensive extracranial metastases predicted worse OS. Insufficient SRS doses predicted greater risk of LP. Wild-type TP53 and alterations in the MYC pathway were independently associated with lower risk of IP. Patients at high risk of IP may be considered for closer surveillance or escalated therapy.

Brain Radiotherapy Combined with Targeted Therapy for HER2-Positive Breast Cancer Patients with Brain Metastases.

Research on the sequencing of brain radiotherapy and targeted chemotherapy after brain metastasis (BM) in HER2-positive breast cancer patients is limited and inconclusive. This study investigated the efficacy of sequential delivery of radiotherapy and targeted therapy in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer with BM. Fifty-seven patients were categorized into two groups: the targeted-radiotherapy group (receiving 2-8 cycles of anti-HER2-targeted therapy followed by radiotherapy after BM) and the radiotherapy-targeted group (undergoing radiotherapy first, followed by regular anti-HER2-targeted therapy). The study endpoints were intracranial progression-free survival (iPFS) and overall survival. Factors associated with intracranial progression and mortality were assessed by univariate and multivariate Cox proportional hazards analysis. Patients in the radiotherapy-targeted group had better iPFS (P < 0.001), while there was no significant difference in overall survival between the two groups (P = 0.145). Multivariate Cox analysis showed that different sequential treatment groups were independent prognostic factors for iPFS. In patients with a modified breast graded prognostic assessment score of 3.5-4.0, the median survival time was 26 months in the radiotherapy-targeted group and 22 months in the targeted-radiotherapy group (P = 0.019). Overall, radiotherapy followed by targeted therapy may improve survival in HER2-positive breast cancer patients with BM, particularly in those with a modified breast graded prognostic assessment score of 3.5-4.0.

Humanin activates integrin αV–TGFβ axis and leads to glioblastoma progression

The role of mitochondria peptides in the spreading of glioblastoma remains poorly understood. In this study, we investigated the mechanism underlying intracranial glioblastoma progression. Our findings demonstrate that the mitochondria-derived peptide, humanin, plays a significant role in enhancing glioblastoma progression through the intratumoral activation of the integrin alpha V (ITGAV)–TGF beta (TGFβ) signaling axis. In glioblastoma tissues, humanin showed a significant upregulation in the tumor area compared to the corresponding normal region. Utilizing multiple in vitro pharmacological and genetic approaches, we observed that humanin activates the ITGAV pathway, leading to cellular attachment and filopodia formation. This process aids the subsequent migration and invasion of attached glioblastoma cells through intracellular TGFβR signaling activation. In addition, our in vivo orthotopic glioblastoma model provides further support for the pro-tumoral function of humanin. We observed a correlation between poor survival and aggressive invasiveness in the humanin-treated group, with noticeable tumor protrusions and induced angiogenesis compared to the control. Intriguingly, the in vivo effect of humanin on glioblastoma was significantly reduced by the treatment of TGFBR1 inhibitor. To strengthen these findings, public database analysis revealed a significant association between genes in the ITGAV–TGFβR axis and poor prognosis in glioblastoma patients. These results collectively highlight humanin as a pro-tumoral factor, making it a promising biological target for treating glioblastoma.

Repeated HyperArc radiosurgery for recurrent intracranial metastases and dosimetric analysis of recurrence pattern to account for diffuse dose effect on microscopical disease

AimsEvaluate effectiveness and safety of multiple HyperArc courses and patterns of progression in patients affected by BMs with intracranial progression. Methods56 patients were treated for 702 BMs with 197 (range 2–8) HyperArc courses in case of exclusive intracranial progression. Primary end-point was the overall survival (OS), secondary end-points were intracranial progression-free survival (iPFS), toxicity, local control (LC), neurological death (ND), and whole-brain RT (WBRT)-free survival. Site of progression was evaluated against isodoses levels (0, 1, 2, 3, 5, 7, 8, 10, 13, 15, 20, and 24 Gy.). ResultsThe 1-year OS was 70 %, and the median was 20.8 months (17–36). At the univariate analysis (UVA) biological equivalent dose (BED) > 51.3 Gy and non-melanoma histology significantly correlated with OS. The median time to iPFS was 4.9 months, and the 1-year iPFS was 15 %. Globally, 538 new BMs occurred after the first HA cycle in patients with extracranial disease controlled. 96.4 % of them occurred within the isodoses range 0–7 Gy as follows: 26.6 % (0 Gy), 16.5 % (1 Gy), 16.5 % (2 Gy), 20.1 % (3 Gy), 13.1 % (5 Gy), 3.4 % (7 Gy) (p = 0.00). Radionecrosis occurred in 2 metastases (0.28 %). No clinical toxicity of grade 3 or higher occurred during follow-up. One- and 2-year LC was 90 % and 79 %, respectively. At the UVA BED > 70 Gy and non-melanoma histology were significant predictors of higher LC. The 2-year WBRT-free survival was 70 %. After a median follow-up of 17.4 months, 12 patients deceased by ND. ConclusionIntracranical relapses can be safely and effectively treated with repeated HyperArc, with the aim to postpone or avoid WBRT. Diffuse dose by volumetric RT might reduce microscopic disease also at relatively low levels, potentially acting as a virtual CTV. Neurological death is not the most common cause of death in this population, which highlights the impact of extracranial disease on overall survival.

Melanoma brain metastasis treated with stereotactic radiosurgery (SRS) and systemic agents (SACT): A single centre perspective from Northeast England.

e21500 Background: Melanoma incidence rates in the UK will increase and given its proclivity for brain metastasis, it will be a growing challenge. Real-world survival data reflecting the impact of modern SACTs and SRS is lacking. Here we report our single-centre experience. Methods: All melanoma brain metastasis patients treated with both SRS and SACT in Newcastle-upon-Tyne, UK between January 2017 and January 2022 were identified. Data was collected from patient records until data-lock in January 2023. Survival analysis was performed using R (version 4.2.2). The primary objective was to measure the overall survival. Results: 51 patients were included. The median age was 60 years. Most patients had ECOG PS of 0 (43%, n = 22) or 1 (53%, n = 27). 15 (29%) had de-novo brain metastasis. 21 (41%) were on SACT before diagnosis of brain metastasis. 28 (55%) patients had solitary brain metastasis. 8 (16%) had no radiologically reported extracranial disease. Superficial spreading melanoma was the most common histological subtype (45%, n = 23). 55% (n = 26) had a sensitizing BRAF mutation. 25 patients (49%) received SRS before SACT. 12 (26%) patients had undergone primary debulking surgery. The median time to start SRS was 54 days (IQR 35 - 90) from brain metastasis diagnosis. Median extracranial progression-free survival was 25 months (95% CI 10 – NA). Median intracranial progression-free survival was 29 months (95% CI 15 – NA). 17 (33%) patients had both intra and extracranial progression. 7 (13%) had in-field intracranial progression. The median target volume was similar between subgroups that had infield (1.78mL, IQR 0.56 - 13.81), out-of-field (1.78mL, IRQ 1.62 - 3.97) or no intracranial progression (2.38mL, IQR 1.29 - 6.73). The median total dose to target was 21 Grays for all subgroups. Median overall survival was 27 months (95% CI 16 - NA). With intracranial progression, the median overall survival was 21 months (95% CI 10 –36). The survival was 15 months (95% CI 9.5 - 27) with extracranial progression, which was significantly less than without extracranial progression (HR = 0.25, 95% CI 0.11 – 0.60, p = 0.002). In the absence of intracranial progression, median overall survival was not reached. Patients with infield progression had an overall survival of 8.6 months (95% CI 6.8 – NA), HR 2.83 (95% CI 1.20 - 6.7), p = 0.018. Those with melanoma-specific Graded Prognostic Assessment score (molGPA) &gt; 2.5 had a median overall survival of 31 months (95% CI 14 – NA) with a HR of 0.73 (95% CI 0.32 - 1.64, p = 0.4). Conclusions: Survival in our cohort is notably better than reports from prior series. This is despite our catchment in the North East of England being adversely affected by health disparity. This could be explained by the selection bias of our cohort. However, in the wake of improved treatment modalities, the need for more up-to-date cancer data tracking cannot be overstated.

Results from METIS (EF-25), an international, multicenter phase III randomized study evaluating the efficacy and safety of tumor treating fields (TTFields) therapy in NSCLC patients with brain metastases.

2008 Background: For non-small cell lung cancer (NSCLC) with brain metastases (BM) stereotactic radiosurgery (SRS) is the current preferred therapy. Due to frequent intracranial failures, there is a high unmet need for salvage therapies. Whole brain radiotherapy (WBRT) reduces intracranial failure but used less frequently due to cognitive consequences. Tumor Treating Fields (TTFields) are electric fields that disrupt cancer cell division and have shown improved survival and safety in patients with glioblastoma and metastatic NSCLC. Phase 3 METIS trial [NCT02831959] aimed to evaluate the efficacy and safety of TTFields therapy in NSCLC patients with BM treated with SRS, specifically in terms of lengthening time to intracranial progression without cognitive decline. Methods: Mutation negative (M-) NSCLC patients with 1–10 BM were randomized 1:1 to receive stereotactic radiosurgery (SRS) followed by Tumor Treating Fields (TTFields; 150 kHz) therapy with best supportive care (BSC) or SRS followed by BSC. Patients with Karnofsky Performance Status (KPS) ≥70, newly diagnosed with one inoperable or 2–10 supra-/infratentorial brain metastases suitable for SRS and receiving optimal extracranial disease therapy were included. Exclusions were prior WBRT and single operable or recurrent brain metastases. Primary endpoint was time to first intracranial progression (RANO-BM) based on cumulative risk. Patients were followed every two months until second intracranial progression. Cognition and patient quality of life (QoL) were evaluated. Results: Between July 2016 and September 2022, 298 patients were randomized. Baseline characteristics were balanced: median age was 63.5 (range 37-84) years, 37.6% females, majority of patients had a KPS ≥ 80, median time from initial NSCLC diagnosis was 1.8 months (range: 0.2-55.7), 77% had adenocarcinoma. Median treatment duration of TTFields was 16 weeks, with a median usage time of 67%. Primary endpoint, time to intracranial progression from SRS, was significantly prolonged with SRS followed by TTFields therapy with BSC vs. TTFields plus BSC arm (median of 21.9 vs. 11.3 months); HR=0.67 [0.48-0.93], p=0.02. TTFields-related AEs were mainly dermatological, and Grade ≤2. TTFields therapy also improved deterioration-free survival of global health status, physical functioning, and fatigue according to QoL, and did not negatively impact cognition. Conclusions: METIS study met its primary endpoint, demonstrating that TTFields therapy following SRS in mutation negative NSCLC patients with BM, significantly prolongs time to intracranial progression and could postpone WBRT, without QoL and cognition decline. Clinical trial information: NCT02831959 .

Brain metastases in patients with pleural mesothelioma receiving dual checkpoint blockade compared to single-agent checkpoint blockade or chemotherapy.

e20093 Background: Immunotherapy (IO) has emerged as a treatment option in pleural mesothelioma (PM). Historically, brain metastases (BM) in PM were rare, thus brain imaging is not routine practice or included in guidelines. We characterize the incidence of BMs by type of treatment received. Methods: In this retrospective analysis,adult patients with PM treated at the Hospital of the University of Pennsylvania between 1/1/2015- 8/31/2023 were included. Patient demographic data, treatment, brain imaging and clinical history were extracted from the electronic medical record.A two-tailed Z score with alpha 0.05 was used to determine a difference in proportion of patients with BM by treatment group. Results: 290 patients were included in the study. 154 (53.1%) were treated with chemotherapy (CT), 94 (32.4%) were treated with pembrolizumab (pembro), 39 (13.4%) were treated with ipilimumab + nivolumab (ipi/nivo), and 3 (1.0%) were treated with another IO. A higher proportion of patients treated with ipi/nivo developed BM compared to those treated with pembro alone (4/39, 10.3% vs 2/94, 2.1%; Z score p= 0.038). None of the 154 patients treated with CT developed BM. All BMs were detected due to symptoms. Of the six patients that developed BM, the median age was 72.5 (range 47-80), 83% were male, 67% identified as Caucasian, and there was an even distribution of histology with 33% each of epithelioid, biphasic, and sarcomatoid. All patients received IO most recently or were currently on it when BM developed. Median time to BM from start of immunotherapy was 144.5 days (range 2-913 days). On imaging, all 6 patients had edema surrounding the brain metastases and 4 also showed hemorrhage. Survival after development of BM was poor (Table1). Four patients (67%) underwent surgery for the BM, while all patients received brain radiation. Two patients received whole brain radiation therapy (WBRT), while four patients received stereotactic radiosurgery (SRS) to a median of four brain metastases (range 1-7). Three patients developed subsequent intracranial progression (out-of-field) including one with rapid intracranial progression 20 days post-radiation. Conclusions: In this large retrospective study of patients with PM treated with systemic therapy, BM was most prevalent in those patients receiving ipi/nivo compared to pembro alone and not seen in those receiving chemotherapy. The presence of edema suggests a possible immune infiltrate while on IO (correlative studies in progress). Brain imaging should be considered prior to starting IO in patients with PM. [Table: see text]

Intracranial outcomes with ipilimumab and nivolumab in melanoma brain metastases following progression on anti-PD-1 therapy.

9555 Background: Ipilimumab + nivolumab (ipi/nivo) is effective for melanoma brain metastases (MBM), but the efficacy of ipi/nivo in MBM in patients (pts) whose melanoma has progressed on anti-PD-1 is unknown. Methods: We conducted a retrospective analysis of pts with progressive MBM who received ipi/nivo at Memorial Sloan Kettering Cancer Center following prior anti-PD-1. Cohort A included pts with ≥1 untreated MBM (≥5mm) without local interventions (such as neurosurgery, radiotherapy). Cohort B included pts who had received local interventions for all MBMs before starting ipi/nivo. The primary endpoint was intracranial (IC) progression free survival (PFS). IC response was assessed based on clinical radiological interpretation for Cohort A. Kaplan-Meier methods were used to estimate time-to-event outcomes. Results: Fifty-seven pts were identified: 28 and 29 in Cohort A and B, respectively. All pts had received prior anti-PD-1, 42% prior ipi, a median of 2 (IQR: 1, 3) prior lines, and 21% (12/57) of pts prior treatment was in the adjuvant setting only. 79% (45/57) of pts had cutaneous, 14% (8/57) acral, 5% (3/57) unknown primary and 2% (1/57) mucosal melanoma. Median age was 64 (IQR: 58, 71) and 55 (IQR: 47, 70) years in Cohort A and B, respectively. Cohort A had median lesion size (largest measurable MBM) of 1.0cm (IQR: 0.60, 2.12), and 64% (18/28) of pts had &gt;5 lesions; Cohort B had a median lesion size 1.5cm (IQR: 1.10, 2.00) and 28% (8/29) of pts had &gt;5 lesions. 14% (8/57) of pts received concurrent steroid (equivalent of ≥dexamethasone 4mg daily) upon starting ipi/nivo, and leptomeningeal disease was present in 14% (4/28) and 7% (2/29) of Cohort A and B, respectively. The IC response rate was 11% (3/28, 2 were complete (CR)) in Cohort A.Both patients with CR were asymptomatic with ≤ 2 lesions and no prior CTLA-4 exposure. Most (20/28, 71%) in Cohort A had best response of progressive disease (PD); all that had a best response of stable disease (SD; 5/28, 18%) sustained that response for less than 6 months. Median IC-PFS was 1.7 (95% CI: 1.3,4.4) and 7.6 (95% CI: 3.6, -) months, and median overall survival (OS) was 6.7 (95% CI: 3.6,10) and 24 (95% CI: 11, -) months in Cohort A and B. 24-month OS was 19% (95% CI: 8.1,45) and 51% (95% CI: 35,75) in Cohort A and B. 30% (8/27) and 66% (19/29) of pts had subsequent systemic therapy, and 48% (13/27) and 52% (15/29) subsequent local therapy in Cohorts A and B. Conclusions: Ipi/nivo has limited efficacy in patients with progressive MBM post-PD-1 therapy in the absence of local therapy. These results highlight the unmet clinical need for more effective therapies to address progressive MBM post-PD-1 therapy, an increasingly relevant clinical scenario particularly in light of the growing use of adjuvant and neoadjuvant anti-PD-1.

Breaking barriers: Real-world data on immunotherapy in non-small cell lung cancer with large brain metastases.

e14002 Background: Non-small cell lung cancer (NSCLC) patients with large brain metastases (BrM) defined as &gt; 2 cm historically face grim prognoses. Immunotherapy, emerging as a state-of-the-art treatment in NSCLC treatment, has not been extensively studied in the context of large BrM. The use of immunotherapy in these patients is complicated by factors such as steroids use and local interventions like surgery and/or radiation treatment. Methods: We conducted a retrospective study across three MedStar Georgetown Cancer Network sites to evaluate outcomes in NSCLC patients with large BrM. Inclusion criteria comprised of patients aged 18 years or older with NSCLC diagnosed between 01/01/17 to 12/31/2022 who started immunotherapy after the diagnosis of at least one BrM 2 cm or more in diameter. Intracranial progression free survival (PFS), overall survival (OS), and relevant clinical factors were analyzed. Steroid use was not included due to documentation limitations. Cox penalized regression was used to assess PFS and OS while power analysis was not done due to the sample size. Results: The study included 36 patients all of whom underwent neurosurgery and/or radiation before starting immunotherapy. Median follow up duration was 17.6 months. The population was 58.3% female, median age 64.4 years, 77.8% lung adenocarcinoma, 91.7% received pembrolizumab for immunotherapy, and median duration of immunotherapy was 178 days. Median intracranial PFS was 9.2 months and median OS reached 31 months. The hazard ratio (HR) was 0.07 (95% confidence interval (CI) 0.02-0.26) for intracranial PFS in patients who received at least 90 days of immunotherapy compared to those who received less than 90 days of immunotherapy. Each additional 30 days of immunotherapy was associated with an OS HR 0.77 (95% CI 0.67-0.90). Higher PD-L1 status was not associated with improved outcomes. Conclusions: The study highlights the potential of immunotherapy as a valuable treatment for NSCLC patients with large BrM, a population often excluded from clinical trials. In our retrospective analysis, extended immunotherapy demonstrated positive impacts on both intracranial PFS and OS. Future directions should focus on prospective evaluation of the optimal timing of immunotherapy relative to upfront large BrM treatment, with a specific emphasis on understanding the role of steroids dosing in this context.