Renal Cell Carcinoma Brain Metastases Research Articles

Brain metastases from renal cell carcinoma: Effects of novel systemic agents on brain metastasis outcomes

ObjectiveThe objective of this study was to examine survival outcomes in 136 patients with renal cell carcinoma with metastases to the brain who were treated with radiation combined with immunotherapy or tyrosine kinase inhibitor compared to those who were treated with radiation therapy alone. MethodsThe Wake Forest Gamma Knife prospective database was searched for all patients with renal cell carcinoma brain metastases. Outcome measurements included overall survival, determined via the Kaplan-Meier Method, and cumulative incidence of local and distant failure, determined using the Fine Gray competing risks analysis with death as a competing risk for the 136 patients included. ResultsOverall survival for the entire population at 6 months, 12 months, and 24 months was 67%, 47% and 30%, respectively. For the TKI (non-immunotherapy-treated) population (n = 37), overall survival was 75%, 61%, and 40% at 6 months, 12 months, and 24 months, respectively. For the immunotherapy-treated population (n = 35), overall survival was 85%, 64%, and 50% at 6 months, 12 months, and 24 months, respectively. Overall survival was significantly increased for patients who received radiation with either immunotherapy or TKI (p < 0.0001). ConclusionPrior series of patients with brain metastases of multiple histologies have demonstrated an improvement in the local efficacy of stereotactic radiosurgery when combined with systemic agents. We found that patients treated with targeted agents and patients treated with immunotherapy demonstrated a trend towards improvement over patients treated in the era prior to the advent of either classes of novel therapies.

Association between systemic treatment with immune checkpoint inhibitor therapy in renal cell carcinoma and reduced risk of brain metastasis development.

Immune checkpoint inhibitor (ICI) efficacy in the treatment of metastatic renal cell carcinoma (RCC) without brain metastases (BMs) is well established in several clinical trials; however, patients with BMs were typically excluded from these trials. Therefore, the efficacy of ICI in the treatment or prevention of BM remains unclear. The primary aim of the study was to address the efficacy of ICI in treatment of patients with RCC BMs compared with patients receiving targeted therapies. A secondary aim was to evaluate the risk of RCC BM development among patients who received ICI versus targeted therapies early in their treatment course. A retrospective single-center review between 2011 and 2018 identified 425 patients treated for metastatic RCC. The study group included patients who received ICI and/or targeted therapies during their disease. Data analyzed included demographic information, systemic treatments, overall survival from RCC diagnosis (OSRCC) and from BM diagnosis (OSBM), and BM development. Fisher's exact test was used to evaluate the frequency of BM occurrence. Survival was assessed using Kaplan-Meier curves and log-rank tests. Of the 425 patients, 125 received ICI and 300 were treated with molecular targeted agents only during their clinical course. BMs occurred in 113 (9.5%) of the 425 patients. Among patients with BMs, OSRCC was improved with the use of ICI (77.2 vs 25.2 months, p < 0.001), with 1-, 2-, and 5-year survival rates of 93.9%, 81.8%, and 62.6%, respectively. The use of ICI was associated with increased OSBM (21.7 vs 8.9 months, p = 0.001). The rate of BM development was lower when patients were treated with ICI (8/100 [8.0%]) compared with targeted therapy (47/267 [17.6%]) (OR 0.41, 95% CI 0.18-0.89; p = 0.021). ICI was associated with improved OSRCC and OSBM in patients with BMs and decreased the probability of BM development in patients with metastatic RCC. Prospective trials are needed to further evaluate optimal use of ICI in treatment of RCC BMs.

Abstract 5788: Single-cell and spatial transcriptomic mapping of human renal cell carcinoma brain metastases uncovers actionable immune-resistance targets

Abstract Introduction: The discovery of immune checkpoint inhibitors has revolutionized metastatic renal cell carcinoma (RCC) treatment. However, in patients with RCC brain metastases, response rates are low and survival outcomes poor. To understand the tumor microenvironmental differences between primary kidney tumors, extracranial metastases, and brain metastases, we developed a detailed single-cell atlas of RCC brain metastases along with their matched extracranial and primary tumors. Methods: We performed single-nucleus RNA-seq on 27 samples (nearly 200,000 cells) from RCC patients; samples included 14 brain metastases, 8 matched primary kidney tumors, and 5 matched extracranial metastases. We performed multiplex IHC to validate selected transcriptomic findings. We used Nanostring CosMx 960-plex RNA spatial molecular imaging technique on selected samples to validate cellular interactions in a spatial context. Results: We established a multi-tissue single-cell atlas of RCC brain metastases by identifying 9 major and 37 minor malignant, immune, and stromal cell clusters. Brain metastases had higher neuronal and glial cells interacting with immune and tumor cells. Brain metastasis tumor cells were also transcriptomically reprogrammed to adapt to the brain microenvironment through enrichment of MYC targets, MTORC1 signaling, epithelial-mesenchymal transition, fatty-acid metabolism, oxidative phosphorylation, and reactive oxygen species pathways. Moreover, cell-to-cell communication and downstream target gene expression analyses showed that brain metastasis tumor cells expressed ligands and receptors that induce tumor cell proliferation in both autocrine and paracrine fashions. Among T-cell populations, we found fewer proliferating cytotoxic T lymphocytes in the brain than in other sites. Moreover, T cells in brain metastases expressed higher levels of several targetable inhibitory checkpoints than did extracranial metastases. In addition, we found that naïve/memory T cells in brain metastases were a favorable prognostic marker for overall survival after craniotomy. Our characterization of myeloid cell populations across the 3 disease sites found fewer dendritic cells and monocytes in the brain compared to other sites. Macrophages in brain metastases more highly expressed an M2 immunosuppressive gene signature than did those in primary RCC tumors. Conclusion: Our findings from the largest single-cell atlas of RCC brain metastases with matched primary and extracranial metastases suggest several unique targetable, immunosuppressive biological mechanisms in the brain microenvironment. These results provide a foundation for a deeper understanding of RCC brain metastasis biology and can serve as a resource for the scientific community to further explore therapeutically targetable tumor and immune-related mechanisms. Citation Format: Elshad Hasanov, Truong Nguyen Anh Lam, Jerome Lin, Patrick K. Reville, Merve Hasanov, Anna K. Casasent, David Shih, Sahin Hanalioglu, Mehmet Asim Bilen, Omar Alhalabi, Berrin Babaoglu, Baylar Baylarov, Adeboye O. Osunkoya, Lisa M. Norberg, Joy Gumin, Tuan M. Tran, Jianzhuo Li, Anh G. Hoang, Haidee D. Chancoco, Brittany C. Parker Kerrigan, Erika J. Thompson, Betty YS Kim, Dima Suki, Melike Mut, Figen Soylemezoglu, Giannicola Genovese, Kadir C. Akdemir, Hussain A. Tawbi, Nizar M. Tannir, Florencia McAllister, Michael A. Davies, Padmanee Sharma, Jason Huse, Frederick Lang, Nicholas Navin, Eric Jonasch. Single-cell and spatial transcriptomic mapping of human renal cell carcinoma brain metastases uncovers actionable immune-resistance targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5788.

Mapping distribution of brain metastases in renal cell carcinoma (RCC) and association with clinical features.

727 Background: Brain metastases (BM) are frequently observed in metastatic RCC (mRCC) with a tendency to present with hemorrhagic BM. Distribution patterns of BM in RCC and associations with clinical outcomes are not well understood. Here we present a detailed distribution analysis in a surgically resected BM RCC cohort with a focus on clinically relevant associations. Methods: A retrospective analysis was performed on patients (pts) with mRCC who underwent craniotomy for BM at our institution. We reviewed gadolinium-enhanced MRI brain and CT head (if available) at the time of BM diagnosis. We assessed the presence of hemosiderin on MRI or hemorrhage on CT in the BM lesion and marked each at their corresponding anatomic location. Public brain atlases were used for distribution analysis. Overall survival (OS) from the date of BM diagnosis and CNS progression free survival (CNS-PFS) from the date of craniotomy were calculated. Results: A total of 67 BM were analyzed from 46 pts. 23 with synchronous BM, 9 with two and 6 with 3 concurrent BM. Most patients were male (n=35, 76%) with a median age at diagnosis of 63 years. Primary histology was clear cell in 42 pts (91%) and 10 pts (22%) had renal vein thrombosis (RVT) at primary diagnosis. IMDC scores at time of BM diagnosis were favorable in 20%, intermediate in 60% and poor in 20%. Hemosiderin (MRI) or hemorrhage (CT) was seen in 82% and 80% of BM, respectively. 55% of lesions were left sided, 45% frontal, 21% parietal, 18% occipital, 7% temporal and 6% cerebellar. Posterior circulation and posterior cerebral artery territories contained 42% and 34% of BM despite supplying only 30% and 16% of the brain volume, respectively. Patients with solitary BM had higher Karnofsky performance status (p=0.006) and lower disease burden (p=0.004) than those with multiple BM. Shorter CNS-PFS was seen in association with hemosiderin on MRI (log-rank p=0.04) and RVT in primary specimen (log-rank p=0.002). IMDC risk scores (log-rank p&lt;0.001) predicted OS. On multivariable OS analysis, BM lateralized to the right (HR 2.6, p=0.06), hemosiderin in BM (HR 6.5, p=0.02) and IMDC risk groups (intermediate HR 2.9, poor risk HR 25.6, p&lt;0.04) were independent prognostic factors for shorter OS. Conclusions: The above-presented lesion mapping method shows clinically relevant findings in RCC BM. Tumoral hemosiderin deposits appear a potential parameter to predict outcomes in RCC BM which deserve further study and validation.

A phase II study of nivolumab with ipilimumab and cabozantinib in patients with untreated renal cell carcinoma brain metastases.

TPS745 Background: A SEER analysis from 2010 to 2013 demonstrated that the incidence of brain metastases(mets) at the diagnosis of renal cell carcinoma(RCC) is 1.51%, and around 12% of patients(pts) with advanced RCC (aRCC) also had mets to the brain. Brain mets confer a poor prognosis. Local management strategies for brain mets from RCC include surgical resection, stereotactic radiosurgery and whole brain radiation therapy. Although systemic therapies including tyrosine kinase inhibitors and immune checkpoint inhibitors have been explored in aRCC pts with brain mets, prospective data is lacking. Cabozantinib is a potent small molecule inhibitor of multiple tyrosine kinases that was approved by FDA for pts with aRCC alone or in combination with nivolumab. Cabozantinib has demonstrated activity in patients with intracranial tumors. A phase III trial (COSMIC-313) recently evaluated cabozantinib in combination with nivolumab and ipilimumab compared to nivolumab plus ipilimumab and demonstrated significantly improved progression-free survival (PFS) in previously untreated pts with aRCC. The combination was found to be safe as frontline systemic treatment. The role of this combination in patients with aRCC with brain mets remains undefined. As such, we propose a study to assess the safety and efficacy of cabozantinib in combination with nivolumab/ipilimumab in RCC pts with untreated brain mets. We believe the results from this trial could provide additional treatment options for pts with RCC brain mets who are typically excluded from clinical trials. Methods: This is a phase II study to assess the safety and efficacy of the combination of nivolumab with ipilimumab and cabozantinib in pts with untreated brain mets from RCC until disease progression or intolerable toxicities or patient withdrawal. Planned accrual is 40 pts. Pts will be treated with nivolumab (3mg/kg) and ipilimumab (1mg/kg) IV every 3 weeks for 4 doses and cabozantinib 40mg daily. Then pts will be treated with nivolumab 480mg IV Q 4 weeks and cabozantinib 40mg daily until progression or intolerable toxicities or patient’s withdrawal. A lead-in group of 6 pts will be closely monitored for dose limiting toxicities(DLT). If stopping criteria (&gt;3 patients develop DLTs) is met, then treatment will be switched to nivolumab plus cabozantinib omitting ipilimumab. The primary objective is intracranial progression free survival(PFS). Secondary objectives include intracranial safety, objective response rate (intracranial + extracranial) by modified RECIST v1.1 and RECIST v1.1, extracranial PFS and overall survival. This phase II trial is currently enrolling pts. Clinical trial information: NCT05048212 .

Concurrent Administration of Immune Checkpoint Inhibitors and Single Fraction Stereotactic Radiosurgery in Patients With Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma Brain Metastases

Stereotactic radiosurgery (SRS) and immune checkpoint inhibitors (ICI) are highly effective treatments for brain metastases, particularly when these therapies are administered concurrently. However, there are limited data reporting the risk of radiation necrosis (RN) in this setting. Patients with brain metastases from primary non-small cell lung cancer, renal cell carcinoma, or melanoma treated with SRS and ICI were considered. Time-to-event analyses were conducted for any grade RN and symptomatic RN (SRN) with death incorporated as a competing risk. As a secondary analysis, recursive partitioning analysis (RPA) was used for model development, and a loop of potential models was analyzed, with the highest-fidelity model selected. Brain V12 Gy thresholds identified on RPA were then incorporated into the competing risks analysis. Concurrent SRS and ICI administration. Six hundred fifty-seven patients with 4182 brain metastases across 11 international institutions were analyzed. The median follow-up for all patients was 13.4 months. The median follow-up was 12.8 months and 14.1 months for the concurrent and nonconcurrent groups, respectively (P=.03). The median patient age was 66 years, and the median Karnofsky Performance Status was 90. In patients with any grade RN, 1- and 2-year rates were 6.4% and 9.9%, respectively. In patients with SRN, 1- and 2-year rates were 4.8% and 7.2%, respectively. On RPA, the highest-fidelity models consistently identified V12 Gy as the dominant variable predictive of RN. Three risk groups were identified by V12 Gy: (1) < 12 cm3; (2) 20 cm3 ≥ V12 Gy ≥ 12 cm3; (3) V12 Gy > 20 cm3. In patients with any grade RN, 1-year rates were 3.7% (V12 Gy < 12 cm3), 10.3% (20 cm3 ≥ V12 Gy ≥ 12 cm3), and 12.6% (V12 Gy > 20 cm3); the 2-year rates were 7.5% (V12 Gy < 12 cm3), 13.8% (20 cm3 ≥ V12 Gy ≥ 12 cm3), and 15.4% (V12 Gy > 20 cm3) (P < 0.001). In patients with any SRN, 1-year rates were 2.4% (V12 Gy < 12 cm3), 8.9% (20 cm3 ≥ V12 Gy ≥ 12 cm3), and 10.3% (V12 Gy > 20 cm3); the 2-year rates were 4.4% (V12 Gy < 12 cm3), 12.4% (20 cm3 ≥ V12 Gy ≥ 12 cm3), and 13.1% (V12 Gy > 20 cm3; P< 0.001). There were no statistically significant differences in rates of any grade RN or SRN when accounting for therapy timing for all patients and by V12 risk group identified on RPA. The use of SRS and ICI results in a low risk of any grade RN and SRN. This risk is not increased with concurrent administration. Therefore, ICI can safely be administered within 4-weeks of SRS. Three risk groups based on V12 Gy were identified, which clinicians may consider to further reduce rates of RN.

The Role of Stereotactic Radiotherapy for the Treatment of Melanoma and Renal Cell Carcinoma Brain Metastases

The Role of Stereotactic Radiotherapy for the Treatment of Melanoma and Renal Cell Carcinoma Brain Metastases

Phase II multicenter trial combining nivolumab and radiosurgery for NSCLC and RCC brain metastases.

Anti-PD-1 has activity in brain metastases (BM). This phase II open labeled non-randomized single arm trial examined the safety and efficacy of combining nivolumab with radiosurgery (SRS) in the treatment of patients with BM from non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC). This was a multicenter trial (NCT02978404) in which patients diagnosed with NSCLC or RCC, having ≤ 10 cc of un-irradiated BM and no prior immunotherapy were eligible. Nivolumab (240 mg or 480 mg IV) was administered for up to 2 years until progression. SRS (15-21 Gy) to all un-irradiated BM was delivered within 14 days after the first dose of nivolumab. The primary endpoint was intracranial progression free survival (iPFS). Twenty-six patients (22 NSCLC and 4 RCC) were enrolled between August 2017 and January 2020. A median of 3 (1-9) BM were treated with SRS. Median follow-up was 16.0 months (0.43-25.9 months). Two patients developed nivolumab and SRS related grade 3 fatigue. One-year iPFS and OS were 45.2% (95% CI 29.3-69.6%) and 61.3% (95% CI 45.1-83.3%), respectively. Overall response (partial or complete) of SRS treated BM was attained in 14 out of the 20 patients with ≥1 evaluable follow-up MRI. Mean FACT-Br total scores were 90.2 at baseline and improved to 146.2 within 2-4 months (P = .0007). The adverse event profile and FACT-Br assessments suggested that SRS during nivolumab was well tolerated. Upfront SRS with the initiation of anti-PD-1 prolonged the 1-year iPFS and achieved high intracranial control. This combined approach merits validation randomized studies.

Artificial Intelligence-Driven Measurement of Brain Metastases' SRS Response – A Comparison with Current Standards for Assessment

<h3>Purpose/Objective(s)</h3> Modern therapeutics for patients with metastatic solid tumors have resulted in improved systemic disease control and overall survival, but these drugs are not generally CNS-active. Thus, the control of brain metastasis (BM) with local therapies such as stereotactic radiosurgery (SRS) has become increasingly important. The current gold standard for evaluating BM response is manual measurement of the maximum axial diameter, a process that becomes more complex as the number of BMs increases. Artificial intelligence (AI) can be used to automate this laborious process and open big data analytics. In this study, BM measurements obtained by AI were compared to the manual human-collected data. <h3>Materials/Methods</h3> From an institutional database, patients with renal-cell carcinoma (RCC) BM who received SRS were retrospectively identified. A tool developed in-house for automated detection and segmentation of intracranial metastases on longitudinal images, the BMTracker, was applied to the dataset. The BMTracker utilizes a 3D convolutional neural network to segment gross tumor volumes (GTVs) on pre- and post-treatment follow-up T1 MR images and automated rigid registration to identify and track each lesion on longitudinal scans. The software then calculates the BM volume and Feret diameter over all available scans following SRS. The Feret diameter is defined as the diameter of the sphere with the minimum volume needed to encompass the lesion in three-dimensions. For evaluation, the correlation between the manual and automated lesion measurements was obtained and the two measurements were compared at each time point. <h3>Results</h3> From 65 patients with RCC BMs, 164 lesions were identified and measured with the BMTracker and manual methods. The pre-SRS treatment MR was median 14.0 days [-18.0, -9.8] before SRS treatment. The AI-derived Feret diameter on the pre-treatment scan was median 11.7 mm [8.0, 19.2], while manual axial diameter measurement was 7.5 mm [4.9, 13.2]. There were n = 100 BMs with at least one follow-up MR (median = 55 days after SRS [40, 84]) and n = 71 with at least two follow-up MRs (median = 145 days after SRS [96, 200]). At first and second follow-up after SRS treatment, AI-derived Feret diameter was median 9.6 mm [4.6, 18.5] and 10.2 mm [0, 19.8], respectively, while manual axial diameter was median 6.3 mm [0.9, 12] and 6.0 mm [0, 14.9], respectively. Based on a one-to-one correlation analysis between the lesion Feret diameter determined by the BMTracker, and the manually measured lesion axial diameter, the correlation coefficient was R² = 0.789 (<i>p</i> = 0.0001). <h3>Conclusion</h3> Using AI to automatically track and measure BM volumes following SRS treatment, this study found a strong correlation between lesion diameter based on AI-driven measurements and the current gold standard. AI allows efficient and accurate segmentation and tracking of BMs. Future studies will compare the BMTracker data to clinical response data.

Effectiveness of immune checkpoint inhibitors in combination with stereotactic radiosurgery for patients with brain metastases from renal cell carcinoma: inverse probability of treatment weighting using propensity scores.

Stereotactic radiosurgery (SRS) is the mainstay for treating brain metastases (BMs) from renal cell carcinoma (RCC). In recent years, immune checkpoint inhibitors (ICIs) have been applied to metastatic RCC and have contributed to improved outcomes. The authors investigated whether SRS with concurrent ICIs for RCC BM prolongs overall survival (OS) and improves intracranial disease control and whether there are any safety concerns. Patients who underwent SRS for RCC BMs at the authors' institution between January 2010 and January 2021 were included. Concurrent use of ICIs was defined as no more than 3 months between SRS and ICI administration. The time-to-event analysis of OS and intracranial progression-free survival (IC-PFS) between the groups with and without ICIs (ICI+SRS and SRS, respectively) was performed using inverse probability of treatment weighting (IPTW) based on propensity scores (PSs) to control for selection bias. Four baseline covariates (Karnofsky Performance Scale score, extracranial metastases, hemoglobin, and number of BMs) were selected to calculate PSs. In total, 57 patients with 147 RCC BMs were eligible. The median OS for all patients was 9.1 months (95% CI 6.0-18.9 months), and the median IC-PFS was 4.4 months (95% CI 3.1-6.8 months). Twelve patients (21%) received concurrent ICIs. The IPTW-adjusted 1-year OS rates in the ICI+SRS and SRS groups were 66% and 38%, respectively (HR 0.30, 95% C 0.13-0.69; p = 0.005), and the IPTW-adjusted 1-year IC-PFS rates were 52% and 16%, respectively (HR 0.30, 95% CI 0.14-0.62; p = 0.001). Severe tumor hemorrhage (Common Terminology Criteria for Adverse Events [CTCAE] grade 4 or 5) occurred immediately after SRS in 2 patients in the SRS group. CTCAE grade 2 or 3 toxicity was observed in 2 patients in the ICI+SRS group and 5 patients in the SRS group. Although the patient number was small and the analysis preliminary, the present study found that SRS with concurrent ICIs for RCC BM patients prolonged survival and provided durable intracranial disease control, with no apparent increase in treatment-related adverse events.

Molecular profile and clinical outcomes of renal cell carcinoma brain metastases treated with stereotactic radiosurgery.

4526 Background: Molecular profiles of renal cell carcinoma (RCC) tumors are associated with systemic treatment (ST) responses and clinical outcomes. However, the molecular profiles of RCC brain metastases (BM) and their correlation with ST response and clinical outcomes are not well characterized. Effective management of BM with locoregional therapies including stereotactic radiosurgery (SRS) is critical as ST advances have improved overall survival (OS). Therefore, we sought to identify the clinical and genomic features of RCC BM in a large cohort of patients treated with SRS. Methods: We performed an institutional retrospective analysis of RCC BM patients treated with SRS and evaluated corresponding genomic next generation sequencing (NGS) data via a targeted sequencing panel (MSK-IMPACT). A comparison cohort of all institutional patients with available NGS data was utilized to investigate genes enriched in our BM cohort using Fisher exact testing. Kaplan Meier analyses were performed for OS and intracranial progression-free survival (iPFS). Clinical factors and genes mutated in ≥ 10% of samples were assessed per patient using Cox proportional hazards models, and per individual BMs using clustered competing risks regression with a competing risk of death. Results: From 2010-2021, 91 RCC BM patients underwent SRS for 212 BMs, including 86% clear cell and 14% non-clear cell RCC. NGS data was available for 76 patients (84%), including 18 resected BMs, 26 extra-cranial metastatic lesions (EM), and 32 primary kidney tumors (Table 1). Median follow-up was 3.2 years with median OS of 21 months (m) and median iPFS of 7.8m. Karnofsky performance status ≥80 and extracranial disease control were significantly associated with improved OS on multivariable analyses (MVA; p=0.049 and 0.01, respectively). No clinical variables were significantly associated with iPFS on MVA. At the BM level, SETD2 alterations approached significance for improved iPFS (HR=0.35; 95%CI 0.11, 1.05; p=0.06). Enrichment in SMARCA4 alterations was seen in the BM cohort as compared to primary kidney and EM samples from patients without BM (17% vs 1% vs 2%, p&lt;0.05). Conclusions: To our knowledge, this is the largest study investigating mutational profiles of RCC BM. SMARCA4 alterations were enriched in BM samples and a trend towards improved iPFS was seen in SETD2 variant BMs, warranting further investigation.[Table: see text]

Improving Brain Metastases Outcomes Through Therapeutic Synergy Between Stereotactic Radiosurgery and Targeted Cancer Therapies.

Brain metastases are the most common form of brain cancer. Increasing knowledge of primary tumor biology, actionable molecular targets and continued improvements in systemic and radiotherapy regimens have helped improve survival but necessitate multidisciplinary collaboration between neurosurgical, medical and radiation oncologists. In this review, we will discuss the advances of targeted therapies to date and discuss findings of studies investigating the synergy between these therapies and stereotactic radiosurgery for non-small cell lung cancer, breast cancer, melanoma, and renal cell carcinoma brain metastases.

Radiation necrosis in renal cell carcinoma brain metastases treated with checkpoint inhibitors and radiosurgery: An international multicenter study

Patients with renal cell carcinoma (RCC) brain metastases are frequently treated with immune checkpoint inhibitors (ICIs) and stereotactic radiosurgery (SRS). However, data reporting on the risk of developing radiation necrosis (RN) are limited. RN rates were compared for concurrent therapy (ICI/SRS administration within 4 weeks of one another) and nonconcurrent therapy with the χ2 test. Univariable logistic regression was used to identify factors associated with developing RN. Fifty patients (23 concurrent and 27 nonconcurrent) with 395 brain metastases were analyzed. The median follow-up was 12.1 months; the median age was 65 years. The median margin dose was 20 Gy, and 4% underwent prior whole-brain radiation therapy (WBRT). The median treated tumor volume was 3.32 cm3 (range, 0.06-42.38 cm3 ); the median volume of normal brain tissue receiving a dose of 12 Gy or higher (V12 Gy) was 8.42 cm3 (range, 0.27-111.22 cm3 ). Any-grade RN occurred in 17.4% and 22.2% in the concurrent and nonconcurrent groups, respectively (P = .67). Symptomatic RN occurred in 4.3% and 14.8% in the concurrent and nonconcurrent groups, respectively (P = .23). Increased tumor volume during SRS (odds ratio [OR], 1.08; 95% confidence interval [CI], 1.01-1.19; P = .04) was associated with developing RN, although V12 Gy (OR, 1.03; 95% CI, 0.99-1.06; P = .06), concurrent therapy (OR, 0.74; 95% CI, 0.17-2.30; P = .76), prior WBRT, and ICI agents were not statistically significant. Symptomatic RN occurs in a minority of patients with RCC brain metastases treated with ICI/SRS. The majority of events were grade 1 to 3 and were managed medically. Concurrent ICI/SRS does not appear to increase this risk. Attempts to improve dose conformality (reduce V12) may be the most successful mitigation strategy in single-fraction SRS.

Survival benefit with resection of brain metastases from renal cell carcinoma in the setting of molecular targeted therapy and/or immune therapy

Patient survival with renal cell carcinoma (RCC) has improved with the use of molecular targeted agents and immunotherapy. Given the potential activity of these agents in treating brain metastases, the role of aggressive local management with surgery and/or radiation may diminish. The aim of this study was to evaluate the role of aggressive local therapy for RCC brain metastasis in the setting of molecular targeted agents and/or checkpoint inhibitor therapy. A retrospective single-center review between 2011-2018 identified patients that developed brain metastasis from RCC. Data analyzed included demographic information, systemic treatments, intracranial interventions, progression free survival and overall survival (OS). Of 1194 patients, 108(9.0%) were diagnosed with brain metastasis from RCC. OS from diagnosis of brain metastasis (OSBM) was 12.3 months. OSBM was analyzed based on three treatment groups: systemic therapy (ST) only (2.0 months, n = 23), systemic and radiotherapy (RT + ST) (12.3 months, n = 52), and systemic and radiotherapy plus resection (Surg + RT + ST) (21.7 months, n = 33). Survival benefit was seen with Surg + RT + ST compared to ST (P = 0.001), but not RT + ST (P = 0.081). Progression free survival was significantly prolonged with Surg + RT + ST compared to RT + ST (10.9 vs 5.9 months, respectively, P = 0.04). Variables such as performance status and number of brain metastases at the time of brain metastasis diagnosis did not differ significantly. In the setting of molecular targeted agents and immunotherapy, resection may benefit the appropriate surgical candidate. Prospective clinical trials are necessary to better understand the role of aggressive RCC brain metastasis treatment.Micro Abstract• Renal cell brain metastasis is often excluded from studies and brain metastases effect a large portion of RCC patients.• Retrospective study of 1194 RCC patients, 108 patients had brain metastasis, determination of the role of surgical resection in the setting of recent advances in checkpoint inhibitors.• A benefit was seen in overall survival in patients that had surgical while undergoing radiation therapy and systemic therapies.• In the setting of molecular targeted agents and immunotherapy, resection may benefit the appropriate surgical candidate(s).

Outcomes of Immunotherapy (ICI) Alone vs. Stereotactic Radiosurgery (SRS) Alone vs. ICI and SRS Combined in Renal Cell Carcinoma Brain Metastasis

Renal cell carcinoma is the fourth most common cause of metastatic brain tumors. Both Immune Checkpoint Inhibitors (ICIs) and Stereotactic Radiosurgery (SRS) have been used as first line treatment for renal cell carcinoma brain metastasis (RCCBM). The efficacy of ICIs alone, SRS alone, or SRS and ICIs combined as treatment is being evaluated. We hypothesize that a combination of SRS and ICIs will lead to an improvement in Overall Survival (OS), when compared to either alone, for patients with RCCBM.Patients with RCCBM treated at our tertiary care center (2010-2020) with either ICIs, SRS, or both were evaluated. Overall Survival (OS) was measured from initiation of immunotherapy or SRS of RCCBM to date of death or last follow up. The Cox proportional hazard model was used to determine differences in OS.210 patients with RCCBM were included. Of these, 26 were treated with ICIs alone, 80 were treated with SRS alone, and 104 were treated with a combination. For treatment with ICIs alone, the median age at diagnosis was 61 years (Interquartile range (IQR) 45-82), 63% of the patients were male, and 96% were white. For treatment with SRS alone the median age at diagnosis was 63 years (IQR 37-84), 70% of the patients were male, and 94% were white. For ICIs/SRS combination treatment, the median age at diagnosis was 63 years (IQR 38-79), 72% of the patients were male, and 97% were white. Overall Survival for patients treated with ICIs alone, SRS alone, and ICIs/SRS combined had a median of 25.4, 29.4, and 81.2 months and a 2 year rate of 56%, 53%, and 89%, respectively. With ICI treatment alone as a reference, SRS treatment alone had an OS hazard ratio, HR = 1.13 (95% CI = 0.69 - 1.84, P = 0.62), and ICI/SRS combination treatment had an OS hazard ratio, HR = 0.41 (95% CI = 0.24 - 0.69, P = < 0.001).In patients with RCCBM, combination treatment with both ICIs and SRS was associated with an increase in Overall Survival when compared to treatment with ICIs alone or SRS alone. Further studies need to be done to control for other patient variables such as KPS/ECOG, number of lesions, and extra-cranial metastasis.

Outcomes of Stereotactic Radiosurgery and Immunotherapy in Renal Cell Carcinoma Patients With Brain Metastases.

The impact of immunotherapy and stereotactic radiosurgery (SRS) in treatment of brain metastases (BM) from renal cell carcinoma (RCC) has not been well investigated. Forty-eight patients with 372 RCC BM were treated with SRS and divided into those ever treated with immunotherapy versus those who never received immunotherapy. Survival and local control (LC) outcomes were studied. χ2 and Mann-Whitney U tests compared categorical and continuous variables, respectively. Kaplan-Meier curves were used to estimate survival and log-rank test was used to compare survival between groups. Immunotherapy and nonimmunotherapy groups contained 29 and 19 patients, respectively. Median follow-up was 23.1 months (range, 6 to 93.8 mo). Demographic and treatment variables were similar except median prescribed margin dose was significantly lower in immunotherapy group (20 vs. 22 Gy, P<0.0001). Median overall survival (OS) was 27.2 months (immunotherapy) and 14.9 months (nonimmunotherapy), P=0.14. Furthermore, patients treated with immune checkpoint inhibitor (ICI) had even better median OS compared with those who never received ICI (33 vs. 16.7 mo, P=0.03). Factors associated with improved LC were use of ICI (P=0.002) and lesion size <1000 mm3 (P=0.046). There was no difference in incidence of radiation necrosis between the 2 groups (P=0.67). Patients with RCC BM undergoing SRS can experience prolonged survival when treated with ICI. Equally effective LC of BM was achieved when treated with immunotherapy using a 2 Gy decrease in SRS dose without increasing the risk of central nervous system toxicity.

Challenges and advances for the treatment of renal cancer patients with brain metastases: From immunological background to upcoming clinical evidence on immune-checkpoint inhibitors.

The introduction of checkpoint inhibitors (ICIs) in renal cell carcinoma (RCC) treatment landscape, resulted in improvements in overall survival (OS) in metastatic patients. Brain metastases (BMs) are a specific metastatic site of interest representing a predictive factor of poor prognosis. Patients with BMs were usually excluded from prospective clinical trials in the past. Despite recent evidence suggest the efficacy and safety of ICIs, the BMs treatment remains a challenge; the immunotherapy responsiveness seems to be multifactorial and dependent on several factors, such as the genetic intratumor heterogeneity and the immunosuppressive role of the brain tumor microenvironment. This review, starting from the immunological background in RCC BMs, provide an overview of the upcoming evidence from clinical trials, address the issues related to the neuroradiological immunotherapy response evaluation and, with a look to the future, describes how the epigenetic modulation of immune evasion could represent a background for new therapeutic strategies.

Abstract 1007: Patient-derived metastatic renal carcinoma cells are highly sensitive to in vitro Tumor Treating Fields (TTFields)

Abstract Background: Until the advent of checkpoint inhibitor (CI) therapies, renal cell carcinoma (RCC) was clinically challenging to treat given its radio- and chemotherapy resistance. Despite the advances with CIs, patients with brain metastases derived from RCC still face challenges with treatment due to limited brain penetration of CI compounds. Anti-mitotic TTFields therapy is FDA-approved for the treatment of glioblastoma and mesothelioma, and clinical trials are underway for the application of TTFields therapy to primary lung cancer as well as lung cancer brain metastases. In this study, in vitro TTFields were applied to patient-derived brain metastasis RCC cells to determine the potential efficacy of this emerging treatment modality. Methods: This study was approved by the Institutional Review Board. A single-cell suspension was generated from tumor tissues obtained from a patient with newly-diagnosed RCC brain metastasis (male, age 52, mutant p53). Cells were cultured in DMEM/F12 media with 10% fetal bovine serum and gentamicin. Prior to TTFields initiation, cells were plated on plastic coverslips (1×104cells/coverslip; n=8/group) and incubated overnight. Then, TTFields were applied at 200 kHz with a field intensity of ~1.6 V/cm for 14 days, with one group of coverslips maintained as untreated controls. At the conclusion of the experiment, cells were harvested, stained with acridine orange/propidium iodide and counted with a Cellometer K2 (Nexcelom Bioscience, Lawrence, MA) that provides viable cell counts and average cell diameter. Groups were compared with a two-tailed t-test (GraphPad Prism v9, GraphPad Software, San Diego, CA) with significance set at P&amp;lt;0.05. Results: Viable cell count per coverslip for the control group was 149,863 ± 85644 (mean ± SD; n=8) and for the TTFields (200 kHz) group was 1,426 ± 1345 (n=6, 2 coverslips had no cell recovery). Average cell diameter was 9.713 ± 0.6312 for the control group and 16.92 ± 2.903 for the TTFields group. TTFields application significantly reduced cell count (P=0.0012) and increased the average cell diameter (P&amp;lt;0.0001) compared to the controls. Conclusions: TTFields application (200 kHz) demonstrated efficacy by markedly reducing cell proliferation (i.e., decreased cell counts) in RCC. The increase in average cell diameter observed with TTFields is consistent with previously reported findings of other research groups also showing increases in cell volume with TTFields in multiple cancer types (brain, lung, pancreas, breast, ovarian, and cervical). This study is the first to demonstrate the efficacy of in vitro TTFields treatment in patient-derived RCC and suggests that patients with renal carcinoma brain metastases may benefit from TTFields therapy. Citation Format: Sharon K. Michelhaugh, Blake C. Walker, Susan Coombe, Sandeep Mittal. Patient-derived metastatic renal carcinoma cells are highly sensitive to in vitro Tumor Treating Fields (TTFields) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1007.

Outcomes of immunotherapy (ICI) alone vs tyrosine kinase inhibitors (TKI) alone versus ICI and TKI combined in renal cell carcinoma brain metastasis.

2030 Background: Renal cancer is the fourth most common cause of metastatic tumors to the brain. Tyrosine kinase inhibitors (TKIs) targeting VEGFR and other receptors, such as sunitinib, pazopanib, etc., have been used as first line for renal cell carcinoma brain metastasis (RCCBM). Immune Checkpoint Inhibitors (ICIs) targeting PD-L1 and CTLA-4 interactions, such as nivolumab and ipilimumab respectively, have also been used as first line treatment for RCCBM. However, the efficacy of TKIs alone, ICIs alone, or TKIs and ICIs combined as first line treatment has emerged as a topic of interest. Methods: Patients with RCCBM treated with either TKIs, ICIs, or both at our tertiary care center from 2010-2019 were evaluated. Overall Survival (OS) was measured from initiation of either TKI or ICI therapy to date of death or last follow up. The Cox proportional hazard model was used to determine differences in OS. Results: 218 patients with RCCBM were included. Of these, 32 were treated with ICIs alone, 112 were treated with TKIs alone, and 76 were treated with a combination of ICIs and TKIs. For ICI treatment alone the median age at diagnosis was 61 years (Interquartile range (IQR) 38-82), 72% of the patients were male, and 97% were white. For TKI treatment alone the median age at diagnosis was 58 years (IQR 37-82), 70% of the patients were male, and 92% were white. For the combination cohort the median age at diagnosis was 63 years (IQR 45-79), 69% of the patients were male, and 97% were white. OS for patients receiving ICI, TKI, and combination treatment had a median of 69.1, 42.7, and 126.0 months and a 2-year rate of 77%, 69%, and 93%, respectively. With ICI treatment as a reference, TKI treated patients had an OS hazard ratio of 1.32 (95% CI = 0.78 - 2.21, p = 0.30) and ICI/TKI combination had an OS hazard ratio of 0.52 (95% CI = 0.30 - 0.92, p = 0.024). Conclusions: A combination treatment of ICIs and TKIs was associated with an increase in OS when compared to treatment with either TKIs or ICIs alone in patients with RCCBM. These results should be interpreted cautiously due to treatment selection bias. Further studies need to be done to control for other patient variables such as performance status, number of intracranial lesions, and extra-cranial metastasis.[Table: see text]

Metastatic renal cell carcinoma to the brain: optimizing patient selection for gamma knife radiosurgery.

The effects of single-fraction gamma knife radiosurgery (sf-GKRS) on patients with renal cell carcinoma (RCC) brain metastases (BM) in the era of targeted agents (TA) and immune checkpoint inhibitors (ICI) are insufficiently studied. Clear cell metastatic RCC patients treated with sf-GKRS due to BM in 2005-2014 at three European centres were retrospectively analysed (n = 43). Median follow-up was 56 months. Ninety-five percent had prior nephrectomy, 53% synchronous metastasis and 86% extracranial disease at first sf-GKRS. Karnofsky performance status (KPS) ranged from 60 to 100%. Outcome measures were overall survival (OS), local control (LC) and adverse radiation effects (ARE). One hundred and ninety-four targets were irradiated. The median number of targets at first sf-GKRS was two. The median prescription dose was 22.0 Gy. Thirty-seven percent had repeated sf-GKRS. Eighty-eight percent received TA. LC rates at 12 and 18 months were 97% and 90%. Median OS from the first sf-GKRS was 15.7 months. Low serum albumin (HR for death 5.3), corticosteroid use pre-sf-GKRS (HR for death 5.8) and KPS < 80 (HR for death 9.1) were independently associated with worse OS. No further prognostic information was gleaned from MSKCC risk group, synchronous metastasis, age, number of BM or extracranial metastases. Other prognostic scores for BM radiosurgery, including DS-GPA, renal-GPA, LLV-SIR and CITV-SIR, again, did not add further prognostic value. ARE were seldom symptomatic and were associated with tumour volume, 10-Gy volume and pre-treatment perifocal oedema. ARE were less common among patients treated with TA within 1 month of sf-GKRS. We identified albumin, corticosteroid use and KPS as independent prognostic factors for sf-GKRS of clear cell RCC BM. Studies focusing on the prognostic significance of albumin in sf-GKRS are rare. Further studies with a larger number of patients are warranted to confirm the above analytical outcome. Also, in keeping with previous studies, our data showed optimal rates of local tumour control and limited toxicity post radiosurgery, rendering GKRS the tool of choice in the management of RCC BM.