Extracranial Disease Control Research Articles

Final outcome analysis from the phase II TUXEDO-1 trial of trastuzumab-deruxtecan in HER2-positive breast cancer patients with active brain metastases

Brain metastases (BM) are a devastating complication of HER2-positive metastatic breast cancer (BC) and treatment strategies providing optimized local and systemic disease control are urgently required. The antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) improved progression-free survival (PFS) and overall survival (OS) over trastuzumab emtansine but data regarding intracranial activity is limited. In the primary outcome analysis of TUXEDO-1, a high intracranial response rate (RR) was reported with T-DXd. Here, we report final PFS and OS results. TUXEDO-1 accrued adult patients with HER2-positive BC and active BM (newly diagnosed or progressing) without indication for immediate local therapy. The primary endpoint was intracranial RR; secondary endpoints included PFS, OS, safety, quality-of-life (QoL), and neurocognitive function. PFS and OS were estimated with the Kaplan-Meier method and analysed in the per-protocol population. At 26.5 months median follow-up, median PFS was 21 months (95% CI 13.3-n.r.) and median OS was not reached (95% CI 22.2-n.r.). With longer follow-up, no new safety signals were observed. The most common grade 3 adverse event was fatigue (20%). Grade 2 interstitial lung disease and a grade 3 symptomatic drop of left-ventricular ejection fraction were observed in one patient each. QoL was maintained over the treatment period. T-DXd yielded prolonged intra- and extracranial disease control in patients with active HER2-positive BC BM in line with results from the pivotal trials. These results support the concept of ADCs as systemic therapy for active BM.

Current trends in lung cancer brain metastases trials.

e14006 Background: Brain metastases are the predominant central nervous system malignancy, primarily originating from lung cancer. In the era of precision medicine, enhanced control of extracranial disease is increasing the incidence of brain metastases, underscoring their status as a growing unmet need in modern Neurooncology. Methods: On December 12, 2023, we searched ClinicalTrials.gov for interventional and therapeutic clinical trials focusing on lung cancer brain metastases (LCBM). We gathered information on trial characteristics, including phase, study design, primary and secondary endpoints, status, enrollment criteria, size, duration, and results. Subsequently, the collected data was subjected to systematic analysis. Results: Among 198 identified trials, the majority were in early phases: 12% in phase I, 6% in phase I/II, and 60% in phase II. Only 27% of trials in phase II & II/III were randomized, with 92% lacking blinding. Trials were concentrated in North America (36%) and Asia/Africa/Australia (33%), predominantly targeting non-small cell lung cancer (NSCLC) (82%). Patients with leptomeningeal metastases were included in only about 10.5% of the trials. Out of 44 completed trials, only 21 resulted in published original articles. Termination occurred in 38 trials, primarily due to insufficient participant enrollment. Tyrosine kinase inhibitors emerged as promising treatments for brain parenchymal and leptomeningeal NSCLC metastases. Conclusions: This study highlights critical deficiencies in LCBM trials, ranging from inadequate trial numbers and recruitment difficulties to the overwhelming focus on NSCLC trials, insufficient randomization and blinding, and a marked scarcity of trials involving patients with leptomeningeal metastases. Addressing these issues is pivotal for advancing the understanding and treatment of LCBM.

Abstract PO2-04-05: FINAL OUTCOME ANALYSIS FROM THE PHASE II TUXEDO-1 TRIAL OF TRASTUZUMAB-DERUXTECAN IN HER2-POSITIVE BREAST CANCER PATIENTS WITH ACTIVE BRAIN METASTASES

Abstract Background Brain metastases (BM) are a severe complication of HER2-positive metastatic breast cancer. In the absence of any immediate indication for local therapy, the tyrosine-kinase inhibitor tucatinib combined with trastuzumab and capecitabine (TTC) is regarded as the preferred systemic treatment option for active BM, while data on the activity of antibody-drug conjugates (ADC) is limited. In the primary outcome analysis of TUXEDO-1, an intracranial response rate (RR) of 73.3% was reported with the ADC trastuzumab-deruxtecan (T-DXd). Here, we report final progression-free survival (PFS) and overall survival (OS) results of this study. Patients and Methods: TUXEDO-1 is a prospective, single-centre, single-arm phase 2 trial. Adult patients with HER2-positive BC and active BM (newly diagnosed untreated or progressing after prior local therapy), prior treatment with trastuzumab and pertuzumab, ECOG performance status 0 or 1 without indication for immediate local therapy were accrued and received T-DXd until progression, inacceptable toxicity, or withdrawal for any other reason. The primary endpoint was intracranial RR centrally assessed by Response Assessment in Neuro-Oncology (RANO)-BM criteria in the intention-to-treat population; secondary endpoints included PFS, OS, safety, quality-of-life (QoL), and neurocognitive function. PFS and OS were estimated with the Kaplan-Meier method and analysed in the per-protocol population (PPP). Results A total number of 15 patients were accrued; one patient was found to have dural metastases only upon restaging, resulting in a PPP of 14 patients. Patients had received a median number of two prior treatment lines (range, 1-5), 60% had progressive brain metastases and 60% had received prior T-DM1. At 26.5 months median follow-up, median PFS was 21 months (95% CI 13.3-n.r.) and median OS was not reached (95% CI 22.2-n.r.). A total of 238 cycles of T-DXd were administered (median 11.5 cycles; range 4-42). With longer follow-up, no new safety signals were observed. The most common grade 3 adverse event (AE) was fatigue (n=3; 20%). A total of 8 serious AEs were reported in 8 patients. Grade 2 interstitial lung disease and a grade 3 symptomatic drop of left-ventricular ejection fraction were observed in one patient each. QoL and neurocognitive functioning were maintained over the entire treatment duration and a significant deterioration of global QoL was observed upon progression (p=0.036). Most patients received TTC (n=5) or local therapy (n=4) as next subsequent treatment line. Ancillary biomarker studies are ongoing, and results will be presented at the meeting. Discussion In TUXEDO-1, T-DXd yielded prolonged intra- and extracranial disease control in patients with active HER2-positive breast cancer BM. The safety profile was consistent with previous reports. T-DXd did not impair QoL and neurocognitive functioning was maintained. Results therefore support the concept of ADCs as systemic therapy for active BM. Citation Format: Rupert Bartsch, Anna Sophie Berghoff, Julia Furtner, Maximilian Marhold, Elisabeth Sophie Bergen, Sophie Roider-Schur, Angelika Maria Starzer, Maximilian Mair, Heidrun Forstner, Beate Rottenmanner, Marie-Bernadette Aretin, Karin Dieckmann, Zsuzsanna Bago-Horvath, Helmuth Haslacher, Georg Widhalm, Aysegül Ilhan-Mutlu, Christoph Minichsdorfer, Thorsten Fuereder, Thomas Szekeres, Leopold Oehler, Birgit Gruenberger, Georg Pfeiler, Christian F. Singer, Ansgar Weltermann, Luzia Berchtold, Matthias Preusser. FINAL OUTCOME ANALYSIS FROM THE PHASE II TUXEDO-1 TRIAL OF TRASTUZUMAB-DERUXTECAN IN HER2-POSITIVE BREAST CANCER PATIENTS WITH ACTIVE BRAIN METASTASES [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-04-05.

Multi-Institutional Outcomes Following Stereotactic Radiosurgery for Gastrointestinal Brain Metastases

Outcomes following stereotactic radiosurgery (SRS) for gastrointestinal (GI) brain metastases (BM) are poorly defined. We analyzed our multi-institutional database of SRS patients, comparing outcomes between GI and non-GI BM patients after SRS. We retrospectively identified all patients completing an initial SRS course across two institutions from 1/2015-12/2020. Demographic and clinical parameters were manually captured. Intracranial progression (ICP) was defined as any concern on post-SRS imaging for recurrence determined by multidisciplinary consensus. Overall survival (OS) and freedom from ICP (FFICP) were estimated via Kaplan Meier models. Cox proportional hazard models were used to assess associations between ICP and parameters. Among 1383 total patients completing SRS for BM, 102 (7.4%) had GI BM. Among these, 46 (45.1%) were of colorectal (CRC) and 34 (33.3%) esophageal origin. Other GI sites (21.6%) included anal, pancreatic, gastric, GI of unknown origin, and hepatocellular carcinoma. Median follow up was 8.7 mos. GI BM patients were more likely to be younger (mean 59.1 vs 63.5 yrs, p = 0.001), male (56.9% vs 44.3%, p = 0.014 ), have more extracranial metastases (mean 1.9 vs 1.6, p = 0.003), have received systemic therapy (73.5% vs 63.9%, p = 0.049) or resection of BM (45.1% vs 25.0%, p < 0.001) prior to SRS, have larger planned target volumes of all BMs (mean 20.3 ccs vs 15.0 ccs, p = 0.013), and were less likely to receive whole brain radiation therapy (WBRT) prior to SRS (3.9% vs 10.8%, p = 0.028) or systemic therapy after SRS (54.9% vs 68.9%, p = 0.004). Among GI patients, median OS was 28.2 mos (95% CI 16.5-35.3), with no significant differences between GI and non-GI patients (p = 0.220) or among GI subgroups (CRC vs other GI: p = 0.731; esophageal vs other GI: p = 0.478). Median FFICP was significantly worse for GI patients (6.2 mos, 95% CI 4.0-9.6 mos) than for non-GI patients (12.4 mos, 95% CI 10.8-13.9 mos; p = 0.004). After accounting for age, sex, performance status, number of irradiated BMs, extracranial disease burden, extracranial disease control, interval from primary cancer diagnosis to BM diagnosis, resection status, receipt of prior WBRT, and receipt of post-SRS systemic therapy, GI origin was significantly associated with worse FFICP (HR 1.50, 95% CI 1.15-2.02, p = 0.007). FFICP was not significantly different between GI subgroups, with CRC and esophageal patients demonstrating median times to ICP of 5.0 mos (95% CI 3.4-9.6) and 7.2 mos (95% CI 2.7-14.1), respectively. Only 2 GI patients (2.0%) had ICP at site of prior SRS. Across a modern, multi-institutional SRS cohort comparing GI to non-GI primary patients, BMs of GI origin demonstrated inferior FFICP to those of non-GI origin. OS did not vary significantly across GI and non-GI cases. Among GI subtypes, no significant differences were identified across FFICP or OS. These data may help inform treatment decisions and post-SRS surveillance.

New strategies for the treatment of breast cancer with leptomeningeal metastasis.

Leptomeningeal metastasis is a complication of metastatic breast cancer that has a rising incidence likely due to the increased availability of novel systemic therapies, which have improved survival with better extracranial disease control but with limited intracranial efficacy. A poor prognosis of less than 6 months has historically been associated with leptomeningeal metastasis and it is often an exclusion factor for enrollment in clinical trials. There are limited evidence-based data supporting use of therapeutics in leptomeningeal metastasis patients and recommendations are largely derived from retrospective reports and small prospective studies. However, in recent years, there has been a surge in effective modern therapeutics with promising intracranial activity. The study aims to review the most recent updates in the management of leptomeningeal metastasis in breast cancer. We discuss the effectiveness and limitations of intrathecal administration, predictive biomarkers in the cerebrospinal fluid, proton radiation therapy and promising new systemic therapies such as antibody drug conjugates. Ongoing development of clinical trials that allow inclusion of leptomeningeal metastasis are essential for establishing efficacy potential and discovering new treatment options in this population of great unmet need.

A 3-month survival model after Gamma Knife surgery in patients with brain metastasis from lung cancer with Karnofsky performance status ≤ 70

Gamma Knife surgery (GKS) for brain metastasis (BM) has been generally advocated for patients with a Karnofsky performance status (KPS) scale of ≥ 70. However, some patients with a poor KPS scale of < 70 are recoverable after GKS and show durable survival. A purpose of this study is to devise a 3-month survival prediction model to screen patients with BM with a KPS of ≤ 70 in whom GKS is needed. A retrospective analysis of 67 patients with a KPS scale of 60–70 undergoing GKS for BM of non-small cell lung cancer (NSCLC) from 2016 to 2020 in our institute was performed. Univariate and multivariate logistic regression analyses were performed to investigate factors related to survival for more than 3 months after GKS. The probability (P) prediction model was designed by giving a weight corresponding to the odds ratio of the variables. The overall survival was 9.9 ± 12.7 months (range 0.2–53.2), with a 3-month survival rate of 59.7% (n = 40). In multivariate logistic regression analysis, extracranial disease (ECD) control (p = .033), focal neurological deficit (FND) (p = .014), and cumulative tumor volume (∑ TV) (p = .005) were associated with 3-month survival. The prediction model of 3-month survival (Harrell’s C index = 0.767) was devised based on associated factors. In conclusion, GKS for BMs is recommended in selected patients, even if the KPS scale is ≤ 70.

Targeting lung cancer brain metastases: a narrative review of emerging insights for anaplastic lymphoma kinase (ALK)-positive disease.

Lung cancer is commonly associated with brain metastasis formation, and certain subtypes, such as anaplastic lymphoma kinase (ALK) rearranged disease, have an especially high propensity for early and frequent central nervous system (CNS) involvement for which treatment can be challenging. Historical management has centered on surgery and radiation therapy (RT), which persist as mainstays of treatment for large, symptomatic lesions and widespread CNS disease. To date, sustained disease control remains elusive, and the role for effective systemic adjunctive therapies is clear. Here we discuss the epidemiology, genomics, pathophysiology, identification, and management of lung cancer brain metastases with a particular emphasis on systemic treatment of ALK-positive disease according to the best available evidence. Review of PubMed and Google Scholar databases as well as ClinicalTrials.gov provided background and seminal trials for the local and systemic management of ALK rearranged lung cancer brain metastases. The development of effective, CNS-penetrant systemic agents-including alectinib, brigatinib, ceritinib, and lorlatinib-has dramatically changed the management and prevention of ALK rearranged brain metastases. Most notably, there is a burgeoning role for upfront systemic therapy for both symptomatic and incidentally discovered lesions. Novel targeted therapies offer patients a pathway to delay, obviate, or supplement traditional local therapies while minimizing neurologic sequelae of treatment and may reduce the risk of brain metastasis formation. However, the selection of patients to whom local and targeted treatments is offered is not trivial, and the risks and benefits of both must be weighed carefully. More work is needed to establish treatment regimens that yield durable intra- and extracranial disease control.

Prognostic impact of extracranial disease control in HER2+ breast cancer-related brain metastases

BackgroundBrain metastases (BM) are common among HER2+ breast cancer (BC) and prognostic stratification is crucial for optimal management. BC-GPA score and subsequent refinements (modified-GPA, updated-GPA) recapitulate prognostic factors. Since none of these indexes includes extracranial disease control, we evaluated its prognostic value in HER2+ BCBM.MethodsPatients diagnosed with HER2+ BCBM at Istituto Oncologico Veneto-Padova (2002–2021) and Montpellier Cancer Institute (2001–2015) were included as exploratory and validation cohorts, respectively. Extracranial disease control at BM diagnosis (no disease/stable disease/response vs. progressive disease) was evaluated.ResultsIn the exploratory cohort of 113 patients (median OS 12.2 months), extracranial control (n = 65, 57.5%) was significantly associated with better OS at univariate (median OS 17.7 vs. 8.7 months, p = 0.005) and multivariate analysis after adjustment for BC-GPA (HR 0.61, 95% CI 0.39–0.94), modified-GPA (HR 0.64, 95% CI 0.42–0.98) and updated-GPA (HR 0.63, 95% CI 0.41–0.98). The prognostic impact of extracranial disease control (n = 66, 56.4%) was then confirmed in the validation cohort (n = 117) at univariate (median OS 20.2 vs. 9.1 months, p < 0.001) and multivariate analysis adjusting for BC-GPA (HR 0.41, 95% CI 0.27–0.61), modified-GPA (HR 0.44, 95% CI 0.29–0.67) and updated-GPA (HR 0.42, 95% CI 0.28–0.63).ConclusionsExtracranial disease control provides independent prognostic information in HER2+ BCBM beyond commonly used prognostic scores.

Low radiotherapy dose is suitable for brain metastases in SCLC compared with high dose.

This study was designed to evaluate the suitable radiotherapy dose in SCLC patients with BM. A retrospective analysis was performed among 121 patients on the prognosis of BM of SCLC who were admitted to our hospital from 2013 to 2023. They all received first line chemotherapy. 80 patients of them received TRT after chemotherapy. The Chi square method was used to compare the categorical data. Univariate survival analysis was estimated by Kaplan Meier method and the logrank was used to compare survival curves between groups. A multivariate prognostic analysis was made by the Cox proportional hazard model. The iOS and iLC of two groups of low dose and high dose were analyzed after propensity score matching (PSM). In all the patients, the median follow-up time was 18.6 months (range 6.30~85.7), the 2-year iOS and iLC rates were 15.4% and 70.3%, respectively, and cerebral necrosis occurred in 2 patients. In univariate analysis related to iOS, extracranial disease control (p=0.023), higher DS-GPA (≥2) (p=0.016), immunotherapy (p=0.049), low-dose(p=0.030), and WBRT+SIB (p=0.009) were significantly associated with an increase in survival rate. After PSM, the 2-year iOS of low dose (n=49) was significantly higher than that of high dose (n=49) (P=0.025), while the 2-year iLC was not significantly improved (P=0.267). In DS-GPA < 2 subgroup, the iOS of low dose group was significantly higher than that of high dose group (p=0.019). In the DS-GPA ≥ 2 subgroup, the 2-year iLC of the low dose group was significantly inferior than that of the high dose group (p=0.044). The iLC was improved along with increasing radiotherapy dose, but high dose had inferior iOS compared to low dose, while there were not significantly improving iLC when radiotherapy BED >56Gy. But in patients with DS-GPA≥2 subgroup, high dose brought better iLC benefits.

DDDR-05. ERK INHIBITION INCREASES SENSITIVITY TO ANTI-PD-1 THERAPY IN A MOUSE MODEL OF BRAF MUTANT MELANOMA BRAIN METASTASIS

Abstract BACKGROUND Immune checkpoint inhibitors (ICI) have revolutionized the landscape of cancer treatment, including brain metastases. However, only a subset of patients with brain metastases respond to ICI. Activating mutations in the mitogen-activated protein kinase (MAPK) signaling pathway, a key regulator of cell processes, are frequently found in brain metastases. LY3214996 (LY321) is a selective ERK 1/2 inhibitor that inhibits MAPK signaling and leads to regression of extracranial disease in preclinical models. Our objective was to evaluate whether with ERK inhibition (ERKi) can improve the efficacy of ICI in preclinical models of brain metastases. METHODS We tested sensitivity to LY321 in a BRAFV600E mutant, ICI resistant murine melanoma cell line (D4M) both in vitro and in vivo. To model brain metastases in vivo, we implanted D4M cells subcutaneously with subsequent intracranial implantation three days later. The treatment arms included LY321 and anti-PD-1 combination therapy, single agent therapies, and respective controls. We tested the efficacies of 2-week versus 4-week LY321 treatments, as well as 3-week treatment in an independent experiment. RESULTS D4M demonstrates in vitro sensitivity to LY321 (IC50 value of 4.75 µM). Our model demonstrated that LY321 in combination with anti-PD-1 improves both intracranial and extracranial disease control. Increased survival with combination therapy was observed with 3-week and 4-week LY321 administration. While individually, LY321 and anti-PD-1 produced better survival outcomes than control groups, combination therapy significantly outperformed both monotherapies. CONCLUSION Previous studies demonstrated that LY321 has minimal intracranial activity. However, we found that ERKi reduces intracranial tumor burden, with improved efficacy in combination with ICI in immunocompetent mice. Together, these data suggest that ERKi increases sensitivity to ICI therapy in pre-clinical brain metastasis models. Further investigation is needed to elucidate the mechanisms of this therapeutic approach, and to ultimately determine whether this combination will improve patient outcomes.

Outcomes of Stereotactic Radiosurgery for Brain Metastases in Patients with Small-Cell Lung Cancer

<h3>Purpose/Objective(s)</h3> Several randomized studies have established stereotactic radiosurgery (SRS) as a first-line treatment modality for limited brain metastases. However, these trials frequently excluded patients with primary small cell lung cancer (SCLC). Here, we assess clinical outcomes of patients with primary SCLC who have undergone SRS for brain metastases. <h3>Materials/Methods</h3> We identified patients with histologically-proven SCLC who underwent first-time SRS for brain metastases at our institution. Overall survival, local recurrence, and time to distant CNS failure were estimated with the Kaplan-Meier method. Univariate log-rank test and multivariate Cox regression were used to assess the significance of prognostic factors including age, sex, prior whole brain radiation, number of brain metastases, and extracranial disease control status. <h3>Results</h3> Fifty-nine patients (median age 64) with SCLC completed SRS for brain metastases at our institution from July 2007 to December 2021. 88.1% (n=52) of patients received Gamma Knife SRS, whereas the remainder received LINAC-based SRS. 61.0% (n=36) had received prior whole brain or prophylactic cranial irradiation. The median number of treated brain metastases was 2 (range 1-11) with a median tumor diameter of 1.0 cm and a marginal dose of 18 Gy. Median overall survival was 11 months. On multivariate Cox regression, both increased number of brain metastases (HR 1.22; 95% CI 1.02-1.44) and increased age (HR 1.09; 95% CI 1.03-1.16) were associated with poorer overall survival. 11.9% (n=7) of patients experienced local recurrence at a median of 5 months post-SRS (range 2-9 months). The median time to distant CNS failure was 6 months. Multivariate analysis identified extracranial disease control status as the sole significant predictor of distant failure. Log-rank test demonstrated that the patient cohort with uncontrolled extracranial disease had a lower time to distant failure compared to those with stable or well-controlled disease (4 vs. 22 months; p=0.0001). <h3>Conclusion</h3> SRS provides excellent local control of SCLC-associated brain metastases without compromising overall survival. Our institutional data support the rationale for future prospective studies to establish the role of intracranial SRS in this patient population.

Association of Baseline Symptom Burden and Survival among Patients with Brain Metastases at a Tertiary Cancer Center

<h3>Purpose/Objective(s)</h3> Brain metastases (BrM) commonly affect patients with solid malignancies and often correlate with significant symptomatology that profoundly impacts patients' quality of life (QOL). As systemic therapies increasingly improve extracranial disease control but lag in intracranial efficacy, a rising incidence of BrM persists. Thus, an urgent need exists to characterize the most common symptoms associated with BrM and to correlate these symptoms with survival. <h3>Materials/Methods</h3> We identified patients who received radiation therapy (RT) within 30 days of BrM diagnosis at a tertiary cancer center between 2017-2020 who prospectively completed the MD Anderson Symptom Instrument-Brain Tumor questionnaire (a validated instrument among patients with BrM for evaluation of 22 symptoms and 6 interference measures linked to daily functioning). Symptom severity score (range 0-10, with higher scores indicating more severe symptomatology) and interference score (range 0-10, with higher scores indicating greater compromise of activity-related/affective function), were compared via t-test or ANOVA by: age (>65 vs. ≤65), sex, Karnofsky performance status (KPS) (high, 90-100 vs. low, <90), Charlson co-morbidity index (CCI) (high, >2 vs. low, 0-2), primary tumor type (lung, breast, melanoma, other), and initial intracranial treatment strategy (surgical resection, stereotactic RT, or whole brain RT). Overall survival (OS) was assessed via Cox regression with the above co-variates; symptom severity and interference were evaluated in separate Cox models. <h3>Results</h3> A total of 101 patients were identified (median age=67 years, female=60%, primary lung cancer=45%). Mean symptom severity and interference scores at time of BrM diagnosis were 2.4 and 3.4, respectively. The most common severe (defined as a score >4) symptoms were: fatigue (47%), distress (40%), sleep disturbances (37%), drowsiness (35%), and sadness (32%). The most common high (score>4) interference measures were: enjoyment of life (47%), ability to work (44%), and walking (35%). Higher symptom severity was more common among females than males (2.8 vs 1.8, respectively; p=0.01); there were no significant differences in mean symptom severity or interference scores by age, KPS, CCI, or initial BrM treatment strategy. On Cox regression, higher symptom severity and higher interference scores were associated with worse OS (HR 1.30 per 1-point increase [95% CI, 1.11-1.51], p<0.001; and HR 1.18 per 1-point increase [95% CI 1.07-1.30], p=0.001, respectively); age, KPS, CCI, and other co-variates were not significantly associated with OS. <h3>Conclusion</h3> High symptom and interference burden is common among patients with BrM and associated with worse survival. Further work should investigate how improving symptoms, such as through palliative care interventions, may impact QOL trajectories and survival among the BrM patient population.

240P Prognostic impact of extracranial disease control in HER2+ breast cancer-related brain metastases

Brain metastases (BM) are a common complication of HER2+ breast cancer (BC). As several treatment options are available, adequate prognostic stratification is crucial for optimal management. Validated scores, e.g. the BC-Graded Prognostic Assessment (GPA) and subsequent refinements (modified-GPA, updated-GPA), have been proposed to recapitulate significant prognostic factors; however, none of these includes extracranial disease control. We here evaluate the prognostic value of extracranial disease control in patients with HER2+ BCBM beyond commonly used indexes.

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]

Risk-reduction strategies for late complications arising from brain metastases treated with radiotherapy: a narrative review.

This review will focus on the late neurological complications from cranial irradiation and relevant mitigation strategies. Radiotherapy (RT) remains an important pillar in the management of brain metastases. Patients being treated in the modern era do experience longer survival, because of superior intra- and extra-cranial disease control. As a result, they can be more prone to developing and manifesting late complications post-brain radiotherapy. A search and narrative review of prospective clinical trials relating to neurological toxicity outcomes was conducted. Neurological toxicities can be challenging to diagnose and manage and should be considered during consideration of radiotherapy in brain metastasis, hence more emphasis should be placed on prevention and upfront mitigation of these complications, with novel strategies showing promising results in prospective trials being adopted into clinical practice.

Neurooncological Challenges in Relapsing Intracranial Melanoma Metastases: A Case Report

Introduction: Treatment of melanoma brain metastases (MBM) is a complex interdisciplinary challenge. Relapsing MBMs pose an extra challenge due to limited therapeutic options and higher complication rate. Multiple surgical interventions and radiation can be indicated in the case of intracranial relapse with extracranial disease control under oncological therapy e.g., immunotherapy. Case Presentation: Here, we report on a 37-year-old female patient with stage IV metastatic melanoma, who underwent six neurosurgical procedures, including five tumor resections, and three courses of different irradiation protocols in 26 months, all while receiving multiple regimens of immunotherapy. Throughout the different therapies, the patient showed varying neurological deficits, including facial nerve palsy, hemiparesis and reduction of cognitive function. The patient died due to symptoms related to leptomeningeal spread of the tumor. Conclusion: With this case, we want to share our experience with multiple neurosurgical interventions and repeated brain irradiation procedures in a patient with relapsing MBM. Neurosurgical interventions contributed to symptom relief, saved steroids and potentially prolonged survival. Therefore, based on the events of this case, repeated surgery could be considered for progressive brain metastases.

Modern Radiation Therapy for the Management of Brain Metastases From Non-Small Cell Lung Cancer: Current Approaches and Future Directions.

Brain metastases (BMs) represent the most frequent event during the course of Non-Small Cell Lung Cancer (NSCLC) disease. Recent advancements in the diagnostic and therapeutic procedures result in increased incidence and earlier diagnosis of BMs, with an emerging need to optimize the prognosis of these patients through the adoption of tailored treatment solutions. Nowadays a personalized and multidisciplinary approach should rely on several clinical and molecular factors like patient’s performance status, extent and location of brain involvement, extracranial disease control and the presence of any “druggable” molecular target. Radiation therapy (RT), in all its focal (radiosurgery and fractionated stereotactic radiotherapy) or extended (whole brain radiotherapy) declinations, is a cornerstone of BMs management, either alone or combined with surgery and systemic therapies. Our review aims to provide an overview of the many modern RT solutions available for the treatment of BMs from NSCLC in the different clinical scenarios (single lesion, oligo and poly-metastasis, leptomeningeal carcinomatosis). This includes a detailed review of the current standard of care in each setting, with a presentation of the literature data and of the possible technical solutions to offer a “state-of-art” treatment to these patients. In addition to the validated treatment options, we will also discuss the future perspectives on emerging RT technical strategies (e.g., hippocampal avoidance whole brain RT, simultaneous integrated boost, radiosurgery for multiple lesions), and present the innovative and promising findings regarding the combination of novel targeted agents such as tyrosine kinase inhibitors and immune checkpoint inhibitors with brain irradiation.

Utility of Short Initial MRI Brain in Brain Metastases Patients Treated With Stereotactic Radiosurgery

The optimal timing of interval MRI surveillance following stereotactic radiosurgery (SRS) to detect most new lesions while asymptomatic and treatable by additional radiosurgery is unknown. As frequent MRI follow-up is an important patient burden and contributor to cost of care for brain metastases, we aimed to characterize the utility of early initial post-treatment MRI brain surveillance and to identify patient characteristics that might be used to risk-stratify patients who may benefit from early surveillance scans.An IRB-approved retrospective single-institution cohort of patients with brain metastases treated with frameless SRS was analyzed. Baseline demographics, treatment characteristics, and timing of follow-up MRI findings were reviewed in the electronic medical record. Fisher's exact test and Pearson's Chi-square test were used to compare proportions. Mann-Whitney-U test was used to compare continuous variables.One hundred consecutive patients treated from January 2018 - March 2020 were included, with plan for 6-week follow-up MRI post-treatment. Thirteen lacked follow-up MRI brain, leaving 87 for analysis. Median time to MRI was 6.7 weeks, with 78% of scans obtained less than 8 weeks post-SRS. Twenty-four (28%) patients had findings concerning for new or progressive disease on follow-up MRI. Nine were symptomatic. Of the 24, ten (42%) received SRS, 1 (8%) received whole brain radiotherapy (WBRT), 1 (4%) received surgery, 1 (4%) started systemic therapy, 7 received a short interval MRI scan, and 3 (12%) went to hospice. Of the 10 who received SRS, 3 were symptomatic, 6 had lesions ≥ 5 mm, and all 10 had lesions ≥ 5 mm. Of the 7 recommended for short interval MRI, 1 received SRS, 1 received WBRT, and 5 had no further evidence of disease progression, resuming routine surveillance. Comparing patients with suspicious findings to those with stable disease on follow-up MRI, there was a statistically significant difference (Table) in the distribution of histology (P = 0.02) and performance status (P = 0.047), but no difference in number of lesions, extra-cranial disease control, prior receipt of SRS, or use of targeted therapy or immune checkpoint inhibitors.A small but significant number of brain metastases patients treated with SRS may have additional therapy based on initial short interval surveillance MRI scans. Further investigation in larger cohorts may help identify patient characteristics that predispose to benefit from short interval MRI scans, and determine the value of earlier detection of new lesions compared with a longer interval to first scan.

Stereotactic radiosurgery combined with immune checkpoint inhibition for the treatment of melanoma brain metastases is associated with high levels of extracranial disease control and survivorship - an abscopal effect?

Abstract Aims Melanoma brain metastases (MBM) are a common presentation to the neuro-oncology MDT. Stereotactic radiosurgery (SRS) is a highly effective treatment for cerebral metastases, with at least 70% control rates of individual metastases,[1] whilst immune checkpoint blockade has revolutionised the management of metastatic melanoma in recent years.[2] Recent studies have demonstrated that immune checkpoint inhibition alone also has activity in the brain, with MBM response rates of 50% or more.[3, 4] When MBM are treated with combination immunotherapy and SRS together, 12-month intracranial progression free survival (PFS) rates of 85% have been achieved.[4, 5] The aim of the current study was to evaluate the local control of MBM treated at our tertiary referral centre, which benefits from specialist neuro-radiology peer review of SRS contour volumes, and further to investigate whether overall survival is also improved, and what the mechanism of this may be. Method A retrospective analysis of all patients treated with SRS for brain metastases at our teriary SRS centre between June 2017 – January 2020 was performed. Inclusion criteria included patients treated for MBM, who received at least 2 doses of any combination of immune checkpoint inhibition concurrently with (defined as at the time of or commenced within 3 months of) SRS. The primary endpoints were the intracranial and extracranial response rates and survival rate at 12 months. Response was defined as complete response, partial response or stable disease. Secondary endpoints included the rate of imaging-defined radionecrosis, median lesional progression free survival (mPFSlesion), non-lesional intracranial PFS (mPFSintracranial), extracranial PFS (mPFSextracranial) and overall survival (mOS), measured from the start date of SRS to the date of event or censored at the start date of data collection. Kaplan-Meier curves and survival statistics were generated using SPSS v26. Results 33 MBM from 18 patients were identified. The median follow up was 25.8 months (minimum 12 months). Of the 18 patients: the median age was 60 (IQR 48 – 72); 17 (94%) patients were ECOG performance status 0-1; the median number of extracranial disease sites was 2 (pre-immunotherapy) and 1 (pre-SRS); the median duration of immunotherapy treatment was 17.6 (12.9 – 28.5) months, and the median number of metastases treated per patient was 2. Of the 33 metastases: 31 (94%) were supratentorial; 6 (18%) underwent prior neurosurgical resection; the median GTV volume (cc) of unresected metastases was 0.5cc (0.1 – 2.7), and 21 (64%) were treated with single fraction SRS. The median OS and PFS for all subtypes were not reached. The rates of OS, PFSlesion, PFSintracranial and PFSextracranial at 12 months were 93.9%, 87.9%, 81.8% &amp; 75.8% respectively. Conclusion Our cohort of MBM patients appear to perform favourably when compared with the current literature. When compared to a recent extensive systematic review of modern management of MBM, our lesional control rate is as good as the weighted average of concurrent SRS + immunotherapy studies (87.9% vs 85.4% 12-month PFS), however we demonstrate a significantly improved 12-month OS rate (93.9% vs 52.8%) compared to the same (mOS of 15.8 – 17.4 months in other studies).[6,7] Our extra-lesional PFS is high and, compared to extracranial PFS rates from 51% at 6-months to 70.4% at 9-months in the literature,[3,4] our 75.8% control at 12 months suggests that extracranial control could drive the OS benefit. This suggests a benefit of SRS beyond the local control of MBM and questions whether patients without brain metastases may benefit from body SABR to extracranial metastases, to elicit a similar, potentially abscopal type effect.

P14.29 The treatment of melanoma brain metastases with stereotactic radiosurgery concurrently with immune checkpoint inhibition is associated with improved extracranial disease control and overall survival compared to the overall metastatic melanoma cohort - a synergistic effect reaching beyond local control?

Abstract BACKGROUND Melanoma brain metastases (MBM) are an increasingly common referral to the neuro-oncology MDT in the context of lengthening survivorship of metastatic melanoma (MM) patients in the immunotherapy era. Stereotactic radiosurgery (SRS) and immune checkpoint inhibition (ICI) are both effective in the management of MBM and, when combined, 12-month local control rates of &amp;gt;85% and overall survival (OS) &amp;gt;80% have been reported.[4,5] Recent local analysis of patients treated at our tertiary SRS referral centre has revealed even greater outcomes in this patient cohort. This study aimed to compare the outcomes of patients with MBM treated with concurrent SRS and ICI compared to the overall metastatic melanoma cohort, to elucidate whether the addition of SRS to ICI may improve disease control outside of the brain as well as within. MATERIAL AND METHODS A retrospective analysis of our local SRS database and an ARIA ePrescribing database search was performed to identify a cohort of patients treated with concurrent SRS and ICI for MBM, as well as a control cohort of MM patients who received ICI alone, over a 4 year period until February 2020. The primary endpoints were the extracranial progression free survival (PFS) and overall survival (OS) at 12 months. Secondary endpoints were the median PFS (mPFS) and OS (mOS). Kaplan-Meier curves and survival statistics were generated using SPSS v26. RESULTS A total of 34 MBM from 19 patients were identified in the SRS+ICI group and there were 200 patients in the control group. The minimum follow up was 12 months. The median patient age, duration of ICI and use of combination ICI favoured the SRS+ICI group. The number of sites of extracranial disease pre-ICI and overall anti-PD-1 usage was well matched. In the SRS+ICI group, there were no cases of extracranial progression and no deaths within 12 months. In the control group, the 12-month PFS and OS rates were 50.5% and 77.5% respectively. In terms of mPFS, this was not reached (estimated 37.6 months) in the SRS+ICI group, versus 13.4 months in the control group (log rank test, p=0.001). In terms of mOS, this was not reached in the SRS+ICI group, versus 55.8 months in the control group (log rank test, p=0.016). CONCLUSION We demonstrate improved extracranial disease control and survivorship amongst metastatic melanoma patients who develop brain metastases and are treated with concurrent SRS and ICI compared to those who do not. The outcomes of our control cohort are comparable to the 4-year follow up of the CheckMate 067 trial (n=945),[6] which strengthens the validity of the statistical comparisons made in this study. The improved extracranial disease control seen when SRS and ICI are combined in the treatment of MBM questions whether an abscopal effect may be at play, and therefore further accents the utility of SRS in MBM beyond that of local control alone. This could influence management in cases of borderline decisions for SRS.