TPS1140 Background: Patients with triple negative breast cancer (TNBC) are at a high risk to develop brain metastases. The prognosis and quality of life for triple negative brain-metastatic breast cancer remains very poor. Treatment options are limited and improvement in efficacy is needed. Sacituzumab govitecan (SG) has shown blood brain barrier (BBB) penetration in preclinical and clinical settings with anti-tumor activity in the phase III ASCENT Trial (NCT02574455). Radiotherapy can open the BBB and has been shown to be safe in combination with anti-PD-1 therapy in our previous trial (NCT03807765). Therefore, combining radiation with the anti-PD-1 monoclonal antibody, zimberelimab, and SG may provide a synergistic anti-tumor approach. We hypothesize the use of SG and zimberelimab with stereotactic radiosurgery (SRS) among patients with metastatic TNBC with brain metastases will be safe and improve progression free survival compared to treatment with SG alone. Methods: The study is designed as a single-arm, nonrandomized, open-label, phase I/II trial of SG and zimberelimab with SRS among patients with metastatic TNBC with brain metastases. The primary endpoint will be neurologic toxicity defined by CTCAE v5 criteria (phase I) and 12 month PFS (phase II). TNBC patients ≥ 18 years old with ≤ 15 brain metastases with at least one measurable lesion ≥ 0.5 cm per RANO-BM criteria will be enrolled. Treatment will be initiated with SRS followed 1 week later by SG on days 1 and 8 (10 mg/kg) with zimberelimab on day 1 (360 mg IV) repeated every 3 weeks. Follow-up imaging response assessments will be conducted at q9 week intervals. An interim analysis will be performed after 21 patients are enrolled. An additional 10 patients will be enrolled if interim futility criteria are not met. Clinical trial information: NCT06238921 .

Patients with polymetastatic cancer have traditionally been treated with systemic therapies, whereas radiation therapy has played a mainly supportive role, typically using simple, nonconformal techniques for palliation of the most symptomatic sites. More recently, however, stereotactic ablative radiotherapy (SABR) therapy has emerged as a feasible and safe option for select patients with widespread polymetastatic disease, building on its established efficacy in the oligometastatic setting and supported by encouraging data from recent clinical trials. In parallel, low-dose radiation therapy (LDRT) has been investigated as an immunomodulatory approach designed to enhance the effectiveness of systemic immunotherapy. As conformal radiation therapy expands into the polymetastatic setting, the integration of SABR or LDRT presents distinct clinical, technical, and logistical challenges that require tailored protocols and workflow adaptations to ensure safety, feasibility, and therapeutic effectiveness. In this article, we provide a practical, evidence-informed overview of SABR and LDRT strategies across the radiation therapy workflow to support their safe and effective implementation in complex clinical scenarios, illustrated through real-world case examples from patients with widespread polymetastatic disease. Our aim is to offer clinicians and multidisciplinary teams a comprehensive, implementation-focused resource to facilitate the integration of SABR and LDRT into the management of polymetastatic cancer.

Relatlimab (rela) with nivolumab (nivo) has demonstrated durable responses in pre-treated advanced melanoma. Intracranial responses have been demonstrated with the combination of ipilimumab (ipi) with nivo in melanoma brain metastases (MBM). We sought to characterize intracranial outcomes in patients treated with nivo/rela following ipi/nivo. A retrospective analysis of patients who received nivo/rela with MBM was performed. Patients had prior ipi/nivo and active MBM. The primary endpoint was central nervous system progression free survival (CNS-PFS). Secondary endpoints included overall survival (OS), extracranial-PFS, and safety with local therapy. We identified 24 patients, with a median follow-up of 14.2-months. Median age was 72 (range 31–85), 75

PURPOSE:Improved treatment strategies are needed for HER2 negative breast cancer brain metastases (BCBM). Stereotactic radiosurgery (SRS) is the standard of care for limited brain metastases. Sacituzumab govitecan (SG) may have intracranial efficacy for BCBM; however, safety and efficacy data remain limited when combined with SRS. METHODS:A multi-institutional retrospective review was performed of patients with HR+/HER2- and triple negative (TNBC) BCBM treated with SG and SRS for active BMs at three institutions. Concurrent SG and SRS was defined as SRS after the date of first SG infusion and before or on the date of last SG infusion. Safety was assessed as well as distant intracranial control (DIC), systemic and central nervous systemic (CNS) progression-free survival (PFS), local control (LC), and overall survival (OS). RESULTS:A total of 277 lesions were treated over 36 SRS courses in 26 patients. Median follow up from SG initiation was 23.3 months. One hundred sixty-eight (61%) lesions were treated with single fraction SRS and 109 (39%) lesions were treated with fractionated SRS (fSRS). One hundred thirty-five (47%) lesions received concurrent SRS and SG. No cases of symptomatic radiation necrosis (SRN) were noted. LC rates at 12- and 24-months were 94% and 84%, respectively. Median CNS-PFS was 5.4 months (95% CI 2.8-7.3). Median systemic PFS was 4.4 months (95% CI 2.2-7.3 months). Median overall survival was 8.4 months with a 24-month rate of 16%. CONCLUSION:In our series, concurrent SRS and SG was associated with excellent local control, without an increased risk of SRN. Prospective investigation into potential synergy is warranted.

The delivery of post-operative radiotherapy (PORT) for solid tumor bone metastases is a well-established practice that aims to enhance patient outcomes following surgical intervention. Surgery for osseous metastases serves to stabilize bone, alleviate pain, reduce tumor volume, and relieve pressure on critical neurological components. Radiotherapy complements surgery by addressing residual malignant disease and cancer-induced pain. Together, they serve to improve local control, maximize functional outcomes, control pain, and improve patients' overall quality of life. Despite the prevalence of non-spine bone metastases (NSBMs) necessitating operative intervention, structured guidelines for palliative PORT are limited. This is, in part, due to a paucity of research specific to this topic. As such, a wide array of doses are deemed acceptable, leading to varied practice patterns. Conversely, there is more extensive literature available, including prospective trials, for the management of post-operative spine bone metastases (SBMs). This includes advances such as stereotactic body radiotherapy (SBRT), separation surgery, and the utilization of simultaneous integrated boosts that enable evidence driven, safe dose escalation. This mini-review aims to provide a summary of the existing literature on palliative postoperative radiotherapy for both NSBMs and SBMs. By offering historical context and summarizing current evidence, this article seeks to aid clinical decision-making and highlight areas for future research to enhance treatment standardization and patient care.

Plan quality and low dose spillage, in the context of single isocenter treatment of multiple metastases, are evaluated for two commercially available treatment planning systems (TPSs): Brainlab Elements Multiple Mets Software v.3.0 and v.4.0 (MBM) and RayStation v.11A (RS) representing a TPS specialized for this application and a more generalized TPS, respectively. Twenty-one patients, originally planned for treatment with MBM, were selected for analysis with 66 (2 to 5 per patient) total lesions with average of 3.1 lesions per isocenter. Organs-at-risk were auto-contoured in Brainlab MBM and reviewed by physicist or physician prior to treatment planning. Gross tumor volumes (GTVs) and planning target volumes (PTVs) were contoured in MBM. All structures, CT, MRI, and registration files were exported to RS. Structures were resampled upon export. Treatment plans were developed in RS. Plans in MBM used dynamic conformal arcs (DCA) and RS plans utilized VMAT, both implementing non-coplanar trajectories. Plan evaluation metrics include planning target volume (PTV) coverage (D98 %), conformity index (CI), gradient index (GI) normal brain V12Gy (cc) and V4Gy (cc). PTV D98 % coverage was comparable between MBM and RS plans demonstrating an average difference of 0.87 Gy (± 1.07 Gy) (with RS having higher average D98 %). The greatest difference between MBM and RS was the dose to the normal brain. Normal brain V12Gy was on average 4.54cc (± 3.02cc) vs 5.47cc (± 3.00cc) and V4Gy was 33.23cc (± 22.08cc) vs 43.35cc (± 26.24cc) for MBM vs RS, respectively. The conformity index (CI) improved in MBM vs RS (1.20 vs 1.56 average). MBM dynamic conformal arcs (DCA) and RS VMAT approaches produce comparable plans, however we found MBM treatment plans to be superior due to better target conformality and subsequent lower normal brain V12Gy and V4Gy.

703 Background: The association between homologous recombination deficiency (HRD) in pancreatic ductal adenocarcinoma (PDAC) and sensitivity to platinum-based chemotherapy highlights the need to further understand how germline DNA repair mutations influence the efficacy of different therapies. Given the recent ALLIANCE data that chemotherapy alone is an acceptable standard of care to enhance R0 resection, the focus has shifted towards the contribution of radiotherapy. However, the relationship between germline DNA repair mutations in general and radiosensitivity remains less understood. This study explores the relationship between germline mutations and the Radiosensitivity Index (RSI) gene signature. Methods: After obtaining institutional review board approval, a retrospective analysis was performed of patients who had both RSI and germline mutation testing (i.e., BRCA1, BRCA2, BLM, ATM, MLH1, MSH2, MSH6, PMS2, and BARD mutations) between 1999 and 2023 at a single institution. Student T, Chi squared, Kaplan Meier (KM), Cox univariate log regression (UVA), and Mann-Whitney U (MWU) tests were used for statistical analyses. Results: A total of 25 patients were included, 13 with mutations and 12 without. MWU analysis demonstrated a significant difference in RSI values, where patients with mutations exhibited greater radiosensitivity (mean 0.379 vs. 0.464, p=0.040). The median age at diagnosis, max diameter of tumor, and baseline CA 19-9 were 67 years (range 47 – 77), 3.4 cm (range 0.8 – 8.2), and 288 (9.5 – 26,100), respectively. Most of the tumors were resectable (84%), stage IIB (36%), and grade 2 (68%). All patients underwent resection, with the majority without neoadjuvant therapy (96%). Most patients received chemotherapy (n=18; 72%), most commonly gemcitabine monotherapy (n=14/18). A majority also received radiation therapy (n=15; 60%), with 93% receiving chemoradiation (n=14/15). The median follow-up was 20.8 months. KM analysis yielded a median overall survival (OS) of 20.0 months (95% CI: 7.1-33.0) and progression-free survival (PFS) of 15.1 months (95% CI: 12.3-18.0) for the entire cohort. At the time of analysis, 15.4% of patients with mutations were alive (>10 years), compared to none without mutations (p=0.157). There were no statistically significant differences between the two cohorts for clinical outcomes on KM analysis. On UVA, worse OS was correlated with stage III (HR 7.9, 95% CI 1.2 – 50.2) and IV (HR 11.8, 95% CI 1.4 – 102.3). No other variables were associated with OS on UVA or on mutant-only subgroup analysis. Conclusions: Our findings demonstrate an increased radiosensitivity in patients with germline DNA repair mutations, suggesting these cancers might be more susceptible to radiation-induced DNA damage. Since our results are constrained by the small sample size, further studies are needed to understand the relationship between PDAC with DNA repair mutations.

The oligometastatic state is an intermediate entity between localized cancer and widely metastatic disease associated with a limited tumor burden and improved prognosis relative to more disseminated disease. Within this state, there is restricted tumor metastatic capacity, and therefore metastasis-directed therapy has curative potential. Promising phase II trials have demonstrated the ability for aggressive local therapy to prolong survival for patients with oligometastatic disease. This has expanded the role of radiation therapy in metastatic disease from improving quality of life through symptom palliation to offering aggressive local therapy as potentially curative treatment. However, the oligometastatic state appears to be an umbrella term representing a multitude of diverse clinical scenarios with widely differing prognoses. This clinical observation, together with a burgeoning arsenal of survival-enhancing systemic therapies, has prompted renewed interest in improving the definition and characterization of the oligometastatic disease state to more accurately identify patients that will most benefit from aggressive local therapy.

Trastuzumab-deruxtecan (T-DXd) has demonstrated intracranial efficacy; however, safety and efficacy data remains limited with stereotactic radiosurgery (SRS). A multi-institutional review was performed with HER2+ or HER2-low metastatic breast cancer treated with T-DXd and SRS for active brain metastases. We identified 215 lesions treated over 48 SRS courses in 34 patients. Median follow up from T-DXd initiation was 13.9 months. The cumulative incidence of symptomatic radiation necrosis at 24 months per lesion was 2.1% and per patient 11%. The 12-month LC was 97%. HER2-low was associated with worse distant intracranial control (DIC) (adjusted HR 2.5, 95% CI 1.1-5.6, p = 0.03) and worse systemic progression free survival (PFS) (HR 4.1, 95% CI 1.6-10.7, p = 0.004). Concurrent SRS and T-DXd has excellent local control, without an increased risk of radiation necrosis. HER2-low disease is associated with worse systemic PFS and DIC with T-DXd compared to HER2+.

Background: EGFR-targeted therapy (ETT) and immune-checkpoint blockade (ICB) have shown promising results in treating NSCLC brain metastases (BM). However, little is known of their effect in treating leptomeningeal disease (LMD).Patients and Methods: This is a retrospective review of 80 patients diagnosed with NSCLC LMD from January 2014 to March 2021. Patients were grouped based on initial LMD treatment: radiotherapy (RT) alone, ETT, ICB, and intrathecal chemotherapy (ITC).Results: EGFR mutation was present in 22 patients (28%). Twenty patients had positive cytology in cerebrospinal fluid, while 60 patients were diagnosed based on MRI with clinical correlation. The RT alone group consisted primarily of whole brain radiation (n=20; 77%), stereotactic radiation (n=3; 12%), and palliative spine radiation (n=2; 7%). There were no significant differences amongst the treatment groups in age, performance status, or neurologic symptoms. Overall, the 6-month overall survival (OS) and craniospinal progression free survival (CS-PFS) were 35% and 24%, respectively. The 6-month OS for the ETT, ICB, ITC, and RT alone groups was 64%, 33%, 57%, and 29% respectively (log-rank p=0.026). The 6-month CS-PFS for the ETT, ICB, ITC, and RT alone groups was 43%, 33%, 29%, and 19% respectively (log-rank p=0.049). Upon univariate analysis, receipt of ETT compared to RT alone reached significance for OS (HR 0.35, p=0.006) and CS-PFS (HR 0.39, p=0.013).Conclusions: The prognosis for patients with NSCLC LMD remains poor overall. However, the receipt of ETT for patients with EGFR-positive disease was associated with improved outcomes.

PurposeA workflow/planning strategy delivering low-dose radiation therapy (LDRT) (1 Gy) to all polymetastatic diseases using conventional planning/delivery (Raystation/Halcyon = "conventional") and the AI-based Ethos online adaptive RT (oART) platform is developed/evaluated.MethodsUsing retrospective data for ten polymetastatic non-small cell lung cancer patients (5-52 lesions each) with PET/CTs, gross tumor volumes (GTVs) were delineated using PET standardized-uptake-value (SUV) thresholding. A 1 cm uniform expansion of GTVs to account for setup/contour uncertainty and organ motion-generated planning target volumes (PTVs). Dose optimization/calculation used the diagnostic CT from PET/CT. Dosimetric objectives were: Dmin,0.03cc >= 95% (acceptable variation (Delta) >= 90%), V100% >= 95% (Delta >= 90%), and D0.03cc <= 120% (Delta <= 125%). Additionally, online adaptation was simulated. When available, subsequent diagnostic CT was used to represent on-treatment CBCT. Otherwise, the CT from PET/CT used for initial planning was deformed to simulate clinically representative changes.ResultsAll initial plans generated, both for Raystation and Ethos, achieved clinical goals within acceptable variation. For all patients, Dmin,0.03cc >= 95%, V100% >= 95%, and D0.03cc <= 120% goals were achieved for 84.8%/99.5%, 97.7%/98.7%, 97.4%/92.3%, in conventional/Ethos plans, respectively. The ratio of 50% isodose volume to PTV volume (R50%), maximum dose at 2 cm from PTV (D2cm), and the ratio of the 100% isodose volume to PTV volume (conformity index) in Raystation/Ethos plans were 7.9/5.9; 102.3%/88.44%; and 0.99/1.01, respectively. In Ethos, online adapted plans maintained PTV coverage whereas scheduled plans often resulted in geographic misses due to changes in tumor size, patient position, and body habitus. The average total duration of the oART workflow was 26:15 (min:sec) ranging from 6:43 to 57:30. The duration of each oART workflow step as a function of a number of targets showed a low correlation coefficient for influencer generation and editing (R2 = 0.04 and 0.02, respectively) and high correlation coefficient for target generation, target editing and plan generation (R2 = 0.68, 0.63 and 0.69, respectively).ConclusionsThis study demonstrates feasibility of conventional planning/treatment with Raystation/Halcyon and highlights efficiency gains when utilizing semi-automated planning/online-adaptive treatment with Ethos for immunostimulatory LDRT conformally delivered to all sites of polymetastatic disease.

Upfront dual checkpoint blockade with immune checkpoint inhibitors (ICI) has demonstrated efficacy for treating melanoma brain metastases (MBM) in asymptomatic patients. Whether the combination of stereotactic radiosurgery (SRS) with dual checkpoint blockade improves outcomes over dual-checkpoint blockade alone is unknown. We evaluated clinical outcomes of patients with MBM receiving ICI with nivolumab and ipilimumab, with and without SRS. 49 patients with 158 MBM receiving nivolumab and ipilimumab for untreated MBM between 2015 and 2022 were identified at our institution. Patient and tumor characteristics including age, Karnofsky Performance Status (KPS), presence of symptoms, cancer history, MBM burden, and therapy course were recorded. Outcomes measured from initiation of MBM-directed therapy included overall survival (OS), local control (LC), and distant intracranial control (DIC). Time-to-event analysis was conducted with the Kaplan–Meier method. 25 patients with 74 MBM received ICI alone, and 24 patients with 84 MBM received concurrent SRS. Median follow-up was 24 months. No differences in age (p = 0.96), KPS (p = 0.85), presence of symptoms (p = 0.79), prior MBM (p = 0.68), prior MBM-directed surgery (p = 0.96) or SRS (p = 0.68), MBM size (p = 0.67), or MBM number (p = 0.94) were seen. There was a higher rate of nivolumab and ipilimumab course completion in the SRS group (54

Abstract BACKGROUND The current standard of care for limited resectable brain metastases is surgical resection followed by post-operative single-fraction stereotactic radiosurgery (sfSRS) to the resection cavity. Recent retrospective studies showed that pre-operative SRS improves tumor bed control and nodular leptomeningeal disease, but prospective data are lacking. We hypothesize that hypofractionated stereotactic radiosurgery (hfSRS) delivered pre-operatively to resectable brain metastases will result in improved durable local control. METHODS This is a single institution phase II study to assess time to local failure in patients with resectable brain metastases (BM) who elect for hfSRS followed by resection. The intervention is hfSRS delivered to a BM designated for resection. The planned target volume for hfSRS is the enhancing tumor + 1-2 mm margin expansion. The dose prescription is 9 Gy per fraction for a total of 3 consecutive daily fractions, to a total of 27 Gy. Surgical resection is planned within 7 days following completion of hfSRS. Other BMs, if present, are treated concurrently with either sfSRS or hfSRS. Key eligibility criteria include patients with at least 1 BM between 1 cm and 6 cm in maximal dimension not previously treated with SRS, deemed resectable by neurosurgery, and are asymptomatic from BM with or without steroids. The primary endpoint is time to local failure at the resection cavity. Other endpoints include time to leptomeningeal disease, changes in neurocognitive function, changes in quality of life (QoL), intracranial distant control, and overall survival. Time-to event outcomes will be analyzed with Kaplan-Meier curves. Changes in neurocognitive function and QoL metrics will be analyzed using descriptive statistics. This study is currently open with 34 patients enrolled at the time of submission. Clinical trial information: NCT05267587

Abstract BACKGROUND HER2+ leptomeningeal disease (LMD) has a poor prognosis with a high unmet clinical need. A previous phase I/II study revealed intrathecal (IT) trastuzumab to be well tolerated with improved overall survival (OS) compared to historical controls in HER2+ breast LMD. Radiotherapy can improve the flow of IT therapy through the cerebrospinal fluid (CSF) and provide symptomatic relief. The monoclonal antibody pertuzumab is used in conjunction with trastuzumab in the systemic management of HER2+ breast cancer. The phase I portion of the current study used a modified toxicity probability interval-2 (mTPI-2) design to determine 80 mg IT pertuzumab as the recommended phase II dose with a fixed dose of 80 mg IT trastuzumab. METHODS The study is designed as a prospective, single-arm, nonrandomized, open-label, phase II trial of radiation therapy followed by IT trastuzumab/pertuzumab in the management of HER2+ breast LMD. HER2+ LMD patients identified by magnetic resonance imaging (MRI) and/or CSF cytology, ≥18, with a life expectancy > 8 weeks are eligible. Treatment is initiated with radiotherapy, whole brain radiotherapy and/or focal brain/spine radiation followed by IT trastuzumab/pertuzumab. The primary objective of the phase II portion is to evaluate OS following IT trastuzumab/pertuzumab. Secondary objectives involve evaluating the response rate (leptomeningeal and parenchymal), and progression free survival (leptomeningeal and parenchymal). A single-arm two-stage trial is designed using the Restricted-Kwak-and-Jung’s Method. The primary endpoint is one-year OS. An interim analysis will be performed after 20 patients are enrolled with plans to enroll an additional 10 patients if criteria are met. This study is open with 14 patients enrolled at the time of submission. Clinical trial information: NCT04588545.

Purpose/Objective(s) We investigated the clinical outcomes of breast cancer brain metastases (BCBMs) treated with stereotactic radiosurgery (SRS) with or without systemic metastasis. Materials/Methods We retrospectively reviewed patients who underwent SRS to BCBMs from 2005-2020 from a prospectively maintained database. Patients were stratified by BCBMs with or without systemic metastasis on the date of SRS. The Kaplan-Meier method was used to calculate overall survival (OS), central nervous system progression free survival (CNS-PFS), and distant intracranial control (DIC) from the date of SRS. Prognostic variables were assessed using the Cox proportional hazards model. Results We identified 223 patients who underwent SRS to 819 BCBMs. Of the 223 patients, 179 (80%) had systemic metastasis with 722 BCBMs, while 44 (20%) had no systemic metastasis with 97 BCBMs on the date of SRS. No differences were noted in patients with or without systemic metastases with regards to histology (P = 0.93), subtype (P = 0.48), age (P = 0.32), or Karnofsky Performance Status (KPS) (P = 0.66). There was a trend towards patients without systemic metastases having fewer brain metastases (P = 0.07) and undergoing surgical resection of brain metastases (P<0.0001). Median follow-up from the date of SRS was 76.4 months (range = 1.3-131.0). In patients with or without systemic metastasis on the date of SRS, the median OS was 22 months (95% CI = 18.3-25.66) and 38.1 months (95% CI = 24.77-46.73) (P = 0.01), respectively. The median CNS-PFS was 8.6 months (95% CI = 7.83-10.37) and 13.0 months (95% CI = 6.93-19.1) (P = 0.078), respectively. The median DIC was 10.0 months (range = 8.4-11.7) and 13.7 months (range = 8.9-31.2) (P = 0.03), respectively. On univariate analysis, absence of systemic metastasis on the date of SRS was associated with improved survival (HR = 0.60, 95% CI = 0.41-0.89, P = 0.01). On multivariate analysis, the HER2 positive subtype was associated with improved survival (adjusted HR = 1.9, 95% CI = 1.04-3.29, P = 0.04). Of the 44 patients who had no systemic metastasis on the date of SRS, 29 patients (66%) received systemic treatment after SRS including CDK 4/6 inhibitors (n = 2; 7%), anti-PD-1 therapy (n = 4; 14%), chemotherapy (n = 7; 29%), HER2 targeted therapy (n = 12; 41%), and endocrine therapy (n = 8; 28%). A total of 14 of these 44 patients (31.8%) eventually developed systemic metastasis after SRS, most commonly to the bone (33%), liver (33%) and lung (27%). Conclusion BCBMs without systemic metastasis is a rare presentation but after SRS these patients were noted to have improved OS and DIC. Further investigation into the biology of patients with brain only breast metastatic disease is warranted.

Abstract BACKGROUND Sacituzumab-govitecan (SG) is an antibody drug conjugate (ADC) with activity against breast cancer brain metastases (BCBM). Efficacy and safety information of SG with stereotactic radiosurgery (SRS) is limited. Reports suggest SRS with ADCs may increase risk of symptomatic radiation necrosis (SRN). METHODS Patients treated with SG from 2020-2023 were reviewed. Patients had BCBM prior to SG and received SRS for active BM within 6 months of SG. Patients with prior leptomeningeal disease (LMD) were excluded. Kaplan-Meier method was used to estimate overall survival (OS), intracranial PFS (CNS-PFS), extracranial PFS (EC-PFS), local control (LC) and distant intracranial control (DIC). RESULTS: Between 2020-2023, 121 lesions were treated over 25 courses in 14 patients. Median follow up was 28.6 months. Median age was 60 (range 30-72). Five (36%) patients had neurologic symptoms, 7 (50%) were HR+. Eleven (9%) lesions received fractionated SRS (fSRS) and 110 (91%) single-fraction. Median dose for single fraction was 24 Gy (range 16-24), and for fSRS was 27 Gy (range 20-30) in median 5 fractions (range 3-5). Seventy-seven (63%) received SRS concurrent with SG. The median gross tumor volume (GTV) was 0.047 cc (range 0.007-17.4) and median planning target volume (PTV) was 0.14 cc (0.032-30). Six (5%) lesions were treated post-operatively. Median OS was 8.4 months (95% CI 4.2-not reached), with 12-month rate of 48%. Median CNS-PFS was 4.2 months (95% CI 1.9-6.3), with 12-month rate of 11%. Median EC-PFS was 4.4 months (95% CI 1.4-8.1), with 12-month rate of 17%. Twelve-month LC from SRS was 91%. Median DIC from SRS was 4.2 months (95% CI 2.1-7.5) with 12-month DIC rate of 12%. Two patients developed LMD. SRN occurred in 1 lesion, which received SRS prior to SG. CONCLUSIONS: SRS and SG demonstrated excellent local control and no increased risk of RN. Prospective investigation is warranted.

BACKGROUND AND PURPOSE:Neoadjuvant stereotactic radiosurgery (NaSRS) is an emerging treatment option for brain metastases (BrM) planned for resection. The aim of this study was to report on the efficacy and safety of NaSRS in an individual patient data pooled analysis. MATERIALS AND METHODS:Patients undergoing single- and multi-fraction NaSRS for BrM at nine institutions in five countries (Australia, Canada, South Korea, Switzerland and USA) were included. Eligibility criteria included BrM from any primary malignancy and no prior local therapy. The primary endpoint was a composite of local recurrence (LR), any grade radionecrosis (RN), and/or nodular leptomeningeal disease (nLMD). Secondary endpoints included these endpoints and Grade ≥ 2 RN. Endpoints were evaluated using cumulative incidence functions. RESULTS:NaSRS was delivered to 179 patients with 189 BrM. Median follow-up was 28.4 months. Primary malignancies included non-small cell lung carcinoma (44 %) and melanoma (17 %). The median BrM diameter was 29 mm (IQR 21-36 mm). Single- and multi-fraction NaSRS was utilised in 100 (53 %) and 89 BrM (47 %) respectively. The median single-fraction dose was 18 Gy (IQR 16-20 Gy). Multi-fraction doses included 24 Gy in three fractions (55 %) and 27 Gy in three fractions (25 %). The 12-month incidence for the composite endpoint was 8.0 %. The 12-month incidence of LR was 4.6 %, any grade RN was 3.6 %, Grade ≥ 2 RN was 1.8 % and nLMD was 1.2 %. CONCLUSION:Neoadjuvant SRS results in favourable rates of LR, RN and nLMD. We provide a global experience of this treatment approach with long-term data and the largest cohort of patients undergoing multi-fraction SRS.

Purpose/Objective(s) To report oncologic and safety outcomes of combined stereotactic radiosurgery (SRS) and the antibody drug conjugate (ADC) trastuzumab-deruxtecan (T-DXd) for the management of HER2+ breast cancer brain metastases (BM). Retrospective series have raised concerns over a potentially increased risk of radiation necrosis when combining ADCs and SRS. Materials/Methods Patients who received T-DXd at 2 institutions from 2021-2023 were identified. Patients were included if they received T-DXd and SRS for the management of active HER2+ BM, within 6 months before T-DXd initiation or after discontinuation. Patients with prior leptomeningeal disease (LMD) were excluded. HER2-low disease was defined as HER2 immunohistochemistry 1+ or 2+ without amplification on in-situ hybridization. The Kaplan-Meier (KM) method was used to estimate extracranial progression free survival (EC-PFS), overall survival (OS), local control (LC), and distant intracranial control (DIC). Adverse events and symptomatic radiation necrosis (RN) were collected and diagnosed after multidisciplinary discussion including available radiologic and clinical information, with the onset of new neurologic symptoms. Cox proportional hazards model was used to identify prognostic variables. Results Between 2021 and 2023, 31 patients received T-DXd and SRS over 48 courses to 171 lesions. Median follow up from T-DXd initiation was 21.2 months (range = 7.4-38.1). Median age at the time of T-DXd was 50 (range = 30-77). Twenty (65%) patients were hormone receptor positive. Sixteen (52%) patients were HER2-low. Seven (23%) patients had neurologic symptoms at the start of T-DXd. One hundred and nineteen (70%) lesions were treated with SRS and 52 (30%) with fractionated (f)SRS. Ninety-two (54%) lesions received concurrent T-DXd and SRS. Median RT dose was 20 Gy (range = 18-24) for lesions treated with SRS, and 24 Gy (range = 15-35) in a median of 3 fractions (range = 3-10) for fSRS. Five lesions were treated post-operatively. Median GTV size was 0.07 cc (range = 0.01-33.04) and median PTV size was 0.31 cc (range = 0.04-65.01). Median OS was 16 months (95% CI = 8-NR), with a 12-month OS rate of 54%. HER2-low disease was associated with decreased OS (HR = 3.3, 95% CI = 1.0-11.4, P = 0.04). Median EC-PFS was 5.2 months (95% CI = 3.0-8.7), and 12-month EC-PFS rate was 33% for HER2+ disease and 0% for HER2-low. HER2-low disease was associated with extracranial progression or death (HR = 4.4, 95% CI = 1.6-12.1, P = 0.004). Median DIC per treatment course was 5.7 months (95% CI = 2.5-8.9) with a 12-month DIC rate of 20%. DIC at 12-months for HER2+ patients was 32% compared to 7% for HER2-low (P = 0.1). The 12-month LC was 97%. RN was noted in 2 (1%) lesions. Four (13%) patients developed LMD. Conclusion The combination of SRS and T-DXd was found to have excellent local control and did not appear to increase the risk of radiation necrosis. HER2-low patients were found to have poorer OS and EC-PFS. Prospective investigation is warranted.

Purpose/Objective(s) Though it is known that leptomeningeal disease (LMD) portends a poor prognosis, little is known of the presentation patterns and outcomes for patients who present with LMD at the time of initial central nervous system (CNS) involvement. Materials/Methods A cohort of 959 patients diagnosed with CNS metastasis (BM) between 2014 and 2019 with primary breast cancer, melanoma, and non-small cell lung cancer (NSCLC) was queried to identify patients diagnosed with LMD at the time of initial CNS metastasis. Time to event outcomes, including overall survival (OS) and craniospinal progression-free survival (CS-PFS), were calculated from the date of LMD diagnosis using the Kaplan-Meier method. Results There were 71 (7.4%) patients who were diagnosed with LMD at the time of initial CNS metastasis, which included 172, 488, and 299 breast cancer, NSCLC, and melanoma patients, respectively. Patients with breast cancer (19%) were significantly more likely to present with LMD compared to those with NSCLC (5%) and melanoma (6%, P<0.001). The diagnosis of LMD was confirmed by positive cerebrospinal fluid cytology in 24 cases (34%), while the remaining cases (66%) were diagnosed based upon MRI of the neuroaxis and clinical correlation. The median age at LMD diagnosis was 61 years (range = 34-86 years). Patients with NSCLC were older at diagnosis (P = 0.001) and had a relatively shorter interval from initial cancer diagnosis (P<0.001). Most patients had intraparenchymal brain metastasis (76%) and extracranial systemic disease (73%) at the time of LMD diagnosis. Most patients received radiation therapy, including whole brain radiation therapy (90%), spinal radiation therapy (11%), or stereotactic radiosurgery (4%). Few patients received intrathecal therapy (N = 22), which included thiotepa (N = 8), methotrexate (N = 6), and trastuzumab (N = 3), amongst other agents. Few received immunotherapy (N = 9), most commonly including pembrolizumab (N = 6). Four patients received HER2-targeted therapy, 2 patients received EGFR-targeted therapy, and 2 patients received BRAF-targeted therapy. The median follow up was 1.6 months (range = 0.1-65 months). The 6-month OS and CS-PFS for the patients with LMD was 26% and 16%, respectively. There were no significant differences in outcomes by primary disease or the presence of concurrent brain metastases. Upon univariate analysis (UVA), only performance status, receipt of IT therapy, and receipt of HER2-targeted therapy predicted for improved OS. Upon univariate analysis (UVA), only performance status and receipt of HER2-targeted therapy predicted for improved CS-PFS. Conclusion The prognosis for patients who present with LMD at the time of initial CNS metastasis is poor overall. Breast cancer patients were the most likely to present with LMD at the time of their initial CNS metastases. Receipt of targeted therapy for patients with HER2+ breast cancer was associated with improved outcomes.