Intracranial Control Research Articles

RADT-15. INTRACRANIAL OUTCOMES OF DUAL IMMUNE-CHECKPOINT INHIBITION AND SRS COMBINATION IN PATIENTS WITH MELANOMA AND NSCLC BRAIN METASTASES

Abstract INTRODUCTION The intracranial benefit of offering dual immune checkpoint inhibition (D-ICPI) with ipilimumab and nivolumab to melanoma and non-small cell lung cancer (NSCLC) patients receiving SRS for brain metastases is unknown. We hypothesized that D-ICPI improves local control compared to SRS alone. METHODS Melanoma and NSCLC patients treated with SRS between 2016-2022 were evaluated. Patients were stratified by treatment with D-ICPI, single ICPI (S-ICPI), or SRS alone. Local recurrence (LR), intracranial progression (IP), and overall survival (OS) were estimated using competing risk and Kaplan-Meier analyses. IP included both local and distant intracranial recurrence. RESULTS 288 patients (44% melanoma, 56% NSCLC) with 1,704 brain metastases were included. 53% of patients had symptomatic metastases. Median follow up was 58.8 months. Patients were treated with D-ICPI (28%), S-ICPI (45%), or SRS alone (27%). 12-month local control rates with D-ICPI, S-ICPI, and SRS alone were 94.73% (95%CI:91.11-96.90%), 91.72% (89.29-93.64%), and 88.22% (84.06-91.41%). Only D-ICPI was significantly associated with reduced LR (p = 0.0032). 173 patients (60%) developed IP. The 12-month cumulative incidence of IP was 41.27% (95%CI:30.27-51.92%), 51.86% (42.78-60.19%), and 57.15% (44.98-67.59%) following D-ICPI, S-ICPI, and SRS alone. On competing risk analysis, only D-ICPI was significantly associated with reduced IP (p = 0.0408). On multivariate Cox regression, D-ICPI (HR:0.595,95%CI:0.373-0.951,p = 0.0300) and presentation with >10 BMs (2.492,1.68-3.725,p < .0001) remained significantly correlated with IP. Median OS following D-ICPI, S-ICPI, and SRS alone was 26.1 (95%CI:15.5-40.7), 21.5 (16.5-29.6) and 17.5 (11.3-23.8) months. Only D-ICPI trended toward improved OS (p = 0.0772). S-ICPI, fractionation, and timing of immunotherapy were not predictive of clinical outcomes. CONCLUSIONS The addition of D-ICPI for melanoma and NSCLC patients undergoing SRS is associated with improved local and intracranial control. This appears to be an effective strategy, including for symptomatic brain metastasis patients, regardless of fractionation or immunotherapy timing. Toxicity with this combination should be evaluated and balanced against clinical benefits.

RADT-44. LONG-TERM OUTCOMES WITH REDUCED-DOSE WHOLE BRAIN RADIOTHERAPY AND A STEREOTACTIC RADIOSURGERY BOOST FOR PRIMARY CNS LYMPHOMA

Abstract BACKGROUND Primary central nervous system lymphoma (PCNSL) is an aggressive diffuse large B-cell lymphoma. Treatment approaches are historically associated with neurotoxicity, particularly with high-dose whole-brain radiotherapy (WBRT). We hypothesized that reduced dose-WBRT (rd-WBRT) followed by a stereotactic radiosurgery (SRS) boost could provide durable disease control without significant adverse effects. METHODS We retrospectively reviewed PCNSL patients treated with rd-WBRT plus an SRS boost at Duke University between 2008 and 2021. Progression-free survival (PFS) and overall survival (OS) were estimated using competing risk and Kaplan Meier methods. RESULTS We identified 23 patients with pathologically confirmed PCNSL. Median age at diagnosis was 69 years (Q1Q3:52–74) and median KPS was 80 (Q1Q3:70–80). Median follow-up was 21 months. Median doses for rd-WBRT and SRS were 23.4Gy (Q1Q3:23.4–23.4) and 12Gy (Q1Q3:12–12.5), respectively. The cumulative incidence of intracranial progression at two years was 23% (95%CI:8-42). Six patients (26%) developed distant radiographic progression while two patients (9%) developed both distant and local progression. Ten patients (44%) were alive without progression at last follow-up. By Kaplan Meier estimate, the two-year overall survival was 69% (95%CI:46-84). There were no reported grade 3+ radiation-induced toxicities. CONCLUSIONS The combination of rd-WBRT with an SRS boost appears well-tolerated with durable intracranial control. This approach represents a treatment option for select patients, such as those with progressive or refractory disease. Further prospective studies are needed to validate these findings and determine whether this approach could be incorporated into consolidation strategies.

Treatment and survival of patients with small cell lung cancer and brain metastasis.

To elucidate treatment patterns and their outcomes in patients with small cell lung cancer (SCLC) and brain metastasis (BM). In this retrospective study, patients with SCLC and BM were stratified by treatment modality into three groups: those treated with systemic therapy only, those treated with stereotactic radiosurgery (SRS) and systemic therapy, and those treated with whole-brain radiotherapy (WBRT) and systemic therapy. The primary outcomes were overall survival (OS) and time to central nervous system progression (TTCP). The analysis included 149 patients. After BM diagnosis, 48 patients (32.2%) received systemic therapy alone, 33 received SRS with systemic therapy, and 68 received WBRT with systemic therapy. The median OS and TTCP were 7.2 months and 8.7 months, respectively. Patients receiving WBRT with systemic therapy exhibited better intracranial control, but not better OS, than did the other patients. Key prognostic factors affecting OS were age, BM lesion count, chemotherapy, and immunotherapy. Notably, the Eastern Cooperative Oncology Group performance status and BM lesion count significantly influenced intracranial control in patients treated with SRS and systemic therapy. Although WBRT combined with systemic therapy offer better intracranial control in patients with SCLC and BM, this approach is not superior to the other approaches in terms of OS benefits. Emerging systemic therapies, such as immunotherapy, may be used as alternative or adjunctive treatments for specific patient populations. Further studies are warranted to refine treatment selection.

Intracranial Control with Combined Dual Immune-Checkpoint Blockade and SRS for Melanoma and NSCLC Brain Metastases

It is unknown whether the use of dual immune-checkpoint inhibition (D-ICI) combined with stereotactic radiosurgery (SRS) affects local control of brain metastases (BMs). We sought to characterize the efficacy of SRS and D-ICI in patients with BMs in a large, single-institution cohort. Patients with melanoma and non-small cell lung cancer (NSCLC) BMs treated with SRS from January 1, 2016 to August 1, 2022 were evaluated. Patients were stratified by treatment with D-ICI versus single ICI (S-ICI). Concurrent ICI was defined as ICI given within four weeks of SRS. Local recurrence (LR), intracranial progression (IP), and overall survival (OS) were estimated using competing risk and Kaplan-Meier analyses. IP included both local and distant intracranial recurrence. One thousand seven hundred four SRS-treated BMs from 288 patients met inclusion criteria. 55% of patients were symptomatic from their BMs at presentation. Median age, KPS, number of lesions, and SRS courses were 64 (Q1Q3:56-70.5), 90 (80-90), 2 (1-4), and 1 (1-2), respectively. One hundred twenty-eight (44%) melanoma and 160 (56%) NSCLC patients were included. 82 (28.5%), 129 (44.8%), and 77 (26.7%) patients were treated with D-ICI, S-ICI, or SRS alone. Median SRS dose, fractions, and PTV were 20 (Q1Q3:20-25), 1 (1-5), and 0.3cc3 (0.1-1.2). The median follow-up was 14.3 months. One hundred twenty-seven (7.45%) BMs recurred post-SRS and the median time to LR was 4.8 months (Q1Q3:3.0-9.2). On competing risk analysis, LR was significantly reduced with D-ICI (HR: 0.452, p = 0.0024), but not with S-ICI (HR: 0.693, p = 0.0596) compared to SRS alone. The 1-year LR was 3.77% (95% CI = 2.19-6.00), 6.8% (5.19-8.70), and 8.96% (6.48-11.93) with D-ICI, S-ICI, and SRS alone. The median time to IP was 4.1 months (Q1Q3 = 2.9-9.5). On competing risk analysis, IP was significantly reduced with D-ICI (HR = 0.638, p = 0.031), but not with S-ICI (HR = 0.756, p = 0.106) compared to SRS alone. 1-year IP was 40.05% (95% CI = 29.14-50.70), 51.86% (42.78-60.19), and 58.49% (46.30-68.84) with D-ICI, S-ICI, and SRS alone. Concurrent delivery of D-ICI and SRS significantly reduced IP (HR = 0.463, p = 0.0071), whereas other combinations of timing and ICI did not reach significance. Median OS was 11.9 months after SRS. On Kaplan Meier analysis, OS was significantly improved with D-ICI (HR = 0.616, 95% CI = 0.412-0.923, p = 0.019), but not with S-ICI (HR = 0.877, 95% CI = 0.633-1.217, p = 0.433) compared to SRS alone. Hospitalizations (p = 0.021) and immune-related adverse events (irAEs) (p<0.001) were increased with D-ICI. Any grade radiation necrosis (RN) was also increased with D-ICI (p = 0.013), but neurologic adverse events were comparable across cohorts (p = 0.572). D-ICI combined with SRS was associated with improved local control, intracranial control, and overall survival compared to SRS alone, whereas S-ICI was not associated with an improvement in these outcomes. However, D-ICI was also associated with increased risks of irAEs and RN.

Upfront Osimertinib Alone vs. Osimertinib and Radiotherapy for the Treatment of EGFR-Positive NSCLC Brain Metastases: A Multi-Institutional Series

Given the increased brain penetrance of osimertinib, the role of upfront radiotherapy (RT) has been questioned for the management of patients with EGFR+ NSCLC brain metastases (BM). We conducted a multi-institutional review of patients with EGFR+ NSCLC treated with upfront osimertinib or osimertinib in combination with RT for new or progressing BM. Our multi-institutional analysis included 128 patients with 714 BM treated between 2013 and 2022. Two BM treatment groups were evaluated: (1) upfront osimertinib alone (n = 66) and (2) osimertinib + RT [whole brain radiation therapy or stereotactic/fractionated radiosurgery (SRS/FSRT)] prior or concurrently with osimertinib (n = 62)]; both groups began treatment within 2 months of BM diagnosis. Time-to-event analysis was conducted with the Kaplan-Meier (KM) method, and outcomes included intracranial control (IC) [both local and distant], intracranial progression free survival (IPFS), and overall survival (OS). A Cox proportional hazards model was utilized for multivariate analysis (MVA). Median follow-up from BM diagnosis was 33.9 months (0.13-76.2 months). No differences in age (p = 0.46), sex (p = 0.72), DS-GPA (p = 0.08), KPS (p = 0.57), number of BM (p = 0.19) or volume of BM (p = 0.45), RT dose (p = 0.45), number of systemic metastases (p = 0.88), and patients symptomatic at presentation (p = 1.0) were noted. Prior treatment of BM was more common in the osimertinib + RT group (50% osimertinib + RT and 27% osimertinib; p = 0.01). The 12-month KM rates for osimertinib vs osimertinib + RT groups for IC were 72% vs 73% (p = 0.33); IPFS 53% vs 66% (p = 0.007); and OS 65% vs 80% (p = 0.025). On MVA, higher KPS (p = 0.002) was associated with increased OS and no extracranial metastasis with increased OS (p = 0.01) and IPFS (p = 0.001). MVA showed no association between osimertinib vs osimertinib + RT for IC, IPFS, or OS. Of the 66 patients treated with upfront osimertinib, 18 patients (27%) with 31 lesions eventually required RT for intracranial progression with the majority 72% being treated with SRS/FSRT at median of 13.5 months (1-22 months) following the start of osimertinib. This study suggests that upfront osimertinib alone may provide sufficient intracranial control to allow RT to be deferred until further intracranial progression in select patients. Prospective trials are warranted to further guide treatment.

Hippocampal Avoidance Whole Brain Radiotherapy with Reduced Whole Brain Dose in Patients with Non-Small Cell Lung Cancer Brain Metastases

Hippocampal avoidance whole brain radiation (HA-WBRT) results in improved neurocognitive function (NCF) compared to standard WBRT, but > 50% of patients still experience NCF failure. We examined whether gentler fractionation of HA-WBRT with lower biologically effective dose (BED), typically delivering 30 Gy over 15 versus 10 fractions, may allow for better hippocampal sparing without impacting intracranial disease control in patients with non-small cell lung cancer (NSCLC). We conducted a retrospective study of patients with NSCLC receiving HA-WBRT between 2014-2022. Endpoints were distant brain failure free survival (DBFFS), local brain failure free survival (LBFFS), left and right hippocampal mean BED2 and BED21%. Kaplan-Meier survival analysis and Welch's t-test were performed. NCF outcomes were graded with CTCAEv5. The IRB approved this study. Sixty-nine consecutive patients treated with HA-WBRT were included, with median follow up of 51.2 weeks. Median age was 63 years and 29% had a targetable mutation. Thirty-six patients received standard HA-WBRT with median dose of 30 Gy (range 30-35 Gy) in 10 fractions (range 10-14). Thirty-three patients received reduced BED HA-WBRT, with median dose of 30 Gy (range 23-30) in 15 fractions (range 9-15) to the radiographically uninvolved brain. All patients in the reduced BED (RD) group had a simultaneous integrated boost (SIB) to gross disease (median 37.5 Gy (range 36-37.5 Gy)), while 18/36 in the standard dose (SD) group had an SIB (median 35 Gy (range 34-39 Gy)). There were no significant differences between SD and RD cohorts in age, systemic therapy use before WBRT or targetable mutations. There was no significant difference in median DBFFS of the SD [23.1 weeks (IQR 11.3-49.3)] and RD groups [40 weeks, (IQR 20.9-109.1)] (p = 0.27). There was also no difference in LBFFS of the SD (median 26.4 weeks, IQR 11.3-76.2) and RD groups (median 40 weeks, IQR (21-71.4) (p = 0.84). For the left and right hippocampi, both mean BED2 and D1% were significantly lower in the RD group (Table 1). Median cognitive disturbance was Grade (G) 0 (range 0-3) in both groups, with 4 G>2 events in the SD cohort vs. 3 in the RD cohort. In this single-institution cohort, HA-WBRT using a gentler fractionation with SIB was associated with improved hippocampal sparing without compromising intracranial control in patients with NSCLC. We suggest that further optimization of HA-WBRT dose and schedule may improve both intracranial control and NCF outcomes. This study is limited by its retrospective nature and potential selection bias. A phase II prospective study to test these concepts is ongoing.

Difference in Radiosensitivity Depending on the Presence and Absence of EGFR Mutations: Clinical and In Vitro Analyses

For stage IV non-small cell lung cancer (NSCLC), the treatment drug is selected based on the gene mutation status. However, the dose or field of radiation therapy is not change based on the genetic status. We evaluated both clinical and in vitro data, showing that the presence or absence of epidermal growth factor receptor (EGFR) mutations affects radiosensitivity in patients with brain metastases (BM) from NSCLC. Patients with BM from NSCLC who received whole brain radiotherapy (WBRT) were enrolled in this study. Patient characteristics are shown in the Table. EGFR mutations were observed in 13 (31.0%) patients. The prescribed dose was 30 Gy in 10 fractions (85.7%). The A549, VMRC-LCD, NCI-H1975, and HCC4006 cell lines were used for the in vitro study. EGFR mutation was negative in A549 and VMRC-LCD and positive in NCI-H1975 (exon21) and HCC4006 (exon19). After irradiation of these cell lines with 0, 2, 4, and 8 Gy, a colony formation assay was performed. DNA double-strand breaks (DSBs) were assessed 30 min and 24 h after 4 Gy irradiation using γH2AX. The median follow-up period was 4 months (range, 1-35). Intracranial recurrence was observed in 14 (33.3%) patients during the follow-up period. Thirty-nine (92.9%) patients died during the follow-up period. Patients with EGFR mutation-positive tumors had significantly better intracranial control rates than those with EGFR mutation-negative tumors (p = 0.0213). A similar tendency was observed in the analysis conducted, except for the cases in which tyrosine kinase inhibitor (TKI) was administered after WBRT. In the EGFR mutation-positive group, no significant difference was observed between patients who received TKI after WBRT and those who did not (p = 0.527). In the colony formation assay, EGFR mutation-positive cell lines showed a significantly lower number of colonies formed after irradiation with 2 and 4 Gy than mutation-negative cell lines (p = 0.00018 and 0.0000291, respectively). EGFR mutation-positive cell lines had significantly more DNA-DSBs remaining 24 h after irradiation than mutation-negative cell lines (p = 0.0000000312). Our data suggest that patients with EGFR mutation-positive NSCLC are more radiosensitive than those with negative EGFR mutations.

A Survival Score for Patients Treated with Whole-Brain Radiotherapy plus Simultaneous Integrated Boost for Brain Metastases

Different types of radiotherapy (RT) are used for brain metastases including whole-brain RT (WBRT) and local therapies (radiosurgery, fractionated stereotactic RT). WBRT plus simultaneous integrated boost (WBRT+SIB) is another treatment option that was reported to improve intracranial control and overall survival (OS) when compared to WBRT alone. This study aimed to create a score to identify patients who may not benefit from this approach due to poor OS. In 128 patients treated with WBRT+SIB for brain metastases (2014-2021), year of RT, interval from tumor diagnosis to RT, WBRT+SIB regimen [(14 x (2.5 + 0.5) Gy vs. 18 x (2.0 + 0.5) Gy], pre-RT systemic treatment, age, gender, performance score, primary tumor type, N lesions, and extracranial metastases were retrospectively evaluated for OS. Univariate analyses (UVA) were performed with Kaplan-Meier method and log-rank test. Factors that showed significant (p<0.05), a strong trend (p<0.07) or a trend (p<0.14) in UVA were included in a Cox proportional hazards model (MVA). To create the appropriate OS score, three models were created, one including factors significant on MVA, a second including factors with p<0.07 on UVA, and a third one including factors with p<0.14 on UVA. For each factor, 6-month OS rates (%) were divided by 10 and resulting points were added for each patient. Based on patient scores, three prognostic groups were designed for each model. Positive predictive values (PPV) of correct prediction of death ≤6 and OS ≥6 months were calculated. On UVA, KPS >80 (p<0.001) and ≤3 lesions (p = 0.006) were associated with OS, age ≤64 years (p = 0.061) showed a strong trend, and no extracranial metastases (p = 0.128) a trend. On MVA, KPS (HR: 0.40, 95% CI: 0.27-0.61, p<0.001) and N lesions (HR: 1.81, 95% CI: 1.23-2.65, p = 0.002) were significant; age (HR: 1.12, 05% CI: 0-76-1.66, p = 0.57) and extracranial metastases (HR: 1.19, 95% CI: 0.79-1.78, p = 0.40) were not significant. In Model 1 (including only KPS and N lesions), groups were 5, 6-8 and 9 points with 6-month OS rates of 15%, 38% and 57%, respectively. PPVs to predict death and OS were 85% and 57%, respectively. In Model 2 (KPS, N lesions, age), groups were 8, 9-12 and 13 points with 6-month OS rates of 17%, 33% and 75%, respectively. PPVs were 83% and 75%, respectively. In Model 3 (KPS, N lesions, age, extracranial metastases), groups were 11, 12-16 and 17 points with 6-month OS rates of 14%, 34% and 78%, respectively. PPVs were 86% and 78%, respectively. All three models achieved high accuracy regarding prediction of death ≤6 months and can help identify patients who may not be ideal candidates for WBRT+SIB. For prediction of OS ≥6 months, Models 2 and 3 were superior. Since differences between Models 2 and 3 were marginal and correct identification of extracranial metastases (Model 3) may require extensive staging, Model 2 appears preferable.

Clinical Verification of a Nomogram Model for Prediction of Brain Metastases in Patients with pⅢA-N2 Non-Small Cell Lung Cancer

Brain metastasis is one of the most common failure patterns of pⅢA-N2 non-small cell lung cancer (NSCLC) after complete resection. Prophylactic Cranial Irradiation (PCI) can improve intracranial control but not overall survival. Thus, it is particularly important to identify risk factors that are associated with brain metastasis and subsequently provide instructions for selecting patients who will optimally benefit from PCI. We have reported a nomogram model which was established based on the condition of histology, bronchial invasion, perineural invasion, and adjuvant chemotherapy, through which we can predict high risk brain metastases in patients with pⅢA-N2 NSCLC. The purpose of this study is to verify the accuracy of the nomogram model by using new cases information. Between January 1, 2015 and December 31, 2019, patients of pⅢA-N2 NSCLC were retrospectively analyzed, to verify the consistency between actual and predictive brain metastases. The verification group was divided into two groups according to the years when genetic testing has been widely used in clinic (group1:2015-2016, group2:2017-2019). ROC curves and calibration curves were chosen for validation. A total of 770 patients were enrolled in our retrospective study (group1:294 patients, group2: 476patients). The 1-, 3- and 5-year survival rates were 97.2%, 76.5%, 63.2% in group1, and 95.8%, 84.5%, 76.9% in group2, respectively. The 1-, 3- and 5-year brain metastasis rates were 7.9%, 19.7%, 25.8%, and 5.4%, 14.5%, 26.3% in group2, respectively. The AUC were 0.74 (95% CI:0.72 - 0.76) in group1, and 0.71(95% CI:0.70 - 0.73) in group 2.The 1.3.5-year calibration curves of the two groups show that the prediction is in good agreement with the actual observation. The nomogram model can predict brain metastases high risk patients with pⅢA-N2 NSCLC. Whether gene test or not, it can be used as a basis to screening out patients of high-risk brain metastases in future clinical trials for PCI.

Feasibility of Cognitive-Sparing Stereotactic Radiosurgery for Brain Metastases: Initial Report of Phase II COG-SRS Trial

Radiotherapy at high doses leads to white matter (WM) and hippocampal injury which can cause cognitive decline. We designed the first, to our knowledge, evidence-based cognitive sparing brain SRS trial for patients with limited brain metastases. In this report we analyze feasibility of cognitive-sparing SRS, utilizing dose constraints for eloquent WM tracts and bilateral hippocampi. This is a single-institution phase II NCI-funded clinical trial (NCT04343157) of cognitive-sparing brain SRS; eloquent regions of interest (ROI) and associated cognitive domains are outlined in Table 1. Patients underwent high-resolution quantitative diffusion and volumetric MRI at baseline and post-SRS follow-up. Comprehensive neurocognitive assessment was performed at baseline and 3 months post-SRS by a neuropsychologist evaluating different neurocognitive domains (Table 1). Clinical processing/workflow was largely automated with robust, validated segmentation tools of eloquent WM tracts and the hippocampi. Single fraction dose constraints to WM tracts were 12 Gy Dmax and 8.4 Gy to hippocampi with 3 and 5 fraction equivalent doses, based on our prior NTCP studies. Patient accrual, follow up imaging and neurocognitive testing is still active. To date, n = 59 patients and 114 lesions have been treated with cognitive-sparing Linac-based SRS on trial. Median age is 63 years. Lung cancer was the most common primary (35.6%), along with breast cancer (23.7%) and melanoma (15.3%). Patients had 1-4 brain metastases; median prescription dose was 24 Gy/1, 27 Gy/3, or 30 Gy/5 depending on target volume. Most patients were treated < 7 business days from MRI. Cognitive endpoints have been collected on 89.5% of patients. Cognitive sparing constraints were met in 79.3% of plans while maintaining standard clinical SRS plan indices and coverage benchmarks. 38.9% of the plans that failed to meet the Dmax constraint kept D0.03cc under constraints. Plans going over constraints had tumors overlying or within 1 mm of eloquent ROIs. Local control for treated lesions at 6 months was 97.9% and 95.7% at 12 months. Distant intracranial control was 68.1% at 6 and 12 months. Median OS was 18 months. Cognitive-sparing SRS treatment planning was successfully implemented for the majority of treated lesions with excellent local control. Mitigation of damage to eloquent structures has potential to further reduce cognitive decline after SRS. Full neurocognitive outcomes will be reported after accrual and testing are complete.

Factors associated with radiation necrosis and intracranial control in patients treated with immune checkpoint inhibitors and stereotactic radiotherapy

Background and PurposeEmerging data suggest immune checkpoint inhibitors (ICI) and stereotactic radiosurgery (SRS) or radiotherapy (SRT) may work synergistically, potentially increasing both efficacy and toxicity. This manuscript characterizes factors associated with intracranial control and radiation necrosis in this group. Materials and MethodsAll patients had non-small cell lung cancer, renal cell carcinoma, or melanoma and were treated from 2013 to 2021 at two institutions with ICI and SRS/SRT. Univariate and multivariate analysis were used to analyze factors associated with local failure (LF) and grade 2+ (G2 + ) radiation necrosis. ResultsThere were 179 patients with 549 metastases. The median follow up from SRS/SRT was 14.7 months and the median tumor size was 7 mm (46 tumors ≥ 20 mm). Rates of LF and G2 + radiation necrosis per metastasis were 5.8% (32/549) and 6.9% (38/549), respectively. LF rates for ICI +/- 1 month from time of radiation versus not were 3% (8/264) and 8% (24/285) (p = 0.01), respectively. G2 + radiation necrosis rates for PD-L1 ≥ 50% versus < 50% were 17% (11/65) and 3% (5/203) (p=<0.001), respectively. PD-L1 ≥ 50% remained significantly associated with G2 + radiation necrosis on multivariate analysis (p = 0.03). Rates of intracranial failure were 54% (80/147) and 17% (4/23) (p = 0.001) for those without and with G2 + radiation necrosis, respectively. ConclusionsPD-L1 expression (≥50%) may be associated with higher rates of G2 + radiation necrosis, and there may be improved intracranial control following the development of radiation necrosis. Administration of ICIs with SRS/SRT is overall safe, and there may be some local control benefit to delivering these concurrently.

The Safety and Efficacy of Concurrent Immune Checkpoint Blockade and Stereotactic Radiosurgery Therapy with Practitioner and Researcher Recommendations

Immune checkpoint inhibitors (ICIs) have shown growing promise in the treatment of brain metastases, especially combined with stereotactic radiosurgery (SRS). The combination of ICIs with SRS has been studied for efficacy as well as increasing radiation necrosis risks. In this review, we compare clinical outcomes of radiation necrosis, intracranial control, and overall survival between patients with brain metastases treated with either SRS alone or SRS-ICI combination therapy. A literature search of PubMed, Scopus, Embase, Web of Science, and Cochrane was performed in May 2023 for articles comparing the safety and efficacy of SRS/ICI versus SRS-alone for treating brain metastases. The search criteria identified 1961 articles, of which 48 met inclusion criteria. Combination therapy with SRS and ICI does not lead to significant increases in incidence of radiation necrosis either radiographically or symptomatically. Overall, no difference was found in intracranial control between SRS-alone and SRS-ICI combination therapy. Combination therapy is associated with increased median overall survival. Notably, some comparative studies observed decreased neurologic deaths, challenging presumptions that improved survival is due to greater systemic control. The literature supports SRS-ICI administration within 4 weeks of another for survival but remains inconclusive, requiring further study for other outcome measures. Combination SRS-ICI therapy is associated with significant overall survival benefit for patients with brain metastases without significantly increasing radiation necrosis risks compared to SRS alone. Although intracranial control rates appear to be similar between the 2 groups, timing of treatment delivery may improve control rates and demands further study attention.

P11.72.A INTRACRANIAL CONTROL OF BRAIN METASTASES IN PATIENTS TREATED WITH RADIOTHERAPY PLUS CHEMOTHERAPY, IMMUNOTHERAPY, TARGETED THERAPY AND IMMUNOCHEMOTHERAPY OR TARGETED THERAPY WITH CHEMOTHERAPY

Abstract BACKGROUND Brain metastases (BM) are the most common intracranial malignancy. For many years, patients with BM were excluded from clinical trials of systemic cancer therapies based on their presumed bad prognosis, which results in a therapeutic nihilism as soon a BM is diagnosed. With the development of immunotherapies and targeted therapies as systemic cancer therapy, we questioned if there is a difference in intracranial response, regardless of the indicated radiotherapy (RT) for the BM. MATERIAL AND METHODS 67 patients older than 18 years, with multiple BM treated between December 2016 and October 2021, with in total 237 metastases were analyzed. The volume of each metastasis on MRI was calculated at the time of appearance and every 3 months thereafter. The primary outcome was intracranial control according to RANO-BM at 6 months. Because of missing data (MRI at 6 months), 92 metastases had to be excluded, leaving 145 for the analysis. Patients were divided into groups (RT+chemotherapy - CT-group, RT+immunotherapy/targeted therapy - IT/TT-group, RT+chemo-immunotherapy/targeted therapy - CT+IT/TT-group). The second outcome measure was time to progression of metastases; for this outcome 183 metastases could be analyzed. For statistical analysis chi-square test and Tarone-Ware test were performed. RESULTS In the CT-group (n=40)10% (n=4) had a progressive disease (PD), 33% (n=13) had a partial response (PR), 57 % (n=23) complete response (CR), and no one stable disease (SD). In the CT+IT/TT-group (n=28) 14% (n=4) had PD, 11% (n=3) SD, 11% (n=3) PR and 64% (n=18) CR. In the IT/TT-group (n=78) 14% (n=11) had PD, 4% (n=3) SD, 26% (n=20) PR and 56% (n=44) CR. The p values for difference in intracranial control were between CT-group/IT/TT-group 0,81 and between CT-group/CT+IT/TT-group 0,58. Patients in the IT/TT-group had a better outcome if a targetable mutation was present (p=0,005). The median time to progression (days) was 474 ± 30 for the CT-group; 581 ± 50 for the IT/TT- group and 360 ± 35 for the CT+IT/TT-group. Tarone-Ware test showed a trend in the progression distributions between the 3 groups favoring the IT/TT-group p= 0,082. CONCLUSION Intracranial response could be achieved in all analyzed subgroups without statistically significant difference. Against the background of this data, the therapeutic nihilism due to the presumed bad prognosis is not justified. A subgroup analysis of the IT /TT group showed a significantly better outcome for patients who had a matching gene. Patients who received immunotherapy or targeted therapies showed a trend towards later progression than chemotherapy or combination therapy. Larger patient cohorts should be investigated to see if this trend could be confirmed.

Stereotactic radiosurgery and anti-PD-1 + CTLA-4 therapy, anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors, BRAF inhibitors, or conventional chemotherapy for the management of melanoma brain metastases

BackgroundImmunotherapy and targeted BRAF/MEK inhibitors (i) have revolutionised the systemic management of advanced melanoma. Given the role of stereotactic radiosurgery (SRS) in the local management of brain metastases, we sought to evaluate clinical outcomes in patients with melanoma brain metastases (MBM) treated with SRS and various systemic therapies. MethodsPatients were included if MBM were diagnosed and treated with SRS within 3 months of receiving anti-PD-1+CTLA-4 therapy, anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK-i, BRAF-i, or conventional chemotherapy. Comparisons between groups were made for overall survival (OS), distant MBM control, local MBM, systemic progression-free survival (sPFS), and neurotoxicity. ResultsIn total, 257 patients with 1048 MBM treated over 368 SRS sessions between 2011 and 2020 were identified. On MVA, treatment with anti-PD1+anti-CTLA-4, anti-PD-1, and BRAF/MEK-i improved distant intracranial control over conventional chemotherapy. No significant differences were noted in local control (LC) between groups (p = 0.78). Kaplan–Meier OS at 12 months for anti-PD-1 + CTLA-4 therapy, anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK-i, BRAF-i, and conventional chemotherapy was 68%, 59%, 45%, 62%, 21%, and 15%, respectively (p = <0.0001). The sPFS rates at 12 months were 57%, 53%, 42%, 45%, 14%, and 6% (p = <0.0001). No significant differences were noted in rates of radiation necrosis (p = 0.93). ConclusionsThis is among the largest series evaluating MBM treated with SRS and various systemic therapy regimens. Our analysis noted significant differences in OS, distant MBM control, and sPFS by systemic therapy. No differences in LC or radiation necrosis risk were noted.

LMAP-15 INTRACRANIAL RADIOTHERAPY WITH TUCATINIB FOR BRAIN METASTASIS FROM HER2-POSITIVE BREAST CANCER: A SINGLE-INSTITUTION SERIES

Abstract BACKGROUND Tucatinib, a HER-2 TKI, has demonstrated intracranial efficacy in the HER2CLIMB study. Treatment of brain metastases frequently includes stereotactic radiosurgery (SRS) or whole brain radiotherapy (WBRT); however, HER2CLIMB did not detail outcomes with RT. METHODS Patients who received tucatinib at our institution from 2020-2022 were identified. Patients who had brain metastases and received intracranial RT within 6 months of receiving tucatinib were included. Patients with history of prior leptomeningeal disease (LMD) were excluded. The Kaplan-Meier (KM) method was used to estimate intracranial failure (ICF), overall survival (OS), and local control (LC). Adverse events and details regarding symptomatic radionecrosis were collected. RESULTS Between 2020 and 2022, 50 patients were treated with tucatinib. Forty patients had diagnosed brain metastasis and received intracranial RT. Median age at tucatinib start was 51 years (range: 33-83). All patients were HER-2+, 47.5% were HR+. Fifty-four separate RT courses were delivered within 6 months of tucatinib, including 45 courses of stereotactic RT (83%) and 9 (17%) WBRT. Twenty-three patients (57.5%) underwent concurrent tucatinib and intracranial RT, defined as RT within 2 months of tucatinib initiation. Median follow up for surviving patients was 18.9 months. Fifteen patients (37%) died at the time of analysis. Median OS was 25.1 months with 24-month KM OS of 52%. Median time to ICF was 12.5 months with 24-month KM ICF of 48%. At the time of ICF, 7 patients (17.5%) developed LMD. In total, 132 discrete lesions were treated with SRS. Ten lesions (7.5%) underwent local failure, with 24-month KM LC of 82%. Three patients (9.1%) undergoing SRS developed symptomatic radionecrosis; all completely resolved with dexamethasone. DISCUSSION In this first series reporting outcomes with RT and tucatinib, no evidence of excess toxicity was noted. Intracranial control appears favorable compared to previous reports. Concurrent RT with tucatinib should be assessed prospectively.

SDPS-09 MIXED RESPONSE OF BRAIN METASTASES TREATED WITH OSIMERTINIB PREDICTS INFERIOR SURVIVAL OUTCOMES: AN ARTIFICIAL INTELLIGENCE-BASED LESION-LEVEL ASSESSMENT FOR CRANIAL CONTROL OF EGFRMUTANT NONSMALL CELL LUNG CANCER

Abstract Osimertinib has been found to be effective for intracranial control in patients with metastatic EGFR-mutant non-small cell lung cancer (NSCLC). However, the lesion-level response of brain metastases to osimertinib has not been thoroughly evaluated. This retrospective study included 73 patients with EGFR-mutant NSCLC and brain metastases who were treated with osimertinib at a single institution from 2016 to 2021. Patients with the leptomeningeal disease were excluded. The study used an FDA-approved brain tumor management artificial intelligence (AI) platform, VBrain, to identify, track, and measure brain metastases on the baseline and follow-up MRI brain scans. Mixed response (MiR) was defined as the occurrence of progressive or new lesions along with synchronous responsive shrinking intracranial lesions at the first follow-up scan. K-means grouping was used to partition patients into two clusters according to their response heterogeneity. With a median follow-up of 23.8 months, a high MiR score (higher than 103%, n=25) was associated with worse cranial-progression-free survival (3.2 vs. 17.9 months, p&amp;lt;0.0001) and significantly inferior overall survival (12.4 vs. 30.1 months, HR=2.35, p=0.016). This poses a similar negative impact on the survivals of 18 patients with pure RANO-BM progression (HR=2.52, p=0.025). Eight patients had the highest MiR score (MiRmax), in whom synchronous new lesions and completely responsive tumors were observed. In a multivariate Cox proportional-hazards regression involving performance status, extracranial failure, tumor volume, lesion number, and RANO-BM classification as variables, MiRmax remained an independent prognosticator for inferior survival (HR=5.20, 95%CI; 2.21–12.23, p=0.002). Our study demonstrates that MiR in brain metastases from EGFR-mutant NSCLC treated with osimertinib is associated with inferior survival outcomes and a higher risk of local progression. Lesion-level response assessment using AI may provide important prognostic information and aid in treatment decision-making for these patients.

LMAP-17 FEASIBILITY OF COGNITIVE-SPARING STEREOTACTIC RADIOSURGERY FOR BRAIN METASTASES: INITIAL REPORT OF PHASE II COG-SRS TRIAL

Abstract Radiotherapy at high doses leads to white matter (WM) and hippocampal injury which can cause cognitive decline. We designed the first, to our knowledge, evidence-based cognitive-sparing brain SRS trial for patients with limited brain metastases. In this report we analyze feasibility of cognitive-sparing SRS, utilizing dose constraints for eloquent WM tracts and bilateral hippocampi. Patients underwent high-resolution quantitative diffusion and volumetric MRI at baseline and post-SRS follow-up. Comprehensive neurocognitive assessment was performed at baseline and 3 months post-SRS evaluating multiple neurocognitive domains. Clinical workflow was largely automated with robust, validated segmentation of eloquent WM tracts and the hippocampi. Single fraction max dose constraints to WM tracts and hippocampi were 12 Gy and 8.4 Gy, respectively, with 3 and 5 fraction equivalent doses based on our prior NTCP studies. Patient accrual, follow-up imaging and neurocognitive testing is still active. To date, 59 patients and 114 lesions have been treated with cognitive-sparing linac-based SRS on trial. Median age is 63 years. Patients had 1-4 brain metastases; median prescription dose was 24Gy/1, 27Gy/3, or 30Gy/5 depending on target volume. Most patients were treated &amp;lt;7 business days from MRI. Cognitive endpoints have been collected on 89.5% of patients. Cognitive-sparing constraints were met in 79.3% of plans while maintaining standard clinical SRS plan indices and coverage benchmarks. Plans going over constraints had tumors overlying or within 1 mm of eloquent ROIs. Local control for treated lesions at 6 months was 97.9% and 95.7% at 12 months. Distant intracranial control was 68.1% at 6 and 12 months. Median OS was 18 months. Cognitive-sparing SRS treatment planning was successfully implemented for the majority of treated lesions with excellent local control. Mitigation of damage to eloquent structures has potential to further reduce cognitive decline after SRS. Full neurocognitive outcomes will be reported after accrual and testing are complete.

Phase I/II study of stereotactic radiosurgery with concurrent olaparib followed by adjuvant durvalumab and physician’s choice systemic therapy in patients with breast cancer brain metastases.

TPS1133 Background: Despite progress in the treatment of brain metastasis for HER2+ breast cancer, outcomes for patients with HER2-negative breast cancer brain metastases remain poor. Current standard of care consists of local therapies, including surgery and radiotherapy, followed by systemic therapy. Preclinical studies show inhibitors of poly(ADP-ribose) polymerase (PARP) are effective in combination with radiation therapy as a DNA damage response inhibitor. Triple-negative breast cancer (TNBC) has higher rates of homologous recombination deficiency compared to other breast cancer subtypes, and together with HER2-negative, BRCA-mutated breast cancer would be particularly sensitive to PARP inhibition. PARP inhibition has also demonstrated promising efficacy combined with immunotherapy in patients with germline BRCA-mutant and metastatic TNBC in clinical trials (MEDIOLA, TOPACIO). In addition, immunotherapy with stereotactic radiosurgery (SRS) is associated with favorable intracranial control and survival in patients with brain metastases. We hypothesize that this biologically-driven combination will enhance local control of SRS-treated brain metastases through synergy with PARP inhibition, while controlling micrometastatic disease in the brain and extracranial sites via potentiation of the immune response. Methods: We are conducting a multi-institution, Phase I/II trial of SRS plus olaparib, followed by durvalumab (with physician’s choice systemic therapy), for patients with TNBC (any BRCA status) or HER2-negative with BRCA-mutated (germline or somatic) breast cancer brain metastases [NCT04711824]. A total of 41 patients are planned for enrollment at 8 sites. The primary objectives are to evaluate safety and tolerability (Phase I) and determine intracranial disease control at 6 months (Phase II) of this treatment combination. Secondary objectives include determining clinical activity via intracranial and global progression-free survival, overall survival, and intracranial and extracranial response rate. Exploratory objectives will assess potential biomarkers of treatment response, including changes in circulating tumor cells and DNA in blood and cerebrospinal fluid, germline and tumor mutations in DNA repair pathway genes, and PD-L1 expression, as well as quality of life and patient-reported outcomes. A surgical sub-study (n=5) will evaluate olaparib concentration/distribution in resected brain metastases. As of January 2023, cohort 1 of phase I has been completed without dose-limiting toxicity. Clinical trial information: NCT04711824 .

PO-1117 HER2 expression correlated with intracranial control and prognosis of breast cancer brain metastases

PO-1117 HER2 expression correlated with intracranial control and prognosis of breast cancer brain metastases

Long duration of immunotherapy before radiosurgery might improve intracranial control of melanoma brain metastases

PurposeDespite significant advances that have been made in management of metastatic melanoma with immune checkpoint therapy, optimal timing of combination immune checkpoint therapy and stereotactic radiosurgery is unknown. We have reported toxicity and efficiency outcomes of patients treated with concurrent immune checkpoint therapy and stereotactic radiosurgery. Patients and methodsFrom January 2014 to December 2016, we analyzed 62 consecutive patients presenting 296 melanoma brain metastases, treated with gamma-knife and receiving concurrent immune checkpoint therapy with anti-CTLA4 or anti-PD1 within the 12 weeks of SRS procedure. Median follow-up time was 18 months (mo) (13–22). Minimal median dose delivered was 18 gray (Gy), with a median volume per lesion of 0.219 cm3. ResultsThe 1-year control rate per irradiated lesion was 89% (CI 95%: 80.41–98.97). Twenty-seven patients (43.5%) developed distant brain metastases after a median time of 7.6 months (CI 95% 1.8–13.3) after gamma-knife. In multivariate analysis, positive predictive factors for intracranial tumor control were: delay since the initiation of immunotherapy exceeding 2 months before gamma-knife procedure (P=0.003) and use of anti-PD1 (P=0.006). Median overall survival (OS) was 14 months (CI 95%: 11–NR). Total irradiated tumor volume<2.1 cm3 was a positive predictive factor for overall survival (P=0.003). Ten patients (16.13%) had adverse events following irradiation, with four grade≥3. Predictive factors of all grade toxicity were: female gender (P=0.001) and previous treatment with MAPK (P=0.05). ConclusionA long duration of immune checkpoint therapy before stereotactic radiosurgery might improve intracranial tumor control, but this relationship and its ideal timing need to be assessed in prospective trials.