CNS Progression-free Survival Research Articles

Tyrosine Kinase Inhibitors With and Without Up-Front Stereotactic Radiosurgery for Brain Metastases From EGFR and ALK Oncogene-Driven Non-Small Cell Lung Cancer (TURBO-NSCLC).

Newer-generation tyrosine kinase inhibitors (TKIs) for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements have demonstrated high CNS activity. The optimal use of up-front stereotactic radiosurgery (SRS) for brain metastases (BM) in patients eligible for CNS-penetrant TKIs is controversial, and data to guide patient management are limited. Data on TKI-naïve patients with EGFR- and ALK-driven NSCLC with BM treated with CNS-penetrant TKIs with and without up-front SRS were retrospectively collected from seven academic centers in the United States. Time-to-CNS progression and overall survival (OS) were analyzed, with multivariable adjustment in Fine & Gray and Cox proportional hazards models for clinically relevant factors. From 2013 to 2022, 317 patients were identified (200 TKI-only and 117 TKI + SRS). Two hundred fifty (79%) and 61 (19%) patients received osimertinib and alectinib, respectively. Patients receiving TKI + SRS were more likely to have BM ≥1 cm (P < .001) and neurologic symptoms (P < .001) at presentation. Median OS was similar between the TKI and TKI + SRS groups (median 41 v 40 months, respectively; P = .5). On multivariable analysis, TKI + SRS was associated with a significant improvement in time-to-CNS progression (hazard ratio [HR], 0.63 [95% CI, 0.42 to 0.96]; P = .033). Local CNS control was significantly improved with TKI + SRS (HR, 0.30 [95% CI, 0.16 to 0.55]; P < .001), whereas no significant differences were observed in distant CNS control. Subgroup analyses demonstrated a greater benefit from TKI + SRS in patients with BM ≥1 cm in diameter for time-to-CNS progression and CNS progression-free survival. The addition of up-front SRS to CNS-penetrant TKI improved time-to-CNS progression and local CNS control, but not OS, in patients with BM from EGFR- and ALK-driven NSCLC. Patients with larger BM (≥1 cm) may benefit the most from up-front SRS.

Prognostic Implications of Small Cell Lung Cancer Transcriptional Subtyping for CNS Metastases.

Small cell lung cancer (SCLC) often metastasizes to the brain and has poor prognosis. SCLC subtypes distinguished by expressing transcriptional factors ASCL1 or NEUROD1 have been identified. This study investigates the impact of transcription factor-defined SCLC subtype on incidence and outcomes of brain metastases (BMs). Patients with SCLC with ASCL1 (A) and NEUROD1 (N) immunohistochemical expression status were identified and classified: (1) A+/N-, (2) A+/N+, (3) A-/N+, and (4) A-/N-. Cumulative incidence competing risk analyses were used to assess incidence of CNS progression. Cox proportional hazards models were used for multivariable analyses of overall survival (OS) and CNS progression-free survival (CNS-PFS). Of 164 patients, most were either A+/N- or A+/N+ (n = 62, n = 63, respectively). BMs were present at diagnosis in 24 patients (15%). Among them, the 12-month cumulative incidence of subsequent CNS progression was numerically highest for A+/N- (50% [95% CI, 10.5 to 74.7]; P = .47). Among those BM-free at diagnosis, the 12-month cumulative incidence of CNS progression was numerically the highest for A+/N- (16% [95% CI, 7.5 to 27.9]) and A-/N+ (9.1% [95% CI, 0.0 to 34.8]; P = .20). Both subtypes, A+/N- and A-/N+, had worse OS compared with A+/N+ (A+/N-: hazard ratio [HR], 1.62 [95% CI, 1.01 to 2.51]; P < .05; A-/N+: HR, 3.02 [95% CI, 1.35 to 6.76]; P = .007). Excellent response rates (28, 65% CR/PR) across subtypes were seen in patients who had CNS-directed radiotherapy versus systemic therapy alone (9, 36% CR/PR). To our knowledge, this report is the first to investigate CNS-specific outcomes based on transcription factor subtypes in patients with SCLC. BM-free patients at diagnosis with A+/N- or A-/N+ subtypes had worse outcomes compared with those with transcriptional factor coexpression. Further investigation into the mechanisms and implications of SCLC subtyping on CNS-specific outcomes is warranted to ultimately guide personalized care.

Craniospinal irradiation for CNS leukemia: rates of response and durability of CNS control.

Management of CNS involvement in leukemia may include craniospinal irradiation (CSI), though data on CSI efficacy are limited. We retrospectively reviewed leukemia patients who underwent CSI at our institution between 2009 and 2021 for CNS involvement. CNS local recurrence (CNS-LR), any recurrence, progression-free survival (PFS), CNS PFS, and overall survival (OS) were estimated. Of thirty-nine eligible patients treated with CSI, most were male (59%) and treated as young adults (median 31 years). The median dose was 18Gy to the brain and 12Gy to the spine. Twenty-five (64%) patients received CSI immediately prior to allogeneic hematopoietic cell transplant, of which 21 (84%) underwent total body irradiation conditioning (median 12Gy). Among 15 patients with CSF-positive disease immediately prior to CSI, all 14 assessed patients had pathologic clearance of blasts (CNS-response rate 100%) at a median of 23 days from CSI start. With a median follow-up of 48 months among survivors, 2-year PFS and OS were 32% (95% CI 18-48%) and 43% (95% CI 27-58%), respectively. Only 5 CNS relapses were noted (2-year CNS-LR 14% (95% CI 5-28%)), which occurred either concurrently or after a systemic relapse. Only systemic relapse after CSI was associated with higher risk of CNS-LR on univariate analysis. No grade 3 or higher acute toxicity was seen during CSI. CSI is a well-tolerated and effective treatment option for patients with CNS leukemia. Control of systemic disease after CSI may be important for CNS local control. CNS recurrence may reflect reseeding from the systemic space.

CTIM-38. NEUROTOXICITY AND MANAGEMENT OF PRIMARY AND SECONDARY CNS LYMPHOMA AFTER ADOPTIVE IMMUNOTHERAPY WITH CD19-DIRECTED CAR T-CELLS

Abstract BACKGROUND Chimeric antigen receptor (CAR) T-cells targeting CD19 have been established as a leading engineered T-cell therapy for systemic B-cell lymphomas; however, efficacy data for patients with CNS involvement are limited. Also, there are concerns about increased neurotoxicities (denoted by the term 'ICANS') when the target antigen is present within the CNS. METHODS We retrospectively report on CNS-specific toxicities, management, and CNS response of 45 consecutive CAR T-cell transfusions for patients with active CNS lymphoma at the Massachusetts General Hospital over a five-year period. RESULTS Our cohort includes 17 patients with primary CNS lymphoma (PCNSL; one patient with two CAR T-cell transfusions) and 27 patients with secondary CNS lymphoma (SCNSL). Mild ICANS (grade 1-2) was observed after 19/45 transfusions (42.2%) and severe ICANS (grade 3-4) after 7/45 transfusions (15.6%). No fatalities were directly attributed to ICANS. A larger increase in C-reactive protein (CRP) levels and higher rates of ICANS were detected in SCNSL. Early fever and baseline C-reactive protein levels were associated with ICANS occurrence. CNS response was seen in 31 cases (68.9%), including a complete response of CNS disease in 18 cases (40.0%) which lasted for a median of 11.4 ± 4.5 months. Similar response rates were seen in both patients with parenchymal and leptomeningeal involvement. Dexamethasone dose at time of lymphodepletion (but not at or after CAR T-cell transfusion) was associated with an increased risk for CNS progression (HR per mg/d: 1.16, p = 0.031). If bridging therapy was warranted, the use of ibrutinib translated into favourable CNS-progression free survival (5 versus 1 month, HR 0.28, CI 0.1-0.7; p = 0.010). CONCLUSION CAR T-cells exhibit promising anti-tumor effects and a favourable safety profile in CNS lymphoma. Further evaluation of the role of bridging regimens and corticosteroids is warranted to boost the success of such therapy.

Stereotactic Radiotherapy or Whole Brain Radiotherapy Combined with Pyrotinib and Capecitabine in HER2-Positive Advanced Breast Cancer Patients with Brain Metastases (BROPTIMA): A Prospective, Phase Ib/II Single-Arm Clinical Study

Approximately half of patients with advanced HER2-positive breast cancer (BC) will develop brain metastases (BM) over time. Local therapy including stereotactic radiotherapy (SRT) and whole brain radiotherapy (WBRT) is the main initial treatment in malignant tumor patients with BM. However, more than 50% patients after radiotherapy in one year suffered intracranial recurrence. Pyrotinib, a small molecule, irreversible, pan-ErbB receptor tyrosine kinase inhibitor (TKI), has a high potency for controlling BM and reducing the occurrence of brain metastases in advanced HER2-positive BC patients. We hypothesized that SRT or WBRT combined with pyrotinib and capecitabine could decrease intracranial progression in HER2 positive BC with newly diagnosed BM. In this prospective single-arm phase Ib/II trial (NCT04582968), eligible patients were assigned to either fractionated stereotactic radiotherapy (FSRT) or whole-brain radiation therapy (WBRT), combined with pyrotinib and capecitabine. The primary endpoint was one-year CNS progression-free survival (PFS) rate. Secondary endpoints included intracranial objective response rate (IC-ORR) according to RANO-BM criteria, progression-free survival (PFS), overall survival (OS) and evaluation of safety and neurocognitive function. From January 2020 to August 2022, 40 patients were enrolled. Twenty-nine patients were treated with FSRT in 8 Gy per fraction with 3 to 5 fractions and 11 were treated with WBRT in 3 Gy per fraction with 10 fractions, and then received chemotherapy in a time frame starting from 0 to 7 days after radiotherapy. At a median follow-up of 17.3 months, 1-year CNS-PFS rate was 74.9% (95% CI 61.9-90.7%) and median CNS-PFS was 18 months (95% CI, 15.5 to NA months). One-year PFS rate was 66.9% (53.1-84.2%) and median PFS time was 17.6 months (95% CI 12.8-34.1 months). The best intracranial response rate (IC-ORR: complete response and partial response) was 92.5% (37/40). The most common grade 3 or worse toxicity was diarrhea (7.5%) and asymptomatic radiation necrosis was detected in 4 of 67(6.0%) lesions treated with FSRT. No differences of neurocognitive function evaluated by MMSE (Mini-Mental State Exam) were observed between different groups at any time point. Radiotherapy combined with pyrotinib and capecitabine resulted in a promising efficacy that crossed the pre-specified boundary in patients with HER2-positive advanced breast cancer with brain metastases. This is the first prospective study showing the efficacy and safety of CNS radiotherapy concurrent with pyrotinib and capecitabine in patients with BM from HER2-positive breast cancer. Further investigation in a randomized controlled study is warranted.

Treating brain metastases in metastatic breast cancer: outcomes after stereotactic radiosurgery examined in a retrospective, single-center cohort analysis

Introduction We examined the role of receptor profiles and other prognostic factors in survival outcomes after stereotactic radiosurgery (SRS) for brain metastases in breast cancer patients, to help improve selection of candidates for SRS. Material and methods We included 149 consecutive patients who received SRS between 2012 and 2019 at the University Hospital of Copenhagen, Rigshospitalet, Denmark. Overall survival (OS) following SRS was determined through the Kaplan–Meier method, while CNS progression-free survival (CNS-PFS) was determined through competing risk analysis. Prognostic factors for both OS and CNS-PFS were evaluated through uni- and multivariate Cox regression and Fine-Gray models, respectively. The proportional hazards assumptions were tested through Schoenfeld residuals, and non-proportionality was accounted for by the inclusion of time-dependent variables. Results Median OS was 14.8 months for the entire cohort and was as follows for the four receptor profiles: 33.3 months for ER+/HER2+ (ER: estrogen receptor, HER2: human epidermal growth factor receptor 2), 11.0 months for ER+/HER2−, 17.7 months for ER−/HER2+, and 5.3 months for ER−/HER2−. In the multivariate model, the ER−/HER2− receptor profile (hazard ratio (HR): 2.00, 95% confidence interval (CI): 1.09–3.67) and the presence of extracranial visceral metastases (HR: 2.90, 95% CI: 1.53–5.50) were associated with worse OS. The ER+/HER2+ receptor profile (HR: 0.43, 95% CI: 0.19–0.96) and 5+ lines of treatment (HR: 0.40, 95% CI: 0.20–0.82) were both associated with improved OS. For CNS-PFS, 5+ lines of treatment (sub-distributional hazard ratio (SHR): 2.88, 95% CI: 1.06–7.81) was associated with worse CNS-PFS, while extracranial visceral metastases (SHR: 0.54, 95% CI: 0.30–0.97) was associated with reduced risk of CNS progression – which is primarily due to patients with extracranial metastases dying before developing new CNS progression. Conclusion Extracranial visceral disease and the ER−/HER2− receptor profile were associated with poor survival outcomes following SRS.

P06.11.B NEUROTOXICITY AND MANAGEMENT OF PRIMARY AND SECONDARY CNS LYMPHOMA AFTER ADOPTIVE IMMUNOTHERAPY WITH CD19-DIRECTED CAR T-CELLS

Abstract BACKGROUND Chimeric antigen receptor (CAR) T-cells targeting CD19 have been established as a leading engineered T-cell therapy for systemic B-cell lymphomas; however, data for patients with CNS involvement are limited. Whether CAR T-cells represent a viable therapeutic avenue for such patients remains therefore unclear. MATERIAL AND METHODS We retrospectively searched our institutional database for patients with primary and secondary CNS lymphoma who were treated with CD19-directed CAR T-cells for active CNS disease. Clinical data, CNS-specific toxicities, imaging findings, and outcome were analyzed. RESULTS We identified 45 consecutive CAR T-cell transfusions for active CNS lymphoma at the Massachusetts General Hospital over a five-year period. This cohort includes 17 patients with primary CNS lymphoma (PCNSL; one patient with two CAR T-cell transfusions) and 27 patients with secondary CNS lymphoma (SCNSL). Mild neurotoxicity (grade 1-2) was observed after 19/45 transfusions (42.2%) and severe neurotoxicity (grade 3-4) after 7/45 transfusions (15.6%). A larger increase in C-reactive protein (CRP) levels and higher rates of neurotoxicity were detected in SCNSL. Early fever and baseline C-reactive protein levels predicted neurotoxicity occurrence. CNS response was seen in 31 cases (68.9%), including a complete response of CNS disease in 18 cases (40.0%) which lasted for a median of 11.4 ± 4.5 months. Dexamethasone dose at time of lymphodepletion (but not at or after CAR T-cell transfusion) was associated with an increased risk for CNS progression (HR per mg/d: 1.16, p = 0.031). If bridging therapy was warranted, the use of Ibrutinib translated into favourable CNS-progression free survival (5 versus 1 month, HR 0.28, CI 0.1-0.7; p = 0.010). CONCLUSION CD19-directed CAR T-cells exhibit promising anti-tumor effects and a favourable safety profile in patients with CNS lymphoma. Further evaluation on the role of bridging regimens and corticosteroids is urgently warranted.

CLRM-09 MAPPING THE DISTRIBUTION AND CLINICAL ASSOCIATIONS OF BRAIN METASTASES IN RENAL CELL CARCINOMA

Abstract Brain metastases (BrM) commonly occur in renal cell carcinoma (RCC) and often present with hemorrhagic features. The distribution patterns of BrM in RCC and their associations with clinical outcomes remain unclear. We conducted a retrospective neuroanatomical distribution analysis combined with clinical review of our surgical RCC BrM cohort. Sixty-seven BrMs from 46patients (age 63±10years, 25males) were included. The majority of BrM (55%) were found in the left hemisphere, with frontal (45%), parietal (21%), and occipital (18%) lobes being the most commonly affected areas. Hemosiderin deposits, as detected by MRI, were present in 82% of BrM, while hemorrhage, as detected by CT, was present in 80% of BrM. Patients with solitary BrM had a higher KPS (p=0.006) and lower disease burden (p=0.004) compared to those with multiple BrM. Mean 1D and 2D(RANO) tumor dimensions were 2.0±1.1cm and 4.7±4.9cm2, respectively, and correlated with the neutrophil count at BrM diagnosis (r=0.3; p=0.01). Hemosiderin deposits were associated with larger tumors (2.6±1.0cm vs. 1.8±0.7cm, p=0.04), lower platelet counts (p=0.01), and higher hemoglobin levels (p=0.08). Shorter Brain Metastasis-Free Survival was associated with hemosiderin deposits on MRI (log-rank p=0.04) and renal vein thrombosis (RVT) in the primary specimen (log-rank p=0.002). RVT at primary diagnosis was associated with both hemosiderin deposits on MRI (p=0.05) and hemorrhage on CT (p=0.03), and CNS progression-free survival was shorter in patients with RVT (7.3±1.7 months vs. 21.0±4.7 months). When including only significant predictors, right hemispheric BrM lateralization (HR 2.6, p=0.06), hemosiderin deposits in BrM (HR 6.5, p=0.02), and IMDC risk groups (intermediate HR=2.9; poor-risk HR=25.6; p&amp;lt;0.04) were independent prognostic factors for shorter OS on multivariable analysis. Our results demonstrate that mapping the BrM distribution o in RCC can provide clinically relevant insights. Hemosiderin deposits in BrM may have prognostic implications. Further analyses are ongoing.

Neurotoxicity and management of primary and secondary central nervous system lymphoma after adoptive immunotherapy with CD19-directed chimeric antigen receptor T-cells.

Chimeric antigen receptor (CAR) T-cells targeting CD19 have been established as a leading engineered T-cell therapy for B-cell lymphomas; however, data for patients with central nervous system (CNS) involvement are limited. We retrospectively report on CNS-specific toxicities, management, and CNS response of 45 consecutive CAR T-cell transfusions for patients with active CNS lymphoma at the Massachusetts General Hospital over a 5-year period. Our cohort includes 17 patients with primary CNS lymphoma (PCNSL; 1 patient with 2 CAR T-cell transfusions) and 27 patients with secondary CNS lymphoma (SCNSL). Mild ICANS (grade 1-2) was observed after 19/45 transfusions (42.2%) and severe immune effector cell-associated neurotoxicity syndrome (ICANS) (grade 3-4) after 7/45 transfusions (15.6%). A larger increase in C-reactive protein (CRP) levels and higher rates of ICANS were detected in SCNSL. Early fever and baseline C-reactive protein levels were associated with ICANS occurrence. CNS response was seen in 31 cases (68.9%), including a complete response of CNS disease in 18 cases (40.0%) which lasted for a median of 11.4 ± 4.5 months. Dexamethasone dose at time of lymphodepletion (but not at or after CAR T-cell transfusion) was associated with an increased risk for CNS progression (hazard ratios [HR] per mg/d: 1.16, P = .031). If bridging therapy was warranted, the use of ibrutinib translated into favorable CNS-progression-free survival (5 vs. 1 month, HR 0.28, CI 0.1-0.7; P = .010). CAR T-cells exhibit promising antitumor effects and a favorable safety profile in CNS lymphoma. Further evaluation of the role of bridging regimens and corticosteroids is warranted.

Intracranial efficacy of sotorasib versus docetaxel in pretreated KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC): Practice-informing data from a global, phase 3, randomized, controlled trial (RCT).

LBA9016 Background: Brain metastases are common (~30%) in patients (pts) with KRAS G12C-mutated advanced NSCLC and have a negative impact on survival and quality of life (QOL). In the CodeBreaK 200 global, phase 3 RCT, sotorasib was the first oral KRASG12C inhibitor to show improved progression-free survival (PFS) and overall response rate (ORR), with a better toxicity profile and QOL, compared with intravenous docetaxel in pretreated KRAS G12C-mutated advanced NSCLC. Here we describe the first RCT data evaluating the intracranial (IC) efficacy of sotorasib versus docetaxel from the CodeBreaK 200 study. Methods: Pts with KRAS G12C-mutated advanced NSCLC who progressed after platinum-based chemotherapy and a checkpoint inhibitor were randomized 1:1 to sotorasib (960 mg daily; n=171) or docetaxel (75 mg/m2 every 3 weeks; n=174). Patients with treated, stable (non-progressing) brain metastases were eligible for study. Baseline brain imaging, by contrast enhanced MRI, was performed for all pts at screening. For pts with history of or brain metastasis at baseline, the brain MRI was repeated at every subsequent imaging assessment (every 6 weeks). A post-hoc analysis on IC efficacy (CNS PFS and time to CNS recurrence) was assessed by blinded independent central review (BICR) per modified Response Assessment in Neuro-Oncology Brain Metastases (mRANO-BM). Systemic response was also assessed by RECIST 1.1. Results: CNS metastases by imaging at baseline were present in 40 pts (23%) in the sotorasib arm and 29 pts (17%) in the docetaxel arm (full analysis set, FAS). With a median follow-up of 20.0 months, the median systemic PFS by RECIST 1.1 in the FAS was 6.1 months versus 4.5 months (HR 0.57 [95% CI: 0.30, 1.07], P=0.045) for sotorasib versus docetaxel, respectively. Time to CNS recurrence in the FAS was 9.6 months with sotorasib versus 5.4 months with docetaxel (HR 0.84 [95% CI: 0.32, 2.19], P=0.37). Treatment-related adverse events of any grade occurred in 77.5% of pts treated with sotorasib versus 89.7% of pts treated with docetaxel. Conclusions: In the first randomized evaluation of IC activity of any KRASG12C inhibitor, sotorasib demonstrated a reduced risk of progression and trend towards delayed time to CNS recurrence versus docetaxel in patients with pretreated KRAS G12C-mutated advanced NSCLC who had treated, stable brain metastases. These results suggest IC activity with sotorasib to complement the overall PFS benefit observed with sotorasib versus docetaxel. Clinical trial information: NCT04303780 .

Safety and efficacy of osimertinib plus bevacizumab as first-line treatment in EGFR-mutated NSCLC with brain metastasis instructed by dynamic monitoring circulating tumor DNA of paired cerebrospinal fluid and plasma.

e21182 Background: The management of brain metastases in lung cancer was always a global challenge. Studies have shown that erlotinib combined with bevacizumab could bring progression-free survival benefit for NSCLC. Osimertinib is a third-generation EGFR tyrosine kinase inhibitor with higher CNS penetration. This study was to evaluate the safety and efficacy of osimertinib plus bevacizumab as the first-line treatment for patients with EGFR-positive NSCLC and brain metatases, and reveal the molecular characteristics of intracranial progression by matching plasma and CSF ctDNA. Methods: Patients with EGFR-positive NSCLC and brain metatases were treated with osimertinib (80mg, daily) plus bevacizumab (5mg/kg, every 4 week) as the first-line treatment. CSF and paird plasma ctDNA were collected before osimertinib and at the time of disease stable, intracranial progression and systematic progression, using the next-generation sequencing (NGS) to explore the dynamic changes between them. The primary end point was median CNS progression-free survival (PFS), CNS objective response rate (ORR). The second end point was to explore the molecular mechanism of CNS progression. Results: As the time of data cutoff (Jan 31, 2023), 15 patients were enrolled. 3 patients (20%) progressed in lung, 2 patients (13.3%) progressed in brain, and 1 patient (6.7%) progressed in leptomeningeal and bone, 2 of them still received oral osimertinib (80mg, daily). 9 patients (60%) were in partial or complete reponse and 8 of them continued to receive the original treatment. The median osimertinib exposure time was 16.8 months. The median bevacizumab exposure time was 9.1 months. The median CNS progression-free survival was 15.5 months (6.8 months to not reached). The CNS objective response rate was 93.33%. Six patients received gamma knife radiotherapy before Osimertinib, the median CNS progression-free survival was 14 months (6.8 months to not reached), the CNS objective response rate was 100%. After progression on Osimertinib, paired CSF and plasma ctDNA were analyzed and EGFR C797S, TP53, CDKN2A and etc could be found as resistanct mechanism. Adverse events of grade 3 or worse were observed in 1 patients (6.7%): severe ulcerative colitis, leading to the suspension of osimertinib. 2 patients (13.3%) stopped bevacizumab because of bleeding. Conclusions: This is a mid-term report with immature data. By the end of follow-up, we expected that osimertinib plus bevacizumab could better reduce the risk of intracranial progression and prolong the progression-free survival compared with osimertinib monotherapy. Clinical trial information: KY2021-155-02.

An Efficient Approach to Mapping the Distribution of Renal Cell Carcinoma (RCC) Brain Metastases (BrM) (P10-13.003)

<h3>Objective:</h3> To assess the distribution of RCC BrM in clinical context. <h3>Background:</h3> RCC frequently presents with hemorrhagic BrMs. BrM distribution patterns and their associations with lab/clinical parameters are poorly understood. <h3>Design/Methods:</h3> We performed a retrospective analysis including RCC patients who underwent BrM resection at our institution. We reviewed gadolinium-enhanced MRI brain and CT head at the time of BrM diagnosis and assessed the presence of hemosiderin (MRI) or hemorrhage (CT) in the BrM. BrMs were marked in their corresponding anatomic location in a brain template. Public brain atlases (Faria and Liu 10.25790/bml0cm.109; Vachet, SCR_002606) were used for distribution analysis. Serum markers were correlated with imaging. <h3>Results:</h3> A total of 67 BM were analyzed from 46 patients (age 63±10years/35M), 23 synchronous BM, 9 patients had two, 6 had 3 concurrent BrMs. 97% of the lesions were spheric in shape. Mean 1D and 2D (RANO) tumor dimensions were 2.0±1.1cm and 4.7±4.9cm², respectively and correlated with neutrophil count at BrM diagnosis (r=0.3, p=0.01). Multilobar edema was seen in 36% of BrM. 82% of BrMs contained hemosiderin and 80% were hemorrhagic. Most BrMs were in the frontal (45%), parietal (21%) and occipital (18%) lobes. Posterior cerebral artery distribution contained 34% of BrM despite it supplying only 16% of brain volume. Higher platelet counts were associated with BrMs in the posterior circulation territories (p=0.05). BrM hemosiderin was associated with larger tumors (p=0.04), lower platelet counts (p=0.01) and higher hemoglobin (p=0.08). Renal vein thrombosis (RVT) at primary diagnosis was associated both BrM hemosiderin (p=0.05) and hemorrhage (p=0.03). CNS progression-free survival was shorter in those who had RVT (p=0.04), or had BrM hemosiderin (p=0.04). <h3>Conclusions:</h3> The presented mapping method offers an objective and efficient way to assess lesion distribution that reveals clinically relevant patterns. BrM hemosiderin deposits are linked to lower platelet counts and may provide prognostic information. Further analyses are underway. <b>Disclosure:</b> The institution of Dr. Kamson has received research support from Maryland Cigarette Restitution Fund. Mr. Feinaj has nothing to disclose. Dr. Elias has nothing to disclose. Mr. Yerrapragada has nothing to disclose. Dr. Bettegowda has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bionaut Labs. Dr. Bettegowda has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Rodey, Dickason, Sloan, Akin &amp; Robb, P.A.. Dr. Bettegowda has stock in OrisDx. The institution of Dr. Bettegowda has received research support from NIH. Dr. Bettegowda has received intellectual property interests from a discovery or technology relating to health care. Mr. Singla has nothing to disclose. Yasser Ged has nothing to disclose.

Abstract P4-01-09: Characterization of breast cancer brain metastases overall and progression-free survival and timing of cyclin-dependent kinase 4/6 inhibitor use: Retrospective single institution experience

Abstract Background Approximately 15% of patients (pts) with hormone receptor (HR)+ human epidermal growth factor receptor 2 (HER2)- breast cancer will develop brain metastases (BM) (Kuksis et al, NeuroOnc 2021). Cyclin dependent kinase 4/6 inhibitors (CDK4/6i) with an endocrine therapy partner are recommended 1st line treatments in HR+HER2- metastatic breast cancer (MBC). Preclinical models show that CDK4/6i can cross the blood brain barrier (BBB). In vitro assays have shown that abemaciclib crosses the BBB more effectively than palbociclib or ribociclib (George et al, Front Oncol 2021). The efficacy of CDK4/6i in patients with breast cancer BM is not well described. Methods We examined prior treatment data for 368 pts with HR+HER2- BM who received a CDK4/6i between 2015 to 2021. The primary endpoint was overall survival (OS) from the time of starting CDK4/6i after BM development. CNS progression free survival (PFS) was assessed in pts who received CDK4/6i after BM development. We examined the relationship between OS, type and timing of CDK4/6i in multivariate analyses. Statistical analyses were conducted using R 4.1.2 software. Results Of the total cohort of 368 pts, 23% (n=86) had de novo MBC and 77% (n=282) had relapsed MBC. At initial presentation of MBC 79% (n=290) of pts had no BM, 19% (n=71) had BM and extracranial disease and 2% (n=7) had BM only. 56% (n=205) received a CDK4/6i before BM development, 37% (n=136) received a CDK4/6i after BM development and 7% (n=27) received a CDK 4/6i both before and after BM development. The most common CDK4/6i used first was palbociclib (85%, n=312) followed by abemaciclib (13%, n=47) and ribociclib (2%, n=9). At the time of data cutoff 277 pts were dead, 55 were alive and 36 were lost to follow up. The median follow-up of surviving pts from BM development was 32 months. 163 pts received a CDK4/6i post BM: palbociclib (66%, n=108), abemaciclib (31%, n=51) and ribociclib (3%, n=4). Of these 163 pts 83% (n=136) received a CDK4/6i as their 1st or 2nd systemic treatment post BM. In the cohort of 163 pts who received a CDK4/6i post BM, 9% did not receive local BM therapy, 40% had whole brain radiotherapy (WBRT), 34% had stereotactic surgery (SRS) alone and 17% had surgery +/- SRS. The median CNS PFS for pts who received a CDK4/6i after BM was 21 months with palbociclib and 14 months with abemaciclib (p value 0.11). Too few pts received ribociclib for analysis. CNS PFS was 21 months for pts receiving a CDK4/6i only after BM development and 10 months for those who received CDK4/6i both before and after BM diagnosis (p = 0.01). Pts who died prior to CNS progression were censored. Median OS from the time of starting CDK4/6i after BM development for pts receiving a CDK4/6i only after BM development was 25 months versus 12 months for those who received it both before and after BM development (p = 0.03). There was no statistically significant difference in OS when adjusting for the type of local BM treatment received, time from initial MBC diagnosis to BM, or the Breast Graded Prognostic Assessment (GPA) score (Sperduto et al, IJROBP 2020). Conclusions This observation suggests that there is a greater OS benefit from the time of starting CDK4/6i after BM development in pts who receive CDK4/6i solely after BM development compared to pts who received a CDK4/6i both before and after BM development. This is not unexpected given the known OS benefit associated with early use of these agents. Our unique observation of longer CNS PFS for patients who did not receive CDK4/6i prior to BM but who received it afterward suggests that CDK4/6i exposure prior to BM development may lead to development of resistance mechanisms that reduces CNS efficacy upon rechallenging with CDK4/6i after BM development. There was no statistically significant difference in post-BM CNS PFS by type of CDK4/6i received. This motivates investigation of biomarkers for patient selection and our ongoing work in collecting a matched comparison cohort of HR+HER2- pts with BM who never received CDK4/6i. Citation Format: Sonya Chew Minmin, Yuan Chen, Daniel Kelly, Mark E. Robson, Andrew D Seidman. Characterization of breast cancer brain metastases overall and progression-free survival and timing of cyclin-dependent kinase 4/6 inhibitor use: Retrospective single institution experience [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-09.

Abstract OT1-10-02: Trial of Neratinib Plus Capecitabine in Subjects With HER2-Negative Metastatic Breast Cancer With Brain Metastases and Abnormally Active HER2 Signaling

Abstract Background: Development of brain metastasis (BM) portends poor prognosis in patients (pts) with metastatic breast cancer (MBC) mainly due to lack of systemic therapy with strong activity in CNS. While survival in HER2+ BC BMs has improved due to development of various HER2 therapies with activity against BM, outcome for HER2- BC BMs remains dismal. A novel assay (CELsignia) which measures underlying HER2 signal (HS) of live cancer cells in response to HER2 agonists &amp; antagonists showed that about 25% of BC deemed HER2- by standard methods have underlying abnormal HS. Preclinical data showed various HER2 therapies inhibit tumor growth of such HER2- BC with abnormal HS. Among tested HER2 inhibitors with known CNS activity, neratinib had the lowest IC50. We propose a trial which identifies HER2- BC BM pts with abnormal HS &amp; assesses activity of neratinib based therapy. Design: This is a phase II single arm study with 2 steps- step 0 (biopsy) &amp; step 1 (treatment). Pts eligible for Step 0 will be registered as “Immediate Treatment (IT)” (intent to register to Step 1 immediately) or “Future Treatment” [registration can be delayed up to 28 weeks (wks)] &amp; undergo biopsy of most accessible extra CNS (eCNS) tumor. Tumor will be sent for CELsignia testing (2 wks turn around). Additional biopsies may be obtained for standard of care (SOC). IT pts can be treated with a brief course of capecitabine 1gm/m2 BID for 1 wk followed by 1 wk off while waiting for CELsigia result. Pts with BC having abnormal HS will be screened &amp; registered to step 1. Enrolled pts will receive neratinib 240mg daily (with SOC antidiarrheal prophylaxis) + capecitabine 750mg/m2 BID for 2 wks in every 3 wks cycle (C). Tumor assessments will be done prior to C3, 5 &amp; 7 then every 12 wks with MRI brain, CT chest abdomen pelvis &amp; bone scan using RECIST1.1 (eCNS disease) and a modified BM RANO criteria (&amp;gt;5mm, measurable disease, CNS). In isolated CNS progression, investigators have option of treatment beyond progression after SOC local treatment of progressing BMs. Key Eligibility Criteria: Step 0: Inclusion Criteria (IC): histologically confirmed HER2- BC (primary or metastatic); has radiological evidence of BM; prior treatment with CDK4/6 inhibitor + endocrine therapy required for hormone receptor+ BC, no prior specific treatment required for triple negative BC; radiological evidence of eCNS measurable disease (RECIST1.1) accessible for biopsy. Exclusion Criteria (EC): prior use of capecitabine in metastatic setting; known/suspected leptomeningeal disease. Step 1: IC: Abnormal HS; New or progressing BM that is measurable (&amp;gt;5mm); minimum washout periods in wks: last chemotherapy 2, hormonal therapy 1 except fulvestrant 4, targeted therapies 3, eCNS radiation 1, any investigational treatment 4. ECOG performance status 0-2; adequate end organ functions. EC: whole brain radiation in last 3 months (m). Endpoints: Co-primary: Overall survival (OS) and CNS progression free survival (CNS PFS). Key Secondary: Objective response rate, clinical benefit rate and duration of response (CNS using BM RANO, eCNS using RECIST1.1), eCNS PFS, various feasibility endpoints. Safety. Statistical methods: To detect 70% improvement in this trial in CNS PFS and OS compared to historical control (BEACON trial BM subset) 2.7m vs. 4.6m and 4.8m vs. 8.2 m with 80% power and 1-sided 5% significance level, a sample size of 22 is required. About 88 patients will undergo biopsy to enroll 22 pts in step 1. One futility assessment is planned when the first 12 pts have been treated for at least 6 wks or have failed (died or progressed) prior to 6 wks. If 9 or more in the first 12 have died or progressed by 6 wks of treatment, the study will close for futility. PFS and OS will be analyzed using Kaplan-Meier survival functions. Contact: Ajay Dhakal MBBS, ajay_dhakal@urmc.rochester.edu NCT#: NCT04965064 Funding: Celcuity, Puma Biotechnology Status: IRB approved. Anticipated activation Aug 2022, Accrual duration: 2 years. Seeking participating sites. Citation Format: Ajay Dhakal, Ruth O’Regan, Carla Falkson, David Hicks, Douglas Hawkins, Bradley Turner, Nimish Mohile. Trial of Neratinib Plus Capecitabine in Subjects With HER2-Negative Metastatic Breast Cancer With Brain Metastases and Abnormally Active HER2 Signaling [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-10-02.

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

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

BIOM-02. MUTATIONAL ANALYSIS AND SINGLE CELL SEQUENCING OF MELANOMA BRAIN METASTASES REVEALS BRAF STATUS CORRELATES WITH CLINICAL OUTCOME AND DIFFERENTIAL IMMUNE POPULATIONS

Abstract Understanding the molecular landscape and microenvironment of melanoma brain metastases is critical to devise improved treatments. Here, we perform bulk and single cell genomic analysis of melanoma brain metastases to identify molecular correlates of clinical outcome. 84 consecutive patients who underwent surgical resection at a single institution with a histo-pathologically confirmed diagnosis of melanoma brain metastasis were retrospectively identified. In 60 patients (71%) with sufficient brain metastasis tissue for targeted next generation sequencing, DNA mutations were assessed with a CLIA certified sequencing assay. Single nuclear RNA sequencing using the 10x platform was performed on n=6 samples from treatment naïve patients. Overall survival (OS) and CNS progression free survival (CNS PFS) from time of brain metastasis diagnosis were estimated using the Kaplan-Meier method. The median patient age was 62 years old (range: 25-78 years), and the median clinical follow up was 17 months. A total of 33 patients (39%) had BRAFV600E melanoma brain metastases. Multivariate analysis incorporating age, performance status, and extracranial disease revealed BRAF status was an independent prognostic factor for OS (p&amp;lt; 0.05). In patients undergoing targeted next generation sequencing, the most common pathogenic variant was TERT promoter mutation (n=44; 73%). With regard to TCGA molecular melanoma subgroups, NRAS mutant (n=22; 37%) brain metastases were most common followed by BRAF mutant (n=20; 33%), NF1 mutant (n=11; 18%), and triple wildtype (n=7; 12%). Evaluation of clinical outcomes in the context of next generation sequencing results revealed no differences by TERT status but demonstrated worse overall survival in the BRAF mutant molecular group (p&amp;lt; 0.01, log-rank test). Single nuclear sequencing of 36,115 nuclei across 6 samples revealed BRAF wildtype tumors exhibit greater infiltrating immune cell populations including microglia and T cell subtypes. Future work will require integration of these findings with different systemic therapy regimens and across larger, prospective, multi-institutional cohorts.

Mutational Analysis and Single Cell Sequencing of Melanoma Brain Metastases

<h3>Purpose/Objective(s)</h3> Melanoma brain metastases are a significant source of morbidity and mortality. While radiosurgery and (CNS) penetrant therapies have improved clinical outcomes, understanding the molecular landscape and microenvironment of brain metastases is critical to devise improved treatments for patients. Here, we perform bulk and single cell genomic analysis of melanoma brain metastases to identify molecular mechanisms underlying therapeutic response. <h3>Materials/Methods</h3> 50 consecutive patients who underwent surgical resection with histo-pathologically confirmed melanoma brain metastases and known BRAF^V600E status treated at a single institution were retrospectively identified. In 25 patients (50%) with sufficient brain metastasis tissue for targeted next generation sequencing, DNA mutations were assessed with a CLIA certified sequencing assay spanning over 500 cancer genes. Single cell RNA sequencing was performed on n=5 samples with sufficient frozen tissue. Overall survival (OS) and CNS progression free survival (CNS PFS) were estimated using the Kaplan-Meier method from time of brain metastasis diagnosis. Single cell analysis was performed using the 10x platform and Seurat R package. <h3>Results</h3> The median patient age was 64 years old (27 – 78 years), and the median clinical follow up was 17 months. 21 patients (42%) had BRAF^V600E melanoma brain metastases. BRAF^V600E mutation was associated with worse CNS PFS (p=0.04, log-rank test) and OS (p=0.03, log-rank test). Multivariate analysis incorporating age, Karnofsky performance score, and presence of extracranial disease supports <i>BRAF</i> status as an independent prognostic factor for OS (p<0.05). In patients undergoing targeted next generation sequencing, the most common pathogenic variant was <i>TERT</i> promoter mutation (n=19; 76%) followed by <i>TP53</i> mutation (n=9; 36%). The four TCGA molecular melanoma subgroups were equally represented: <i>NRAS</i> mutant (n=8; 32%), <i>NF1</i> mutant (n=6; 24%), <i>BRAF</i> mutant (n=6; 24%) or triple wildtype (n=5; 20%) Evaluation of clinical outcomes in the context of next generation sequencing results revealed no differences by <i>TERT</i> status but demonstrated worse overall survival in <i>BRAF</i> mutant tumors (median OS: 11 months; p=0.01, log-rank test). Single cell sequencing of 31,219 nuclei across 5 samples revealed distinct subpopulations between <i>BRAF</i> mutant and <i>BRAF</i> wildtype tumors in both the tumor and the brain microenvironment, with increased immune infiltration in <i>BRAF</i> wildtype tumors and greater neuronal subpopulations in <i>BRAF</i> mutant lesions. <h3>Conclusion</h3> Our data suggest <i>BRAF</i> may be useful as a prognostic biomarker and <i>TERT</i> promoter mutations as a recurrent intracranial molecular alteration in melanoma. Single cell analysis shows brain metastases exhibit distinct neuronal and immune populations. Future work will require integration of molecular status with treatment to help guide therapy and interrogation of larger, prospective, multi-institutional cohorts to validate these observations.

Aumolertinib activity in patients with CNS metastases and EGFR-mutated NSCLC treated in the randomized double-blind phase III trial (AENEAS).

9096 Background: We previously reported (Lu, ASCO 2021, abstract # 9013) that treatment with aumolertinib (Au), a 3rd generation EGFR TKI, led to robust improvement in progression free survival (PFS) (median PFS 19.3 to 9.9 months, HR = 0.46, p &lt; 0.0001) when compared to gefitinib (G) with a predictable and encouraging safety profile. This benefit was maintained across all prespecified stratification factors including the subset of ̃ 27% of patients (pts) with CNS metastases (HR = 0.38). Here we undertook this analysis to more fully characterize the activity and benefit of Au as compared to G in this clinically important subset of EGFR mutant NSCLC pts. Methods: Pts with previously untreated metastatic or locally advanced NSCLC with EGFR sensitizing mutations were enrolled and randomly assigned in a 1:1 ratio to receive either Au (110 mg QD) or G (250 mg QD). Predefined stratification factors were EGFR-mutated status (Ex19del vs L858R) and CNS metastases (yes vs no). Patients with stable, asymptomatic CNS metastases were eligible for enrollment. All pts had baseline brain imaging by magnetic resonance imaging or computed tomography. The primary endpoint was PFS assessed by investigator per RECIST v1.1 in full analysis set (systemic analysis). Independent CNS efficacy was performed both in pts with baseline CNS metastases (CNS full analysis set, cFAS) and in pts with baseline CNS target lesions (CNS evaluable-for-response set, cEFS) by blinded independent central neuroradiology review (BICR) per RECIST v1.1. Results: Of 429 pts, 106 pts (Au, n = 51; G, n = 55) were found to have CNS metastases (cFAS) and 61 pts (Au, n = 29; G, n = 32) had CNS target lesions as defined by RECIST 1.1 (cEFS) at baseline by BICR. At the cutoff date (Aug 6, 2021), based on cEFS, CNS PFS events were observed in 11 pts (38%) treated with Au versus 20 pts (63%) who were randomized to receive G. Treatment with Au significantly prolonged CNS median PFS compared with G (29.0 vs 8.3 months; HR = 0.300; 95% CI, 0.137-0.657; P = 0.0015). Estimated CNS PFS rate at 12 and 18 months were 71% and 62% in Au arm compared with 23% and 0% in G arm. The confirmed CNS ORR were 82.8% and 75.0% in pts treated with Au and G, respectively (odds ratio = 1.600; 95% CI, 0.457-5.597; P = 0.4621). Au also achieved longer CNS median PFS over G in cFAS (29.0 vs 8.3 months; HR = 0.323; 95% CI, 0.181-0.576; P &lt; 0.0001). No new safety findings were observed. Conclusions: Au demonstrated superior clinical efficacy against CNS metastases over G as first-line therapy in EGFR-mutated advanced NSCLC, and the safety profile was consistent with that reported previously. Additional randomized studies of Au in pts with CNS metastases are ongoing (NCT04870190). Clinical trial information: NCT03849768.

Abstract P1-18-26: Intracranial efficacy of tucatinib, palbociclib and letrozole combination in patients with HR+/HER2+ breast cancer and brain metastases

Abstract Background: The phase IB/II clinical trial of tucatinib, palbociclib and letrozole (NCT03054363) showed activity in heavily pretreated patients (pts) with HR+/HER2+ metastatic breast cancer (Shagisultanova et. al, Cancer Res 2021:81(4), PS10-03). Here we report an exploratory analysis of intracranial efficacy in enrolled pts with central nervous system metastases (CNS MTS). Methods: Pts with HR+/HER2+ metastatic breast cancer previously treated with at least 2 HER2-targeted agents were enrolled in this phase IB/II clinical trial. Pts with untreated asymptomatic or treated stable CNS MTS were allowed. Efficacy was assessed using RANO-BM and RECIST1.1 criteria based on investigator assessment. CNS progression free survival (CNS-PFS), defined as intracranial progression or death, and bi-compartmental PFS (CNS and/or non-CNS progression or death) were evaluated; best confirmed CNS responses were summarized. Results: The study enrolled 15 pts with CNS MTS: 2 pts had untreated asymptomatic CNS MTS; 12 patients had treated stable CNS MTS; 1 pt had resection of a solitary CNS MTS prior to initiation of study treatment; this pt subsequently had no evidence of CNS disease for 24 months on study. Among 14 pts with evaluable disease, 13 had stable disease (SD) - 6 for ≥6 months, 7 for &amp;lt;6 months, and 1 pt who had stereotactic radiation to 1.8cm cerebellar lesion prior to enrollment achieved complete response in the CNS after 4 months on study. Among 2pts with untreated CNS lesions, 1pt with non-measurable disease had SD for 5 months on study, and 1pt with measurable disease had SD for 8 months on study. At 6.31.2021 data cutoff and median follow up time of 15 months, median CNS-PFS was 8 months, with 3 out of 15 pts (20%) achieving CNS-PFS of 1 year or greater. Bi-compartmental PFS was 9 months. Among 10 pts who came off study because of PD, 5 had PD in the CNS, 3 had systemic and CNS PD, and 2 had systemic PD. Two pts came off study for reasons other than PD. Three patients are remaining on study with a follow up time of 15, 16 and 28 months. Conclusion: Because the majority of patients had treated (non-target) CNS lesions, evaluation of CNS response was limited and biased towards SD. However, the prolonged CNS-PFS in this small patient subset suggests anti-tumor activity of this non-chemotherapy based targeted regimen in the CNS. Citation Format: Elena Shagisultanova, William Gradishar, Ursa Brown-Glaberman, Pavani Chalasani, Andrew Brenner, Alison Stopeck, Jose Mayordomo, Jennifer Diamond, Peter Kabos, Virginia F. Borges. Intracranial efficacy of tucatinib, palbociclib and letrozole combination in patients with HR+/HER2+ breast cancer and brain metastases [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-26.

Abstract OT2-26-01: Open-label, multinational, multicenter, phase 3b/4 study of trastuzumab deruxtecan (T-DXd) in patients with or without baseline brain metastasis with previously treated advanced/metastatic human epidermal growth factor receptor 2-positive breast cancer (HER2+ BC): DESTINY-Breast12

Abstract Background: HER2+ BC is associated with a high incidence (up to 50%) of brain metastasis (BM) despite advances in treatment (Zimmer AS et al. Cancer Rep (Hoboken). 2020;e1274; Hurvitz SA et al. Clin Cancer Res. 2019;25:2433-2441). Although several agents have been studied in patients (pts) with HER2+ BC with BM, an unmet medical need remains due to the poor prognosis in this pt population. In DESTINY-Breast01, T-DXd demonstrated efficacy in the overall population and preliminary efficacy in a pt subgroup with stable BM, with a confirmed objective response rate (ORR) of 61.4% and an extracranial confirmed ORR by independent central review (ICR) of 58.3%, respectively, median progression-free survival (PFS) of 19.4 and 18.1 mo, respectively, and median duration of response (DOR) of 20.8 and 16.9 mo, respectively (Modi S et al. Cancer Res. 2021. Abst PD3-06; Jerusalem G et al. Ann Oncol. 2020. Abst 138O). Here we describe a trial evaluating T-DXd in pts ± BM with previously treated advanced/metastatic HER2+ BC. Trial design: DESTINY-Breast12 (NCT04739761) is an open-label, multicenter, international (86 sites in the US, Europe, Australia, and Japan), phase 3b/4 study assessing the efficacy and safety of T-DXd 5.4 mg/kg q3w in pts with HER2+ BC ± BM. Pts will be enrolled in 1 of 2 cohorts (250 pts each): cohort 1 (−BM at baseline) and cohort 2 (+BM at baseline). Pts must have previously treated advanced/metastatic HER2+ BC that has progressed with ≥1 prior anti-HER2-based regimen and received ≤2 lines of therapy in the metastatic setting (excludes pts with prior tucatinib). Pts with BM must have untreated BM not needing immediate local therapy or previously treated stable or progressing BM. Primary endpoints are ORR in cohort 1 and PFS in cohort 2 (both by RECIST version 1.1 per ICR). Secondary endpoints in both cohorts are OS, DOR, time to progression, duration of subsequent therapy, PFS2, safety, and changes in symptoms, functioning, and QOL. Incidence of new symptomatic CNS metastasis (CNSM) is a secondary endpoint in cohort 1, and ORR and CNS ORR by RECIST 1.1 per ICR, CNS PFS and DOR, and time to new CNSM are secondary endpoints in cohort 2. Citation Format: Nancy U Lin, Eva Ciruelos, Guy Jerusalem, Volkmar Müller, Naoki Niikura, Giuseppe Viale, Emma Oscroft, Shawn Anand, Graham Walker, Nadia Harbeck. Open-label, multinational, multicenter, phase 3b/4 study of trastuzumab deruxtecan (T-DXd) in patients with or without baseline brain metastasis with previously treated advanced/metastatic human epidermal growth factor receptor 2-positive breast cancer (HER2+ BC): DESTINY-Breast12 [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-26-01.