Citations

3509 Background: HER2 overexpression/amplification (HER2+) occurs in ~3%-5% of pts with metastatic colorectal cancer (mCRC) and up to ~10% of pts with RAS/BRAF wild-type (WT) mCRC. The primary results of the MOUNTAINEER study (NCT03043313) demonstrated that the combination of tucatinib (TUC), a highly selective HER2-directed TKI, and trastuzumab (Tras) was well tolerated with clinically meaningful activity in pts with chemo-refractory HER2+ mCRC. Confirmed ORR was 38.1%, median DOR was 12.4 months, and median OS was 24.1 months. Here, we present results from the final analysis of MOUNTAINEER. Methods: MOUNTAINEER is a multi-center, open-label, randomized, phase 2 trial. Eligible pts had HER2+ and RAS WT mCRC with progression on or intolerance to last systemic therapy. Previous HER2-directed therapies were not permitted. The trial consisted of Cohort A, comprising pts treated with TUC (300 mg PO BID) + Tras (8 mg/kg IV then 6 mg/kg IV Q3W), as well as pts randomized 4:3 to receive TUC+Tras (Cohort B) or TUC monotherapy (Cohort C). Pts randomized to Cohort C were allowed to crossover and receive TUC+Tras on radiographic progression or if they did not achieve a complete or partial response by Week 12. Study endpoints evaluated at final analysis include DOR per BICR, PFS per BICR, OS, and safety. Results: The median duration of follow-up was 32.4 months (IQR, 25.1-46.7), with an additional 16.1 months of follow-up since the primary analysis (data cutoff, 02-Nov-2023). A total of 116 pts received at least 1 dose of study treatment (Cohorts A+B, N = 86; Cohort C, N = 30). In Cohorts A+B, median DOR per BICR was 15.2 months (95% CI, 8.9-20.5), median PFS per BICR was 8.1 months (95% CI, 4.2-10.2), and median OS was 23.9 months (95% CI, 18.7-28.3). In Cohort C post-crossover (N = 28), median DOR was not reached (95% CI, 2.8 months-NE). Median OS in Cohort C was 21.1 months (95% CI, 17.0-NE). The most common TEAEs in Cohorts A+B were diarrhea (66.3%), fatigue (44.2%), and nausea (34.9%). The majority of TEAEs were low grade, and rates were stable with longer follow-up. The most common grade ≥3 TEAE was hypertension (7.0%). TEAEs leading to TUC discontinuation in Cohorts A+B occurred in 5.8% of pts, which was unchanged from the primary analysis. In Cohort C, the most common TEAEs post-crossover were diarrhea (39.3%), back pain (21.4%), and pyrexia (21.4%); the most common grade ≥3 TEAE was AST increase (10.7%). No deaths resulted from TEAEs in any cohort and no new safety signals were identified. Conclusions: TUC+Tras continued to be well tolerated with sustained efficacy in pts with chemo-refractory RAS WT HER2+ mCRC, demonstrating clinically meaningful activity of the combination on longer follow-up. TUC+Tras is an important chemotherapy-free treatment option in HER2+ mCRC. TUC+Tras is being further evaluated in the first-line setting in combination with chemotherapy in the ongoing phase 3 MOUNTAINEER-03 trial (NCT05253651) for pts with HER2+ mCRC. Clinical trial information: NCT03043313 .

e15146 Background: Wnt/ß-catenin signaling dysregulation is found in approximately 25% of hepatocellular carcinoma (HCC) patients. The impact of B-catenin activation on HCC overall survival has remained controversial. Prior studies suggest activating CTNNB1 mutations may predict for immunotherapy (IO) resistance while others did not corroborate this finding. Here we describe the clinical outcomes of advanced HCC patients (pts) with CTNNB1 (+) and without CTNNB1 (-) mutations treated with novel first line IO/anti-VEGF therapies. Methods: We conducted a multicenter, retrospective analysis of pts with HCC who had molecular analysis performed between 2019 and 2023 at Mayo Clinic in Minnesota, Arizona, and Florida. The study was reviewed and approved by the IRB. Clinical and molecular features were compared descriptively. The primary outcomes were time to treatment failure (TTF), defined as time from first-line treatment initiation to off treatment or death, and overall survival (OS), defined as time from first-line treatment initiation to death, compared between the two cohorts using the Kaplan-Meier method. Results: We identified 29 CTNNB1+ and 62 CTNNB1- (wt) pts with HCC. Median age at diagnosis was 66 (range 30-86), 80 (88%) were Caucasian, 68 (75%) were male gender, and 22 (24%) had etiology as hepatitis B/hepatitis C, 82 (90%) were Child-Pugh A and 77 (85%) were Barcelona Clinic Liver Clinic (BCLC)=C at diagnosis. Eighteen (90%, n=20) CTNNB 1+ pts received first-line IO (Atezolizumab/bevacizumab [AB]) vs 39 (72%, n=54) in CTNNB1- pts. All pts were microsatellite stable (MSS). CTNNB1+ had a similar median tumor mutational burden (TMB), higher rate of TERT co-mutation, and lower rate of TP53 co-mutation (table) compared to CTNNB-. Of 57 AB pts, 5 (27%) of CTNNB1 + had an objective response, compared to 6 (16.7%) CTNNB1- pts. Time to treatment failure with first-line AB and overall survival were similar between the two cohorts (Table). Conclusions: Our study suggests CTNNB1 status is not prognostic in HCC pts receiving IO based therapy. Prospective study is warranted to further investigate predictive biomarkers for HCC sensitivity to immune checkpoint inhibitors and VEGF-targeted therapy. [Table: see text]

e15138 Background: Neuroendocrine carcinomas (NECs) are poorly characterized due to their innate heterogeneity, thus limiting treatment and clinical trial options for patients. Here, we used whole exome sequencing (WES) and RNA sequencing (RNA-seq) to explore the genetic and microenvironmental landscape of NECs in order to understand the unique features of different NEC types, with the aim of improving treatment modalities. Methods: We analyzed 51 NEC clinical samples morphologically verified by a pathologist: lung NEC (20 small cell NEC and 1 large cell NEC cases), gastroenteropancreatic NEC (GEP, 12 cases), cancer of unknown primary (7 cases), Merkel cell carcinoma (MCC, 5 cases), genitourinary tract NEC (3 cases), and breast NEC (3 cases). Findings on tumor mutational burden (TMB, mut/Mb), microsatellite instability (MSI), gene expression signatures, and tumor microenvironment (TME) profiling were reported. Small cell lung cancer (SCLC) subtyping was performed as reported by Gay et al. on the entire NEC cohort. Results: Half of the patients with lung NEC and 84% of those with extrapulmonary NEC satisfied the molecular inclusion criteria for clinical trials, with the most frequent criterion being KRAS G12X or G13X mutations. Among the extrapulmonary NEC samples, 13.7% were deemed eligible for targeted therapy, specifically for cases with BRAF V600E mutation and/or high TMB (> 10 mut/Mb). We detected varying TMB and distinct gene expression features across the entire cohort. Specifically, we found 2 MCC cases to be Merkel cell polyomavirus-positive with low TMB and devoid of UV-associated mutations. One GEP-NEC case exhibited a high MSI (MSI-high) status. We detected 6 SCLC cases (3 non-smokers, 3 former smokers) with surprisingly low levels of tobacco-associated mutations (<10% of all mutations). Two GEP-NEC cases had high levels of mutations associated with tobacco smoking. While TME profiling showed no significant difference in cell population makeup across all samples, transcriptional SCLC subtyping revealed significant differences among the cases. Inflammatory SCLC (SCLC-I) samples showed statistically significant enrichment of all subpopulations of the immune microenvironment (i.e., B cells, T cells, NK cells), supporting the use of immune checkpoint blockade for treatment. The POU2F3+ SCLC (SCLC-P) samples showed low expression of all neuroendocrine diagnostic markers (i.e., INSM1, NCAM1, SYP, CHGA). Conclusions: Given the heterogeneous molecular features across diverse NEC tumors, a uniform treatment strategy is unlikely to benefit all NEC patients. Hence, our ability to detect these unique molecular features is crucial for matching individual NEC patients with specific clinical trials and targeted therapies that may improve their outcomes. Thus, a concerted effort using in-depth genomic, transcriptomic, and TME profiling for NEC tumors is warranted.

e15046 Background: ctDNA assays can be used to assess molecular residual disease, and the value of ctDNA monitoring in disease surveillance and treatment response assessment has been demonstrated in colon, breast, lung, and bladder cancers. However, the data of ctDNA in rare cancers has been lacking. We conducted this retrospective study to investigate the potential roles of ctDNA monitoring in rare tumors in both surveillance and response evaluation. Methods: ctDNA assay results of 12 patients (pts) with rare cancers including adrenocortical carcinoma (ACC) (4 pts), salivary gland cancers (3 pts), pleural or peritoneal malignant mesothelioma (4 pts), and anaplastic thyroid cancer (ATC) (1pt) undergoing treatment or surveillance in 2023 at Mayo Clinic Florida were analyzed. The trends of ctDNA levels were correlated with radiographic images findings. Results: Among the 12 patients, ctDNA was detected in at least one time point in 9 (75%) pts, including 1 (100%) ATC pt, 2 (66%) salivary gland pts, 3 (75%) malignant mesothelioma pts, and 3 (75%) ACC pts. Among these 9 pts, 5 pts had ctDNA collected at more than one timepoints, and the trends of ctDNA levels were consistent with image findings in all 5 pts. Among these 5 pts, one pt received definitive surgery for ACC with clearance of ctDNA after the surgery and one salivary gland cancer pt was undergoing surveillance and later developed disease progression. The other 3 pts were undergoing palliative systemic therapy and had responded to treatments. Conclusions: ctDNA was detectable in majority of the patients with rare malignancies reviewed in this study, including ACC, ATC, pleural or peritoneal malignant mesothelioma, and salivary gland cancers. Further study is warranted to investigate the role of ctDNA monitoring in surveillance and treatment response evaluation in rare malignancies.

e15045 Background: Human papillomavirus (HPV) is an oncogenic driver of several human cancers, including those of the anal canal, uterine cervix, and head and neck (predominantly oropharynx). Despite advancements in our understanding of HPV-related cancers, there remains an unmet need for a comprehensive biomarker-driven registry to establish correlations between biomarker detectability and clinicopathologic features in patients diagnosed and treated for HPV-driven cancers. To address this need, the NAVigate-HPV Registry has been established to systematically collect and analyze integrated biomarker and clinical data from many U.S. cancer centers. Methods: NavDx (Naveris, Inc.) is a clinically validated blood-based assay detecting circulating cell-free tumor tissue modified viral (TTMV)-HPV DNA. The NAVigate-HPV Registry is a web-based data platform based on a centrally IRB approved protocol. Participating investigators will include providers that order NavDx tests in the routine clinical care of their patients and agree to the terms and conditions for use of the registry. Eligible subjects will have or have had an HPV-driven cancer (with an initial focus on HPV-driven oropharynx cancer with confirmatory tissue testing) and have received one or more NavDx blood tests during routine clinical care. Clinical data and TTMV-HPV DNA scores will be collected at enrollment and defined intervals over five years or until death. Results: In the initial phase, the registry has enlisted participation and established a steering committee composed of a representative from each of 14 institutions. These institutions are geographically diverse centers ranging from community hospitals to clinics and academic medical facilities. An IRB protocol governing the registry will maintain ethical standards, ensuring compliance and ethical conduct throughout the registry process. Data extraction methods have been previously established to evaluate an initial cohort of 543 patients (Hanna GJ, Roof SA, et. al 2023). Conclusions: Naveris and collaborators have together successfully launched the NAVigate-HPV registry with the aim of creating a robust database linking tumor biomarker results from NavDx with clinical outcomes data for HPV-related cancers. The NAVigate-HPV database is expected to encompass more than 1,000 patients within 1 year and grow to > 5,000 patients within 5 years, serving as a powerful tool for precision cancer medicine in this patient cancer population. Establishing this registry will deepen insights into HPV-related cancers and advance diagnostic and therapeutic approaches to improve patient outcomes.

PURPOSE Phosphatidylinositol 3-kinase/AKT-serine threonine kinase/mammalian target of rapamycin (mTOR) pathway abnormalities contribute to endocrine resistance. Everolimus, an mTOR inhibitor, improved progression-free survival in hormone receptor–positive metastatic breast cancer (BC) when combined with endocrine therapy (ET). In this phase III randomized, placebo-controlled trial, we assessed the efficacy of everolimus + ET as adjuvant therapy in high-risk, hormone receptor–positive, human epidermal growth factor receptor 2–negative BC after adjuvant/neoadjuvant chemotherapy. METHODS Patients were randomly assigned 1:1 to physician's choice ET and 1 year of everolimus (10 mg orally once daily) or placebo stratified by risk group. The primary end point was invasive disease-free survival (IDFS) evaluated by a stratified log-rank test with the hazard ratio (HR) estimated by Cox regression. Subset analyses included preplanned evaluation by risk group and exploratory analyses by menopausal status and age. Secondary end points included overall survival (OS) and safety. Everolimus did not improve IDFS/OS when added to ET in patients with early-stage high-risk, hormone receptor–positive BC. RESULTS One thousand and nine hundred thirty-nine patients were randomly assigned with 1,792 eligible for analysis. Overall, no benefit of everolimus was seen for IDFS (HR, 0.94 [95% CI, 0.77 to 1.14]) or OS (HR, 0.97 [95% CI, 0.75 to 1.26]). The assumption of proportional hazards was not met suggesting significant variability in the HR over time since the start of treatment. In an unplanned subgroup analysis among postmenopausal patients (N = 1,221), no difference in IDFS (HR, 1.08 [95% CI, 0.86 to 1.36]) or OS (HR, 1.19 [95% CI, 0.89 to 1.60]) was seen. In premenopausal patients (N = 571), everolimus improved both IDFS (HR, 0.64 [95% CI, 0.44 to 0.94]) and OS (HR, 0.49 [95% CI, 0.28 to 0.86]). Treatment completion rates were lower in the everolimus arm compared with placebo (48% v 73%) with higher grade 3 and 4 adverse events (35% v 7%). CONCLUSION One year of adjuvant everolimus + ET did not improve overall outcomes. Subset analysis suggests mTOR inhibition as a possible target for patients who remain premenopausal after chemotherapy.

e14535 Background: Cytokine release syndrome (CRS) is the most common complication of chimeric antigen receptor T cells (CAR-T) for hematologic malignancies. We hypothesized that patients undergoing CAR-T therapy who are on metformin will experience a lower incidence or severity of CRS than patients not on this medication. Methods: We evaluated all patients treated with CAR-T at Mayo Clinic Rochester between 1/1/2018 and 1/31/2023, and abstracted relevant clinical and laboratory characteristics to determine the incidence and severity of CRS, PFS as well as OS in patients who were, or were not, on metformin before and during CAR-T therapy for Type 2 diabetes mellitus. We used the Chi-Square test, Mann-Whitney test and the Kaplan-Meier method to analyze data. Results: In the 5-year interval under consideration 237 patients received CAR-T, 168 for non-Hodgkin lymphoma (NHL), and 69 for multiple myeloma (MM). 23 patients (15 NHL and 8 MM) were on metformin at the time of CAR-T. 15 patient developed CRS while on metformin and 175 patients not on metformin (p=0.05). Grade 3 or 4 CRS incidence was 4% in both groups (p=0.41). Of the 153 patients with NHL not on metformin, 121 developed any grade of CRS, while 10 of 15 patients on metformin developed CRS (p=0.268). 4 NHL patients developed CRS Grade ≥3 or higher, while 0 of 15 on metformin developed Grade ≥3 CRS (p=0.237). For the MM patients, the incidence of CRS was 49 patients not on metformin and 5 patients on metformin (p<0.001). 3 MM patients developed CRS Grade ≥3 or higher, while 0 of 8 on metformin developed Grade ≥3 CRS (p=0.346). 12 of 15 patients on metformin with NHL achieved CR compared to 92 of 153 patients not on metformin (p=0.1305). 3 of 8 patients with MM on metformin compared to 24 of 61 patients with MM not on metformin achieved CR or better post CAR-T (p=0.92). Tocilizumab was used in 40% of patients on metformin but in 66% of patients not on metformin (p=0.0016). In NHL patients, PFS from CAR-T infusion was not reached (range: 6.3 to NR) for patients on metformin versus 9.9 months (range: 6.3–19.5) in patients not on metformin (p = 0.3332). In the MM patients, progression-free survival (PFS) from CAR-T infusion was 8.4 months (95% CI: 7.9–not reached [NR]) for patients on metformin and 22.6 months (13.7–NR) for those not on metformin (p = 0.07). Median OS for NHL patients on metformin was not reached (9.766–NR) versus 32.6 months (18.6–NR) for patients not on metformin (p = 0.7022). Median OS was 17 months (95% CI: 8.3 to NR) for patients with MM on metformin vs NR (95% CI: 9.4 to NR) for patients not on metformin (p = 0.2559). Conclusions: In this retrospective study, the co-administration of metformin during CAR-T cell therapy for NHL and MM appears to be associated with a numerically reduced incidence of CRS. The effect appears to be particularly marked in patients with multiple myeloma. Metformin therapy did not seem to affect the response to CAR-T therapy in either NHL or MM.

2565 Background: Mesothelin (MSLN) is overexpressed in mesothelioma and other solid tumors making it the focus of multiple targeted therapies, including antibody drug conjugates (ADCs), T cell receptor (TCR) fusion constructs, and chimeric antigen receptor T-cell (CAR-T) products. However, the clinical efficacy of these treatments remains limited. We hypothesize that soluble MSLN (sMSLN) in the plasma binds to MSLN-targeted therapies before reaching the tumor. Our study aimed to evaluate the effects of sMSLN on a MSLN-targeting antibody, anetumab, and explore methods to reduce sMSLN. Methods: Exploratory analysis in NCT03126630: sMSLN testing was performed on blood samples from participants enrolled in NCT03126630 at the Molecular Targets Core Lab, National Cancer Institute. The median was used to categorize high and low levels of sMSLN. Survival was estimated with the Kaplan-Meier method and compared between groups with the log rank test. Anetumab immunoprecipitation: Anetumab was covalently coupled to Dynabeads at 5 µg per mg of beads to immunoprecipitate MSLN from two plasma samples. Assays were performed in duplicate. Therapeutics plasma exchange (TPE):Whole blood samples were collected before and after one plasma volume of TPE with albumin as the replacement fluid in patients undergoing routine TPE for various medical conditions, such as autoimmune diseases and hyperviscosity syndromes. Plasma levels of sMSLN were measured with an ELISA assay in matched pre- and post-TPE plasma samples. Results: We obtained sMSLN levels from 40 patients enrolled in NCT03126630. For patients treated with both anetumab ravtansine and pembrolizumab, median progression free survival (PFS) was shorter in the high sMSLN group (5 months) vs the low sMSLN group (12 months). For patients treated with pembrolizumab alone, PFS was similar for patients with high and low sMSLN (4 vs 3.4 months). Anetumab significantly reduced the concentration of sMSLN in plasma samples as detected by MSLN ELISA (p<0.05), demonstrating that sMSLN can bind to and sequester anetumab. Next, we evaluated TPE as a mechanism to reduce sMSLN. We obtained pre- and post-TPE plasma samples from 15 patients undergoing routine TPE for various medical conditions. TPE consistently reduced sMSLN (p<0.05) with an average decrease of 43.6% or 15.4 ng/mL. Conclusions: We found that high sMSLN levels are associated with shorter PFS for anetumab ravtansine, but not pembrolizumab. Additionally, anetumab binds to sMSLN in the plasma, which suggests that sMSLN can sequester anti-MSLN antibodies and may limit the efficacy of MSLN-targeted therapies. High levels of sMSLN could potentially be used as a biomarker to select which patients should not receive MSLN-targeting therapies. Furthermore, our results indicate that sMSLN reduction is feasible with TPE. Decreasing sMSLN could restore the activity of MSLN-targeted therapies.

2087 Background: PCNSL is a rare and aggressive form of NHL in the central nervous system or vitreoretinal space. Despite high initial rates of responses to HD-MTX-based induction chemotherapies, most patients relapse in two years. R/R PCNSL is associated with poor prognosis, representing a clear unmet medical need, as there are no currently approved treatments for this disease. IRAK4 kinase activity is required for TLR and IL-1R signaling in a variety of myeloid and lymphoid cell types, including PCNSL. Recruitment of IRAK4 to these receptors and subsequent activation is facilitated by the MyD88 adaptor protein, which is mutated in ~70% of PCNSL. This leads to constitutive activation of the NF-κB signaling pathway, increased inflammation, and tumor growth. Emavusertib is a novel and potent oral inhibitor of IRAK4 and FLT3, which has demonstrated the ability to cross the blood-brain barrier in PCNSL xenografts. In preclinical studies, the combination of emavusertib with ibrutinib overcomes resistance to BTK inhibitors. This combination has an acceptable safety profile across a broad population of R/R NHL patients, including PCNSL. Here we present updated safety and efficacy data for emavusertib in combination with ibrutinib in patients with R/R PCNSL. Methods: The safety, clinical activity, and potential biomarkers of emavusertib in R/R PCNSL are being investigated in the ongoing open-label, Phase 1/2 TakeAim Lymphoma trial (NCT03328078). The eligible patients with R/R PCNSL received emavusertib (100-300 mg BID) in combination with ibrutinib (560 mg QD) in a 21-day cycle until tumor progression or unacceptable toxicity. Results: Here, we present updated data from R/R PCNSL patients with prior ibrutinib exposure who were treated with emavusertib in combination with ibrutinib. The median number of prior lines of anti-cancer therapies was 3 (range: 2-5), all patients were R/R to both frontline therapy and subsequent ibrutinib regimens. Prior responses to ibrutinib based regimens included only 1 CR. Here, we report a higher CR rate when these patients are subsequently treated with emavusertib in combination with ibrutinib.Results revealed no dose-limiting toxicities. Conclusions: Emavusertib in combination with ibrutinib was well tolerated with an acceptable safety profile and promising efficacy in R/R PCNSL patients with previous exposure to ibrutinib (BTKi). Enrollment in this trial is ongoing (NCT03328078). Clinical trial information: NCT03328078 .

2071 Background: Brigimadlin (BI 907828) is a potent small molecule inhibitor of the p53-MDM2 pathway currently in a phase 0/1 clinical trial in combination with radiotherapy in newly diagnosed MGMTunmethylated glioblastoma (GBM). To inform development of brigimadlin for GBM, we developed a pharmacokinetic (PK)/ pharmacodynamic (PD)/ efficacy model using GBM patient derived xenografts (PDXs). Methods: Brigimadlin PK parameters were evaluated in FVB wild-type and knockout (Mdr1a/b-/-Bcrp1-/-) mice and in athymic nude mice. Drug binding was measured by rapid equilibrium dialysis, and drug levels quantified by LC/MS-MS. Dose-response relationships were evaluated in subcutaneous and orthotopic PDXs across a range of doses. Response to brigimadlin (2 mg/kg weekly) +/- RT (2 Gy x 10 fractions) was evaluated in orthotopic PDXs. Results: Brigimadlin significantly delayed median time to regrowth of GBM108 ( MDM2amplified) subcutaneous tumors (vs. placebo; p<0.05) at dose levels of 0.25 mg/kg (1.3-fold), 0.5 mg/kg (1.5-fold), 1 mg/kg (2.6-fold), and 2 mg/kg (5.3-fold). A single dose of brigimadlin resulted in corresponding intra-tumoral drug levels 24 hours post-dose: 84 nM (0.25 mg/kg), 175 nM (0.5 mg/kg), 398 nM (1 mg/kg) and 924 nM (2 mg/kg) and dose-dependent upregulation of p53 target genes (p21 and PUMA). In contrast, GBM14 ( MDM2non-amplified) showed regrowth delay (1.6-fold) only at 2 mg/kg (p=0.008). Brigimadlin was highly bound (fraction unbound = 0.0006 in brain; 0.0017 in GBM tumor tissue), and CNS distribution was limited by efflux; in wild-type mice Kp,uu_brain = 0.002 ± 0.003; in Mdr1a/b-/-Bcrp1-/- mice Kp,uu = 0.043 ± 0.025. Efficacy of brigimadlin was compared in orthotopic GBM108 PDXs grown in athymic nude mice vs. immuno/efflux-deficient (Rag2-/-Mdr1a-/-Bcrp1-/-) mice. In nude mice, median survival was extended at 2 mg/kg brigimadlin (1.4-fold, p=0.009), with corresponding intra-tumoral drug levels of 29 nM. In efflux deficient mice, median survival was extended (p<0.05) at 0.25 mg/kg (1.5-fold), 0.5 mg/kg (1.5-fold), 1 mg/kg (1.8-fold), and 2 mg/kg (>4-fold). Measurement of intra-tumoral drug levels is in progress. In combination with RT in GBM108, brigimadlin (2 mg/kg x 2 weeks) extended median survival vs. vehicle (66 vs. 50 days; p=0.012) and enhanced median survival following RT (128.5 vs. 82 days; p=0.009). In GBM14, 2 mg/kg brigimadlin (2 mg/kg x 12 weeks) extended median survival (39.5 vs. 32.5 days; p=0.0004) and enhanced survival following RT (97 vs. 81 days; p<0.0001). Conclusions: Efficacy of brigimadlin is dependent on adequate CNS delivery. Studies in subcutaneous PDX demonstrated intra-tumoral total drug levels in the mid-nanomolar range provide meaningful tumor effects in a highly sensitive, MDM2 amplified PDX. In orthotopic PDXs with and without MDM2 amplification, brigimadlin provided further benefit in combination with RT. These data support ongoing clinical evaluation of brigimadlin in GBM.