Citations

Abstract How do brain networks limit seizure activity? In the interictal suppression hypothesis, we recently postulated that high inward connectivity to seizure onset zones (SOZs) from non-involved zones (NIZs) is a sign of broader network suppression. If broad networks appear to be responsible for interictal SOZ suppression, what changes during seizure initiation, spread and termination? For patients with drug-resistant epilepsy, intracranial monitoring offers a view into the electrographic networks that organize around and in response to the SOZ. In this manuscript, we investigate network dynamics in the peri-ictal periods to assess possible mechanisms of seizure suppression and the consequences of this suppression being overwhelmed. Peri-ictal network dynamics were derived from stereo electroencephalography recordings from 75 patients with drug-resistant epilepsy undergoing presurgical evaluation at Vanderbilt University Medical Center. We computed directed connectivity from 5 s windows in the periods between, immediately before, during and after 668 seizures. We aligned connectivity matrices across seizures and patients, then calculated net connectivity changes from the SOZ, propagative zone and NIZ. Across all seizure types, we observed two phases: a rapid increase in directed communication towards the SOZ, followed by a collapse in network connectivity. During the first phase, SOZs could be distinguished from all other regions (one-way ANOVA, P = 8.32 × 10−19–2.22 × 10−7). In the second phase and post-ictal period, SOZ inward connectivity decreased yet remained distinct (one-way ANOVA, P = 2.58 × 10−10–1.66 × 10−2). NIZs appeared to drive increased SOZ connectivity while intra-NIZ connectivity decreased concordantly. Stratifying by seizure subtype, we found that consciousness-impairing seizures decrease inward connectivity from the NIZ earlier than consciousness-sparing seizures (one-way ANOVA, P < 0.01 after false discovery correction). Tracking network reorganization against a surrogate for seizure involvement highlighted a possible antagonism between seizure propagation and the ability of the NIZ to maintain high connectivity to the SOZ. Finally, we found that inclusion of peri-ictal connectivity improved the accuracy of SOZ classification from previous models to a combined area under the curve of 93%. Overall, NIZs appear actively to increase inhibitory signaling towards the SOZ during seizure onset, possibly to thwart seizure activity. Although inhibition appears insufficient to prevent seizure onset, the inability to restrict seizure propagation might contribute to loss of consciousness during larger seizures. Dynamic connectivity patterns uncovered in this work might: (i) facilitate accurate delineation of surgical targets in focal epilepsy; (ii) reveal why interictal suppression of SOZs might be insufficient to prevent all seizures; and (iii) provide insight into mechanisms of loss of consciousness during certain seizures.

e13124 Background: Bria-IMT, an allogeneic whole-cell cancer vaccine (SV-BR-1-GM), was administered w/ an anti PD1 checkpoint inhibitor (CPI) to evaluate its safety and efficacy in advanced/metastatic breast cancer (MBC). SV-BR-1-GM breast cancer cells were engineered to directly stimulate anti-tumor immunity through expression of tumor associated antigens and secretion of GM-CSF to enhance endogenous dendritic cell activation. Addition of a CPI potentiates SV-BR-1-GM action by overcoming the immune suppressive tumor microenvironment and may have a differential impact vs monotherapy SV-BR-1-GM. Methods: In this exploratory analysis of the Phase 1 + randomized Phase 2, HLA matching status was assessed to explore potential correlations w/ clinical outcomes. Pts were stratified by overall HLA match by Class I or II (0 vs ≥1 matches), formulation and MBC subtype to assess objective response rate (ORR), clinical benefit rate (CBR), progression free survival (PFS), and overall survival (OS). Partial HLA matching (≥1 Class I and ≥1 Class II allele) was also analyzed. Results: In the total pt population, the ORR was 10%, CBR 56%, PFS 3.2 months and OS 9.9 months. In those pts treated w/ the phase 3 formulation, ORR was 15%, CBR 63%, PFS 3.6 months and OS 13.4 months. Using available HLA data (n = 52), 25% had 0, 34.6% 1, 32.6% 2, and 8% ≥3 matches. While OS and PFS were greater (Undefined vs 8.5 mos ; p = .02) in pts without an HLA match compared w/ those w/ ≥1 match (see Table), ORR and CBR were similar. This was also the case for pts who had 0 HLA Class I matches vs those w/ ≥1 Class I match (15.6 vs 7.2 mos; p = .002). ORR, CBR, PFS and OS were generally similar for pts who had 0 Class II HLA matches vs those w/ ≥1 match. Pts who matched at least at 1 Class I and 1 Class II allele had a higher ORR and CBR than those who matched at a single Class I or a single Class II allele although PFS and OS were similar between the groups. Similar observations were seen for pts treated w/ the phase 3 formulation. Conclusions: Matching at Class I seemed to decrease PFS & OS, but did not have a similar effect on ORR and CBR. Both matched and non matched pts demonstrated favorable OS and response rates. These findings support further investigation into specific mechanisms and the clinical significance of HLA matching in immunotherapy response. A randomized phase 3 trial is ongoing comparing Bria-IMT vs treatment of physician's choice (NCT06072612). Clinical trial information: NCT03328026 . n (Evaluable) % of Cohort Best ORR Best CBR PFS OS Full Cohort 52 (41) 10% 56% 3.2 9.9 No Match (Overall) 13 (10) 25% 20% 60% 4.2 Undefined Any Match (Overall) 39 (31) 75% 6% 55% 3 8.5 MHC Class I No Match / Any Match 27 (20) / 25 (21) 52% / 48% 10% /10% 55% /57% 3.5 / 2.7 15.6 / 7.23 MHC Class II Any Match 27 (19) 52% 11% 63% 3.2 11.4 MHC Class I&II Match 13 (9) 25% 22% 77% 2.8 8.6 Phase 3 Formulation (N=35) 35 (27) 15% 63% 3.57 13.43 No Match (Phase 3 Formulation) 11 (9) 31% 22% 67% 5.6 Undefined MHC Class I&II Match (Phase 3 Formulation) 11 (7) 31% 29% 71% 2.7 7.23

6008 Background: ATC patients present with advanced, often surgically unresectable disease with historically dismal prognosis. Median PFS and OS of DT without pembrolizumab were 6.7 and 13.5 months, respectively, in the ROAR trial. Neoadjuvant DTP achieved locoregional control without radical surgery in a retrospective series of BRAF m-ATC patients, providing rationale to evaluate efficacy and safety in a phase 2 prospective trial. Methods: In this single-arm multicenter phase 2 trial, patients with BRAF m-ATC stage IVB/IVC were enrolled in 5 US centers. Following a 3-6 week run-in with D (150 mg BID) and T (2 mg daily), P (200 mg Q3W) was added, with restaging every three (21-day) cycles. Post-operatively, patients continued P (or DTP) with radiotherapy or transitioned directly to adjuvant DTP (up to 26 cycles). Primary endpoints included R0/R1 resection rate (historically 5%) and overall survival (OS). Secondary endpoints included RECIST 1.1 response after DTP and progression-free survival (PFS). Results: Between 9/2021-1/2025, 42 patients were enrolled; 36 are included in the current analysis (3 not evaluable, 3 pending surgery) (Table). Patients received median 4 (range: 2-7) neoadjuvant DTP cycles, with 26 (72%) achieving radiographic PR/CR. 30 patients (83%) had surgery after neoadjuvant DTP, achieving R0/R1 resection in 29/30 (97%). Mean surgical morbidity score (0-4 scale, 4=unresectable) improved from 3.3 to 1.6 after DTP (p<0.01). Complete ATC pathologic response occurred in 20/30 patients (67%), while 10/30 (33%) had residual ATC in the surgical specimen. Postoperatively, 11/30 (37%) received adjuvant neck radiation, and 28/36 (78%) completed a median of 11 (range: 1-26) adjuvant DTP cycles. With median follow up 18 months, 15/36 (42%) patients died. Median OS was 20 months (95% CI: 12.6-NR); 1- and 2-year OS were 71% and 48%. Complete pathologic responders had better 2-year OS than those with residual ATC (69% vs. 22%, p=0.02). Median PFS was 13.9 months (95% CI, 7.5-NR); 1- and 2-year PFS were 57% and 36%. Grade 5 adverse events occurred in 8 patients (22%), including one possible (duodenal perforation), one probable (kidney injury with sepsis), and 6 unlikely/unrelated treatment-related deaths. Conclusions: Neoadjuvant DTP enables surgical resection in BRAF m-ATC compared with historical controls, and leads to improved PFS and OS. This approach should now be considered a standard of care for BRAF m-ATC. Clinical trial information: NCT04675710 . Total N=36 Age (y), median (range) 67 (46-86) Stage IVB/IVC, n (%) 15 (42%)/21 (58%) Best RECIST response neoadjuvant phase, n (%) CR 2 (6%) PR 24 (67%) SD 6 (17%) PD 4 (11%) Percent change target lesion diameter, mean (95% CI) -44% (-54%, -34%) Surgical morbidity score change, mean (95% CI) -1.7 (-2.1, -1.3)

1096 Background: Bria-IMT is a combination immunotherapy consisting of allogeneic whole cell cancer vaccine (SV-BR-1-GM) administered w/ immune checkpoint inhibitor (CPI). SV-BR-1-GM breast cancer cells are engineered to directly stimulate anti tumor immunity via expression of tumor associated antigens and secretion of GM-CSF to enhance dendritic cell activation. Addition of CPI potentiates SV-BR-1-GM to overcome the immune suppressive tumor microenvironment. Methods: This Ph I/randomized Ph II study evaluated the Bria-IMT regimen in pts w/ metastatic breast cancer; CTX (300 mg/m²) on day -2/-3, SV-BR-1-GM and CPI on Day 0, w/ low dose peg interferon α at inoculation sites on day 2 (±1) . Phase II pts were randomized 1:1 to receive CPI at cycle 1 or cycle 2. Two SV-BR-1-GM formulations (w/ vs w/o IFNγ incubation) were evaluated. Biomarkers included cancer-associated macrophage-like cells, circulating tumor cells, PD-L1 scores, and delayed-type hypersensitivity skin tests. Results: 54 pts (22 Ph I, 32 Ph II) enrolled; 11 received pembrolizumab, 44 retifanlimab (1 crossover). 33 (61%) pts were ER+/PR+/HER2-, 18 (33%) TNBC, 3 (6%) HER2+. Median OS, PFS, ORR, and CBR were evaluated against two pivotal Ph 3 trials, ASCENT 1 (SG in TNBC) and TROPiCS-02 2 (SG in HR+/HER2- MBC) (see Table 1). In randomized pts, C1 vs C2 CPI had PFS (3.7 vs 3.2 mos, P=0.09) and OS (11.4 vs 7.4 mos, P=0.19). Pts receiving Ph 3 formulation (w/o IFNγ; N=37) had greater PFS (3.6 vs 2.6 mos, P=0.01) and OS (13.4 vs 6.9 mos, P=0.01). Bria-IMT was well tolerated w/ no Tx related D/Cs. Conclusions: The Bria-IMT Ph 3 formulation cohort OS was comparable to ASCENT and TROPiCS-02 (13.43 vs 11.8, 14.4 mos), exceeding TPC arms (6.9, 11.2 mos). CBR (61%) compared favorably to ASCENT (40%) and TROPiCS-02 (34%); ORR (14%) matched or exceeded TPC arms (4%, 14%). These outcomes were observed in a more heavily pretreated population, demonstrating Bria-IMT’s clinical activity. Randomized Ph 2 results suggest efficacy and safety in heavily pretreated MBC, w/ no significant OS difference between C1 and C2 CPI initiation and 22% of pts still in active survival follow up. Superior outcomes w/ the Ph 3 formulation support its continued evaluation. A randomized Ph 3 trial is ongoing, comparing Bria-IMT vs treatment of physician’s choice (NCT06072612). Clinical trial information: NCT03328026 . Trial (Cohort) Age (Median, Range) Prior Therapies (Median) OS (Median, mos) PFS (Median, mos) ORR (%) CBR (%) Bria-IMT (Overall Cohort) 61 (38-81) 6 (2-13) 9.9 (1.8-30.3) 3.6 10% 55% Bria-IMT (Ph 3 Formulation) 62 (44-80) 6 (2-13) 13.43 (1.8-30.3) 3.6 (1.8-16.5) 14% 61% ASCENT (SG) 54 (27-82) 4 (2-17) 11.8 4.8 31% 40% ASCENT (TPC) 53 (27-81) 4 (2-14) 6.9 1.7 4% 8% TROPiCS-02 (SG) 57 (49-65) 3 14.4 5.5 21% 34% TROPiCS-02 (TPC) 55 (48-63) 3 11.2 4 14% 22% References: Bardia A et al. J Clin Oncol. 2024 May 20;42(15):1738-1744Rugo, Hope S et al. The Lancet, Volume 402, Issue 10411, 1423 – 1433.

Abstract Infection is increasingly recognized as a significant cause of morbidity and mortality in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) receiving CD19 chimeric antigen receptor (CAR) T-cell therapy. The current study analyzed the natural history, risk factors, and outcomes of infection in 3350 patients with R/R LBCL receiving commercial CD19 CAR T-cell therapy (n = 2804 axicabtagene ciloleucel [axi-cel], n = 546 tisagenlecleucel) from December 2017 to June 2022. Infection developed in 834 patients (24.9%) within 100 days after infusion, resulting in an infection density of 0.43 per 100 patient days and a 100-day cumulative incidence of 22%. Bacterial, viral, and fungal infections were recorded in 527 (15.7%), 374 (11.2%), and 108 patients (3.2%), respectively, with corresponding infection densities of 0.23, 0.15, and 0.04 per 100 patient days. After a 24-month median follow-up, 1482 patients (44%) had died, with infection as the primary cause in 173 cases (12%). The 100-day infection-related mortality (IRM) was 1.6% (95% confidence interval, 1.2-2.0). Patients with a Karnofsky performance score of ≤80, infection history before CAR T-cell therapy, axi-cel therapy, severe cytokine release syndrome (grade ≥3), and severe immune effector cell–associated neurotoxicity syndrome (grade ≥3) had increased infection risk. Infections within 100 days were an independent risk factor for inferior overall survival beyond day 100 after CD19 CAR T-cell therapy. In conclusion, study results show a significant incidence of infection and IRM in patients with R/R LBCL treated with CD19 CAR T-cell therapy. Furthermore, results identify patients at a heightened risk of infection, offering insights to guide potential interventions aimed at mitigating infection and improving patient outcomes after CAR T-cell therapy.

e13828 Background: Disparities in cancer outcomes between rural and urban populations are often linked to limited healthcare resources in rural areas. However, the impact of socioeconomic factors, particularly income inequality, requires further investigation. Methods: We analyzed cancer mortality rates using the Surveillance, Epidemiology, and End Results (SEER) database, focusing on rural-urban continuum codes and median county income, the proportions of patients with de novo metastatic disease at diagnosis, those aged 80 and older, and those experiencing a treatment delay of three months or more. Results: Our findings indicate that non-metropolitan counties (56.7%, 95% CI: 56.6%, 56.8%) and those with lower median incomes (54.9%, 95% CI: 54.8%, 55.1%) have significantly lower cancer survival rates than metropolitan counties (62.6%, 95% CI: 62.5%, 62.6%) and higher-income rural counties (62.6%, 95% CI: 62.6%, 62.7%), a trend consistent over the observation period. Higher proportions of de novo metastatic disease and increased treatment delays were observed in counties with lower income and greater rurality, with these counties also demonstrating higher annual percentage rates of change for both de novo metastatic disease (P < 0.05) and treatment delays (P < 0.05). Conclusions: Lower county-level median household income is associated with higher cancer mortality rates, increased de novo metastatic disease, and longer treatment delays. These results underscore the need to appreciate the role of income disparities in cancer outcomes and to improve access to oncology care in underserved rural populations.

e15045 Background: Increased cancer cell mitosis in tumor tissue is widely regarded as an indicator of aggressive disease, a predictor of shorter survival, and an indicator of response to specific anthracycline based chemotherapies. Circulating tumor cells (CTCs) are cancer cells that detach from primary tumors, enter the bloodstream, and seed metastatic sites, which in patients (pts) with metastatic breast cancer (mBC) are also predictors of poor prognosis and reduced therapy response. Furthermore, small preliminary studies have identified a specific subtype of mitotic CTCs that appears to correlate with poor survival rates compared to CTC detection alone. However, larger studies have yet to be conducted to validate the clinical utility of mitotic CTCs. In this large multi-institutional prospective study, we isolated CTCs from the blood of n = 155 mBC pts to subtype mitotic CTCs to assess progression-free survival (PFS) and overall survival (OS) over 2 years. Methods: Peripheral blood samples (7.5ml) were prospectively collected from n = 155 mBC pts progressing on systemic therapies and prior to new systemic therapy induction (i.e., chemotherapy n = 90, hormone therapy n = 13, immunotherapy n = 51, targeted therapy n = 62). Samples were processed using CellSieve microfilters to isolate CTCs via size exclusion and fluorescently stained for CD45, Cytokeratin, and DAPI. CTCs were imaged, enumerated, and subtyped based on the presence of ≥1 mitotic event, using established visual indicators. PFS and OS were assessed over 2 years by censored univariate and multivariate analyses. Results: CTCs were detected in ~45% (n = 70/155) of pts, while mitotic CTCs were identified in a subset of this group, ~23% (n = 35/155). The presence of any CTC was associated with poor outcomes (PFS HR = 2.16, 95%CI = 1.4-3.2, p = 0.0002 and OS: HR = 2.51, 95%CI = 1.5-4.0, p = 0.0002). The presence of mitotic CTCs correlated with significantly poorer outcomes (PFS: HR = 5.6, 95%CI = 3.1-10.2, p < 0.0001 and OS: HR = 7.3, 95%CI = 3.7-14.5, p < 0.0001). Overall, pts with no CTCs had a median PFS (mPFS) of 7 months and median OS (mOS) of 24 months, pts with non-mitotic CTCs had a mPFS of 6 months and mOS of 15 months; pts with both CTCs and mitotic CTCs had a mPFS of 3 months and mOS of 5 months. Notably, 97% of pts with a mitotic CTC progressed within 6 months, regardless of systemic therapy type. Interestingly at 2 years, a sole non-progressive pt with a mitotic CTC was receiving alpelisib (a specialized PI3KCA inhibitor). Conclusions: Overall, the detection of CTCs indicated poor outcomes in pts, with mitotic CTCs correlating with significantly more aggressive disease and further reduced survival rates regardless of systemic therapy type. This study highlights the need for larger, more comprehensive studies to expand upon and validate these findings.

TPS4632 Background: There is currently no Food and Drug Administration (FDA)-approved treatment for intermediate-risk non–muscle-invasive bladder cancer (IR NMIBC), defined as recurrence of low-grade (LG) Ta within 1 year, solitary LG Ta > 3 cm, multifocal LG Ta, high-grade (HG) Ta (≤3 cm), and/or LG T1. Nadofaragene firadenovec-vncg is the first FDA-approved intravesical nonreplicating gene therapy for treating high-risk BCG-unresponsive NMIBC with carcinoma in situ (CIS) ± papillary tumors. In a nonrandomized, multicenter, open-label, repeat-dose, phase 3 study, 53.4% of participants (55/103) with CIS ± HG Ta/T1 achieved complete response 3 months after the first instillation. Nadofaragene firadenovec was well tolerated, with no grade 4/5 study drug-related AEs. Because maintenance treatment with nadofaragene firadenovec following tumor resection may improve clinical outcomes in patients with IR NMIBC, the ABLE-32 open-label randomized study is being conducted to evaluate the efficacy of nadofaragene firadenovec administered every 3 months versus observation in participants with IR NMIBC. Methods: This phase 3 study includes approximately 100 global sites with 454 anticipated participants. Adults aged ≥18 years, diagnosed with new or recurrent IR NMIBC, and having undergone transurethral resection of bladder tumor within 60 days prior to randomization are eligible. Participants will be randomly assigned 1:1 to receive nadofaragene firadenovec or continue observation. The nadofaragene firadenovec group will receive quarterly doses unless disease recurs or progresses. The observation group will be followed quarterly and may receive nadofaragene firadenovec if IR NMIBC recurs within 24 months. All participants will be evaluated for recurrence and progression using cytology, cystoscopy, and for-cause biopsy for up to 5 years. The primary endpoint is recurrence-free survival (RFS), from randomization to first documented recurrence, progression, or death. Secondary endpoints include RFS at 12 and 24 months and safety. Exploratory endpoints include effect on potential biomarkers and health-related quality of life. Final results are expected in 2031. Clinical trial information: NCT06510374 .

AbstractObjectiveEpilepsy is a debilitating disorder affecting more than 50 million people worldwide, and one third of patients continue to have seizures despite maximal medical management. If patients' seizures localize to a discrete brain region, termed a seizure onset zone, resection may be curative. Localization is often confirmed with stereotactic electroencephalography; however, this may require patients to stay in the hospital for weeks to capture spontaneous seizures. Automated localization of seizure onset zones could therefore improve presurgical evaluation and decrease morbidity.MethodsUsing more than 1 000 000 interictal stereotactic electroencephalography segments collected from 78 patients, we performed five‐fold cross‐validation and testing on a multichannel, multiscale, one‐dimensional convolutional neural network to classify seizure onset zones.ResultsAcross held‐out test sets, our models achieved a seizure onset zone classification sensitivity of .702 (95% confidence interval [CI] = .549–.805), specificity of .741 (95% CI = .652–.835), and accuracy of .738 (95% CI = .687–.795), which was significantly better than models trained on random labels. The models performed well across the entire brain, with top five region performance demonstrating accuracies between 70.0% and 88.4%. When split by outcomes, the models performed significantly better on patients with favorable Engel outcomes after resection or who were responsive neurostimulation responders. Finally, SHAP (Shapley Additive Explanation) value analysis on median‐normalized input data assigned consistently high feature importance to interictal spikes and large deflections, whereas similar analyses on histogram‐equalized data revealed differences in feature importance assignments to low‐amplitude segments.SignificanceThis work serves as evidence that deep learning on brief interictal intracranial data can classify seizure onset zones across the brain. Furthermore, our findings corroborate current understandings of interictal epileptiform discharges and may help uncover novel interictal morphologies. Clinical application of our models may reduce dependence on recorded seizures for localization and shorten presurgical evaluation time for drug‐resistant epilepsy patients, reducing patient morbidity and hospital costs.