Citations

270 Background: While immune checkpoint blockade (ICB) is used to treat metastatic deficient mismatch repair (dMMR) colorectal cancers (CRCs), such tumors are heterogeneous and resistance to ICB is frequent. To date, biomarkers that can consistently predict patient response to ICB are lacking. We determined whether biomarkers that integrate tumor and immune-related molecular mechanisms could predict ICB response. Methods: Consecutive patients with metastatic dMMR CRCs (N=32) who had been treated with anti-PD-1 therapy were profiled using a validated immune-enhanced exome and transcriptome platform (ImmunoID NeXT, Personalis) using tumor and paired normal tissue. This platform provides antigen-specificity of T or B cells, indicated by the TCR or BCR respectively, neoantigen prediction, tumor mutation burden (TMB), immune profile, HLA allele-specific loss of heterogeneity (LOH) and a Neoantigen Presentation Score (NEOPS) that combines a neoantigen prediction tool with mechanisms of immune evasion. Tumor variables were analyzed in relationship to objective tumor response, and a Cox proportional hazards model was fit to predict progression-free survival (PFS) or overall survival (OS). Results: In CRCs, TCR and BCR repertoire diversity were each significantly increased in tumors from responders versus those with stable or progressive disease after anti-PD-1 treatment (p=0.015 and p=0.048, respectively). Neoantigen burden score, TMB, and HLA allele-specific LOH (reflects loss of antigen presentation machinery) were each unable to distinguish responders from nonresponders. An immune checkpoint gene expression signature was increased in nonresponders relative to responders (P= 0.005). Neoantigen presentation score (NEOPS) was prognostic when adjusted for tumor grade only for OS (p=0.048). Conclusions: The T-cell and B-cell receptor (TCR/BCR) repertoire, as well as NEOPS, were each significantly predictive of favorable response to anti-PD-1 therapy in dMMR tumors. In addition, an immune checkpoint gene expression signature was predictive of resistance to ICB.

770 Background: Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis and limited treatment options. A 584 bp deletion in CTRB2 , which impairs chymotrypsin B2 function, has been linked to increased PDAC risk. This study investigates the impact of this deletion on progression and survival outcomes in patients with PDAC. Methods: There were 633 patients in whom CTRB2ex6 deletion was genotyped; 263 patients received chemotherapy and had time to progression (TTP) information. TTP was calculated from diagnosis date until earliest of 1) progression date (event), 2) surgery, death, or next chemotherapy date (competing risk), or 3) date last known to be alive (censor). Overall survival (OS) was calculated for the cohort from diagnosis until date of death (event) or date last known to be alive (censor). TTP was analyzed using cumulative incidence methods accounting for competing risks; OS was analyzed using Kaplan-Meier methods. Cox proportional hazard models adjusted for age and sex were used to test associations and compute hazard ratios (HR) and 95% confidence intervals (CI). Results: Median TTP in those with CTRB2ex6 deletion negative carrier status (n=209) was 1.3 years vs 5.9 years for those with positive carrier status (n=54). Estimated 3-year progression rates were 54.2% for patients with no CTRB2ex6 deletions, 43.7% for patients with one deletion (n=48), and 33.3% for patients with two CTRB2ex6 deletions (n=6). TTP was not associated with CTRB2 deletion carrier status (HR: 0.8, 95% CI: 0.6-1.3). Median OS for CTRB2ex6 deletion negative carriers (n=514) was 1.0 year vs 0.9 years for positive carriers (n=119); within deletion carriers, heterozygous carriers (n=110) had a median OS of 0.9 years, and homozygous carriers (n=9) had a median OS of 2.6 years. OS was not associated with CTRB2 deletion carrier status (HR: 1.0, 95% CI: 0.9-1.3). Conclusions: Although we did not detect statistically significant differences in TTP and OS by CTRB2ex6 deletion carrier status, there was an interesting trend toward longer TTP and OS in the small number of patients who carried homozygous CTRB2ex6 deletions. Larger studies are warranted to validate these findings.

727 Background: PARP inhibition (PARPi) is a standard maintenance therapy for patients (pts) with germline BRCA1/2 mutations in pancreatic cancer. Combination of PARPi therapy and immunotherapy has potential to increase efficacy and may offer benefit beyond germline BRCA1/2 . Methods: We performed a multisite single-arm phase 2 study using the highly potent PARPi niraparib with anti-PD1 drug dostarlimab in pts with germline or somatic HRD mutations in BRCA1/2, PALB2, RAD51C/D, or BARD1 . Pts were required to have metastasis, progressed on ≥1 regimen, and prior platinum-exposure unless refused/intolerant. Pts were treated with niraparib 200 mg orally once daily continuously. Dostarlimab 500 mg was administered IV every 3 weeks for 4 cycles, then 1000 mg IV every 6 weeks. The primary endpoint was disease control rate (DCR) at 12 weeks (DCR12) using iRECIST criteria. At least 8 pts with DCR12 in the first 19 eligible pts (41%) would be considered promising for further trials. Results: 22 pts were enrolled from Dec 2020 to Oct 2023. Two pts withdrew prior to receiving therapy, and 2 were later found to be ineligible, leaving 18 eligible pts for final analyses. Median age was 63.0 yrs, 39% male, 94% non-Hispanic white, 1 black (6%). 17 pts were platinum exposed, 7 were platinum-refractory, and 5 had previously progressed on PARPi maintenance. Mutation distribution was: BRCA2 13/18 (72%), BRCA1 4/18 (22%), BARD1 2/18 (11%). One pt had both BRCA1 (somatic) and BRCA2 (germline) mutations. Germline mutations were identified in 14/18 (78%). DCR12 was achieved in 5/18 (27.8%), so the primary endpoint (>41%) was not met. Pts received a median 2 cycles (range 1-8) of niraparib + dostarlimab. No clinical factors were significantly associated with improved DCR12 (all p > 0.05) in subgroup analyses, but we did observe the following statistically nonsignificant associations. Pts who were platinum-refractory had a lower DCR12 compared to those not (14.3% vs. 36.4%). Counterintuitively, PARPi exposed/refractory pts had a higher DCR12 than non-exposed/non-refractory (50 vs 17% exposed/nonexposed and 40% vs 23% refractory/nonrefractory). Pts with germline mutations had a higher DCR12 compared to those without (38.5% vs. 0%). Non- BRCA2 mutations had a higher DCR12 than those with BRCA2 mutations (50% vs.17%), with highest DCR12 rates among BRCA1 patients (67%). Tolerability was in line with similar combinations, with 60% non-hematologic Gr3 or higher, including fatigue (15%), AST increase (10%), nausea/vomiting (10%), sepsis (10%). Two grade 5 events were not attributed to treatment. Conclusions: PARPi plus anti-PD1 checkpoint inhibition was not sufficiently active as later line therapy in metastatic pancreatic cancer for the majority of patients with HRD mutations. Additional molecular analyses to elucidate predictive markers of sensitivity/resistance are ongoing. Clinical trial information: NCT04493060 .

163 Background: CRC with PM has a poor prognosis and limited treatment options. Immunotherapy has shown promise in improving outcomes for patients with microsatellite instability-high (MSI-H), mismatch repair-deficient (dMMR), and high tumor mutational burden (TMB-H) tumors. However the peritoneal niche has a unique microenvironment, which can influence the effectiveness of immune check point inhibitors (ICIs). We assessed the impact of ICI on progression-free survival (PFS) and overall survival (OS) in CRC patients (pts) and PM, considering key clinical and molecular characteristics. Methods: A retrospective review aiming to identify CRC pts with MSI-H/dMMR and PM treated with immunotherapy between 2015 and 2023 was performed. Data collected included pt demographics, tumor characteristics, and treatment details. Responses were evaluated using RECIST v1.1 criteria. Results: 37 pts were included, 9 (24%) had Lynch syndrome. The median age of diagnosis was 61 years and most pts were females (65%). Most pts had MSI-H/dMMR tumors, while one pt was treated based on ultra-hypermutated phenotype (TMB 202) and POLE mutation. Among those with available TMB data, the median TMB was 52 mutations/Mb (0-202). Common mutations were PMS2 (51%), MLH1 (38%), MSH6 (16.2%), and MSH2 (16.2%). Right-sided tumors were in 54%, mucinous histology in 62%, and ascites in 54%. Pts received a median of 11 cycles of ICI (2-52). Pembrolizumab was the most frequently used ICI (78%), while Nivolumab was used either alone (11%) or in combination with Ipilimumab (11%). Median PFS in our cohort was 7.8 months and median OS was 29.9 months. The disease control rate (DCR) was 81%, with an objective response rate (ORR) of 51.3% (9 complete responses, 12 partial responses). At the time of data collection, 30% of pts were off systemic therapy and 5-FU-based chemotherapy combined with a biologic agent was the most common subsequent treatment in 32% who had PD. Univariate analysis showed no significant differences in PFS or OS based on tumor sidedness, isolated PM, liver metastases, mucinous vs. non mucinous histology or BRAF / RAS status (WT vs mutant). Malignant ascites was associated with worse OS(HR 0.3; p= 0.03). Conclusions: Treatment with ICIs in pts with MSI-H/dMMR and/or TMB-H CRC and PM improved disease control in CRC pts with PM, however, as compared to historical controls for patients with MSI-H/d-MMR disease treated with ICI, this group showed less favorable outcomes. Malignant ascites was associated with poorer overall survival. Further research of the immune response and tumor microenvironment in the peritoneal cavity is warranted.

Abstract Background Crohn’s disease (CD) treatment is associated with increased risks of infection and malignancies. Although the safety of certolizumab pegol (CZP) is well established, long-term data from community-based observational studies are lacking. Aim This study aimed to evaluate long-term safety outcomes of patients from the SECURE registry receiving CZP relative to other CD treatments, including corticosteroids, immunosuppressants, and biologics. The primary outcome of this observational study was the evaluation of malignancies. Methods Adult patients with CD were prospectively monitored for up to 8 years. Pre-specified data were collected for all enrolled patients. Adverse events of interest (AEoIs) were reported per 100 patient-years (PY) of exposure. Incidence rate ratios (IRRs) were calculated for AEoIs using multivariate regression analysis accounting for exposure to multiple treatments. Malignancies reported after any exposure to CZP were attributed to CZP. Post-hoc analyses were conducted to evaluate non-melanoma skin cancer (NMSC), lymphoma, and pregnancy outcomes. Results A total of 3072 patients were enrolled in the study. The risk of AEoIs was similar between patients with only CZP exposure versus comparator exposure. Among patients with any CZP exposure, there was a higher frequency of serious infections (IRR: 2.56 [95% confidence interval (CI): 2.00, 3.29]) and hypersensitivity or anaphylactic reactions (IRR: 4.11 [95% CI: 1.80, 9.38]) versus patients with comparator exposure. Malignancy rates were similar across groups; however, concomitant use of thiopurines was associated with higher odds of NMSC (odds ratio: 2.30 [95% CI: 1.09, 4.89]). Most cases of lymphoma (5/7) occurred in patients with exposure to thiopurines. Pregnancy outcomes were similar across groups. Conclusions No new safety signals were identified for CZP; the use of thiopurines was identified as a risk factor for NMSC. Trial registration NCT00844285.

ABSTRACT Background Pulsed‐field ablation (PFA) is an innovative non‐thermal method for arrhythmia treatment. The efficacy of various PFA configurations in relation to contact force (CF) has not been well‐studied in vivo. Objectives This study evaluated the effect of CF on acute bipolar PFA lesions in both a vegetal and an in vivo porcine heart model. Methods Bipolar PFA (500 V, 20 μs for 50 pulses) was applied to eight porcine ventricles, with CF categorized as standard (5–15 g), high (16–30 g), or very high (> 30 g) using the CARTO 3 system. PFA lesions were assessed by gross pathology, histology, and post‐ablation voltage amplitude. Additionally, a vegetal model using oscillating russet potatoes replicated the motion of a beating heart to compare lesion parameters under dynamic conditions and various PFA configurations (monopolar vs. bipolar). Results A total of 61 in vivo bipolar PFA lesions across all groups were analyzed. No significant differences in lesion surface diameter, depth, or volume were found among CF groups. In the vegetal model, monopolar setting had a better correlation between CF and lesion depth compared to bipolar setting. In addition, oscillations and catheter position (perpendicular or parallel) significantly affected lesion dimensions. Conclusion Increasing CF has a minimal effect on the size of acute bipolar PFA lesions in the porcine ventricle, suggesting that, for bipolar PFA, adequate CF is more critical than its intensity in a beating heart. For monopolar PFA, greater CF can impact lesion depth.

Abstract Background Adult onset medulloblastoma (aMB) is a rare tumor with limited available evidence. We present a large multi-institutional retrospective cohort of aMB patients treated in the modern era, with an emphasis on understanding the role of chemotherapy at initial diagnosis. Methods We included 267 consecutive patients with aMB treated at 7 different institutions from 2000-present, controlling for chemotherapy regimen and cycles received. Results Treatment factors were highly intercorrelated with one another and with treating institution. Concurrent chemotherapy was not associated with overall survival (OS). Adjuvant chemotherapy was associated with OS on univariable analyses (HR = 0.55, P = .029) and on multivariable analysis when adjusting for risk status (HR 0.55, P = .026) but not when also adjusting for treating institution. Proton craniospinal irradiation was associated with improved survival on univariable (HR = 0.50, P = .019) and multivariable analysis adjusting for risk status (HR = 0.51, P = .024) but not when treating institution was also considered. On subgroup analysis, adjuvant chemotherapy was associated with improved survival in M0 (HR = 0.55, P = .043) but not M1 disease, in patients with subtotal resection (HR = 0.43, P = .048) but not those with GTR. Similarly, progression-free survival was improved with chemotherapy in patients with M0 (HR = 0.57, P = .032) but not M1 disease, and in patients with subtotal (HR = 0.50, P = .054) but not gross total resection. Conclusions There was no benefit of concurrent chemotherapy. Adjuvant chemotherapy was associated with improved overall survival and this effect was driven by select subgroups, specifically those with M0 disease and those with residual tumor. We could not confirm that these associations are independent of the treating institution.

ABSTRACT Background In recent years, transcatheter implantation devices to restrict pulmonary arterial flow have emerged as a potential alternative to surgical pulmonary artery banding. Case Presentation A term male was diagnosed with critical aortic stenosis (AS) and severely reduced left ventricle (LV) systolic function. He underwent aortic balloon valvuloplasty on day 2 of life, resulting in some antegrade flow, but LV ejection fraction only improved to 15%. He remained ductal dependent for systemic perfusion. Pulmonary over‐circulation ensued with systemic steal evident in his second week of life. On day 14, he underwent a transcatheter stage 1 procedure including the placement of bilateral pulmonary flow restrictor (PFR) devices and ductal stenting. Post‐procedure, he improved clinically, weaned off respiratory support, and transitioned to oral feeds while awaiting cardiac transplant. Twelve days later, he received a donor heart, with an uneventful recovery. He is now 3 years post‐transplant and has excellent graft function, and his transplant course has been unremarkable. Conclusion Transcatheter‐based palliation for a neonate with critical AS, utilizing endoluminal PFRs, proved effective in stabilizing the infant and successfully bridging him to transplant. This highlights an opportunity for the utilization of PFRs in neonatal conditions where control of pulmonary blood flow is imperative as a bridge to transplantation.