Citations

PURPOSE Long-term outcomes of patients with stage I human epidermal growth factor receptor 2 (HER2)–positive breast cancer receiving adjuvant trastuzumab emtansine (T-DM1) remain undefined, and prognostic predictors represent an unmet need. METHODS In the ATEMPT phase II trial, patients with stage I centrally confirmed HER2-positive breast cancer were randomly assigned 3:1 to adjuvant T-DM1 for 1 year or paclitaxel plus trastuzumab (TH). Coprimary objectives were to compare the incidence of clinically relevant toxicities between arms and to evaluate invasive disease-free survival (iDFS) with T-DM1. Correlative analyses included the HER2DX genomic tool, multiomic evaluations of HER2 heterogeneity, and predictors of thrombocytopenia. RESULTS After a median follow-up of 5.8 years, 11 iDFS events were observed in the T-DM1 arm, consistent with a 5-year iDFS of 97.0% (95% CI, 95.2 to 98.7). At 5 years, the recurrence-free interval (RFI) was 98.3% (95% CI, 97.0 to 99.7), the overall survival was 97.8% (95% CI, 96.3 to 99.3), and the breast cancer-specific survival was 99.4% (95% CI, 98.6 to 100). Comparable iDFS was observed with T-DM1 irrespective of tumor size, hormone receptor status, centrally determined HER2 immunohistochemical score, and receipt of T-DM1 for more or less than 6 months. Although ATEMPT was not powered for this end point, the 5-year iDFS in the TH arm was 91.1%. Among patients with sufficient tissue for HER2DX testing (n = 187), 5-year outcomes significantly differed according to HER2DX risk score, with better RFI (98.1% v 81.8%, hazard ratio [HR], 0.10, P = .01) and iDFS (96.3% v 81.8%, HR, 0.20, P = .047) among patients with HER2DX low-risk versus high-risk tumors, respectively. CONCLUSION Adjuvant T-DM1 for 1 year leads to outstanding long-term outcomes for patients with stage I HER2-positive breast cancer. A high HER2DX risk score predicted a higher risk of recurrence in ATEMPT.

8013 Background: For patients (pts) with unresectable locally-advanced NSCLC, standard of care involves durva consolidation after concurrent CRT, although its benefit in ALK+ tumors is unclear. The ALINA trial demonstrated adjuvant efficacy of alectinib in resected ALK+ NSCLC, but the optimal consolidation strategy for unresectable locally-advanced ALK+ NSCLC remains elusive. Methods: This multi-institutional international retrospective analysis included pts with stage III unresectable ALK+ NSCLC who received an ALK TKI, durva, or obs alone after concurrent CRT between 2015-2022. Baseline characteristics of age, sex, smoking history, and PD-L1 status were collected. Clinical outcomes including real-world progression-free survival (rw-PFS), overall survival (OS), and treatment-related adverse events (trAE) as defined using CTCAE 5.0 were assessed, and multivariate cox regression models were performed. Results: Sixty-four pts across 16 institutions were included. The median age was 57 (IQR 49-66) and 61% were females. The majority had adenocarcinoma (97%) and had never smoked (58%). 15 received ALK TKI (10 alectinib, 3 crizotinib, 1 brigatinib, 1 lorlatinib), 30 received durva, and 19 received obs alone. There was no significant difference in stage of cancer (IIIA, B, or C) or PD-L1 status among groups. After adjusting for stage and age at CRT initiation, median rw-PFS was significantly longer for ALK TKI (rw-PFS not reached [NR], 95% CI 22.7-NR) vs durva (11.3 months (mo), 95% CI 9.2-18.5, p= 0.005, HR = 0.12) or obs (7.4 mo, 95% CI 3.4-12.5, p < 0.0001). Two (13%) pts progressed on ALK TKI. 25 pts (83%) progressed on durva leading to treatment with ALK TKI in 23, and 18 (95%) progressed while under obs leading to treatment with ALK TKI in 15. 3-year OS was 100% for ALK TKI vs 90.5% for durva vs 63.5% for obs. Median OS was NR (95% CI NR-NR) for both ALK TKI and durva vs 70.6 mo (24.9-NR) in the obs group ( p= 0.03 for both ALK TKI and durva compared to obs). Median duration of therapy was 24.7 mo with ALK TKI and 6.5 mo with durva. Grade ≥3 trAE occurred in 27%, 7%, 6% of pts treated with ALK TKI (1 fatigue, 1 diarrhea, 1 hyperbilirubinemia, 1 pneumonitis), durva (1 fatigue, 1 neutropenia), and obs (1 neutropenia) respectively. Treatment discontinuation due to toxicity occurred in 4 (27%) with ALK TKI and in 3 (10%) with durva. Conclusions: In this retrospective study of stage III ALK+ NSCLC, consolidation ALK TKI demonstrated clinically meaningful improvement in PFS and OS over durva and obs, while showing a slightly higher rate of trAE over dura and obs. Furthermore, we show a high rate of progression following CRT alone in ALK+ NSCLC. These findings underscore the need for prospective molecularly driven trials to determine the optimal consolidation therapy for unresectable ALK+ NSCLC.

Background: While criteria for the diagnosis of nosocomial pneumonias exist, objective definitions are a challenge and there is no gold standard for diagnosis. We analyzed the impact of the implementation of a logical, consensus-based diagnostic and treatment protocol for managing nosocomial pneumonias in the cardiovascular surgery intensive care unit (CVS-ICU). Methods: We conducted a quasi-experimental, interrupted time series analysis to evaluate the impact of a diagnostic and treatment protocol for nosocomial pneumonias in the CVS-ICU. Impacts were measured relative to patient outcomes, diagnostic processes, and antimicrobial stewardship improvement. Descriptive statistics were used to analyze results. Results: Overall, 35 pre-protocol and 39 post-protocol patients were included. Primary clinical variables suggesting pneumonia in pre- and post-protocol patients were new lung consolidation (50% vs. 71%), new leukocytosis (59% vs. 64%), and positive culture (32% vs. 55%). Appropriate diagnostic testing improved (23% vs. 54%, p = 0.008) after protocol implementation. The proportion of patients meeting the criteria for nosocomial pneumonia (77% vs. 87%) was not statistically significant, though more patients in the post-protocol group met probable diagnostic criteria (51% vs. 77%). Duration of therapy was not significantly different (6 days [IQR = 5.0, 10.0] vs. 7 days [IQR = 6.0, 9.0]). Conclusions: The implementation of a diagnostic and treatment protocol for management of nosocomial pneumonias in the CVS-ICU resulted in improved diagnostic accuracy, advanced antimicrobial and diagnostic stewardship efforts, and laboratory cost savings without an adverse impact on patient-centered outcomes.

Abstract Aims Lipoprotein(a) [Lp(a)] has demonstrated its association with atherosclerosis and myocardial infarction. However, its role in the development of in-stent restenosis (ISR) after percutaneous coronary intervention (PCI) is not clearly established. The aim of this study is to investigate the association between Lp(a) and ISR. Methods and results A retrospective study of adult patients who underwent successful PCI between January 2006 and December 2017 at the three Mayo Clinic sites and had a preprocedural Lp(a) measurement was conducted. Patients were divided into two groups according to the serum Lp(a) concentration [high Lp(a) ≥ 50 mg/dL and low Lp(a) &lt; 50 mg/dL]. Univariable and multivariable analyses were performed to compare risk of ISR between patients with high Lp(a) vs. those with low Lp(a). A total of 1209 patients were included, with mean age 65.9 ± 11.7 years and 71.8% were male. Median follow-up after baseline PCI was 8.8 [interquartile range (IQR) 7.4] years. Restenosis was observed in 162 (13.4%) patients. Median serum levels of Lp(a) were significantly higher in patients affected by ISR vs. non-affected cases: 27 (IQR 73.8) vs. 20 (IQR 57.5) mg/dL, P = 0.008. The rate of ISR was significantly higher among patients with high Lp(a) vs. patients with low Lp(a) values (17.0% vs. 11.6%, P = 0.010). High Lp(a) values were independently associated with ISR events (hazard ratio 1.67, 95% confidence interval 1.18–2.37, P = 0.004), and this association was more prominent after the first year following the PCI. Conclusion Lipoprotein(a) is an independent predictor for long-term ISR and should be considered in the evaluation of patients undergoing PCI.

Background: Patients with telomere biology disorders (TBD) develop hepatic disease, including hepatitis, cirrhosis, and hepatopulmonary syndrome. No specific treatment exists for TBD-related liver disease, and the role of liver transplantation (LT) remains controversial. Our study objectives were to describe the clinical characteristics, management, and outcomes in patients with TBD-related liver disease, and their LT outcomes. Methods: Data from 83 patients with TBD-associated liver disease were obtained from 17 participating centers in the Clinical Care Consortium of Telomere-Associated Ailments and by self-report for our retrospective, multicenter, international cohort study. Results: Group A (“Advanced”) included 40 patients with advanced liver disease. Of these, 20 underwent LT (Group A T ). Group M (“Mild”) included 43 patients not warranting LT evaluation, none of whom were felt to be medically unfit for liver transplantation. Supplemental oxygen requirement, pulmonary arteriovenous malformation, hepatopulmonary syndrome, and higher bilirubin and international normalized ratio values were associated with Group A. Other demographics, clinical manifestations, and laboratory findings were similar between groups. Six group A patients were declined for LT; 3 died on the waitlist. Median follow-up post-LT was 2.9 years (range 0.6–13.2 y). One-year survival post-LT was 73%. Median survival post-LT has not been reached. Group A T patients had improved survival by age compared to all nontransplant patients (log-rank test p = 0.02). Of 14 patients with pretransplant hypoxemia, 8 (57%) had improved oxygenation after transplant. Conclusions: LT recipients with TBD do not exhibit excessive posttransplant mortality, and LT improved respiratory status in 57%. A TBD diagnosis should not exclude LT consideration.

AbstractBackground and ObjectivesThe SARS‐COVID‐19 pandemic significantly limited healthcare access. We sought to evaluate whether California's lockdown in March 2020 affected staging and time to treatment of pancreatic ductal adenocarcinoma (PDAC). We hypothesized that patients diagnosed after the lockdown would have longer time to treatment and higher stage at presentation.MethodsWe retrospectively identified and categorized 1294 patients presenting to five University of California healthcare systems with a new diagnosis of PDAC into “pre‐lockdown” and “post‐lockdown” groups based on timing of pathologic diagnosis.ResultsIn the 12 months pre‐lockdown, 835 patients were diagnosed with PDAC, and 459 patients in the 6 months post‐lockdown. Demographics, staging, and treatment type were similar between eras. There was a decreased male:female ratio post‐ versus pre‐lockdown (0.97 vs. 1.25; p = 0.03). Time from symptom onset to first treatment was significantly increased among females post‐lockdown (p = 0.001). However, overall time from diagnosis to first treatment was shorter in the post‐lockdown era (median 23 vs. 26 days, p < 0.001).ConclusionsThe COVID‐19 lockdown did not significantly delay initial presentation, diagnosis, or treatment of newly diagnosed PDAC patients. Time from diagnosis to first treatment was shorter post‐lockdown. Reduced healthcare utilization for minor complaints and increased telehealth utilization may have contributed.

Abstract BACKGROUND One of the most significant unmet clinical challenges in paediatric oncology is the development of novel therapeutic strategies for recurrent medulloblastoma (R-MB). MYC-driven MBs are defined as classically cold tumours with a low incidence of infiltrating immune cells, resulting in a therapeutic challenge. The identification of cell-cell communications, particularly ligand–receptor pairs, allows for the inference of significant intercellular communications based on the expression of corresponding genes. Consequently, we hypothesised that the most influential cell-cell interactions within the tumour immune microenvironment (TME) of MYC-driven MB could unveil prevalent immune-suppressive interactions and potential vulnerabilities for therapeutic exploration. METHODS/RESULTS Paired primary-recurrent bulk RNA-sequencing data, confirmed myeloid cells as the most infiltrating immune cell type in group3-MB and group4-MB. Comprehensive spatial phenotypic and cell-cell communication analyses corroborated this discovery, validating an increased incidence of macrophages in the matched-recurrent tumours. Subsequently, we used innovative algorithms for MB single-cell data to predict interactions between tumour-cell ligands and immune-cell receptors within the TME; macrophages emerged as the core immune-cells involved in interactions throughout the TMEs, with the most significant ligand-receptor interaction and inflammatory response between MIF and CD74. In-depth immunohistochemistry analyses of primary and recurrent group3 and group4 tumours, and exhaustive tissue microarrays demonstrated expression of both CD74 and MIF, with limited expression of CD74 within the brain. To investigate the therapeutic potential of CD74, we developed recurrent, immune competent MYC-driven medulloblastoma mouse models. Comprehensive deconvolution analysis confirmed the TME integrity of our models to mirror that of the human disease. Locoregional delivery and repeat dosing of a bioactive-CD74 peptide demonstrated complete tumour clearance in our immune-competent mouse models, demonstrating the significant therapeutic potential of targeting the CD74-MIF axis in MYC-driven primary and recurrent MB. CONCLUSIONS Essential cellular interactions and therapeutic vulnerabilities have been identified in the tumour-microenvironment of MYC-driven primary-recurrent MB.

Abstract BACKGROUND Treatment and clinical management decisions for children with NF1-OPGs remain challenging as most existing data are retrospective and have not included standardized visual outcomes. In this study, we prospectively enrolled newly diagnosed NF1-OPGs and performed standardized neuro-oncology and ophthalmology assessments in order to develop evidence-based guidelines for monitoring and treatment. METHODS Children with NF1-OPG on MRI who were evaluated by both a study ophthalmologist and neuro-oncologist/NF1 expert within 1 month of radiologic diagnosis were eligible for enrollment. All subjects attempted quantitative visual acuity using Teller acuity cards (TAC) as well as ATS-HOTV testing. The neuro-oncologist/NF1 expert provided reasons for obtaining the MRI as well as initiating treatment, if applicable. Descriptive statistics calculated the success rate of acquiring TAC and reasons to obtain the MRI. RESULTS Two-hundred fifty subjects from 22 institutions were enrolled and had at least one visit beyond baseline (Median age 3.1 years, range 0.1–16.8; 53% female). TAC was successfully acquired in both eyes (N=195, 78%) and at least one eye in (N=206, 82%). ATS-HOTV was successfully acquired in both eyes (N=97, 39%) and at least one eye in (N=98, 39%). The two most common reasons to obtain an MRI were screening due to a diagnosis of NF1 (N=99, 39%) and ophthalmologic concern (N=81, 32%). At enrollment, continued observation occurred in a majority of subjects (N=221, 88%) while treatment with chemotherapy was initiated in only 11% (N=29). Twenty-nine (11%) subjects initially observed transitioned to treatment after enrollment (range: 2.5–25 months) thus far. DISCUSSION We present a prospective multicenter study of children with newly diagnosed NF1-OPGs. The ability to acquire quantitative visual acuity was higher than anticipated. The frequency of NF1-OPGs requiring treatment is lower than previously reported. Regression models of clinical and MRI features that prompted immediate treatment with chemotherapy versus observation will be discussed.

Abstract BACKGROUND NF1-OPGs are amorphous tumors involving either single or multiple locations (optic nerve, chiasm, tract) along the anterior visual pathway (AVP). In this prospective study, we investigated how volumetric MRI measures of the AVP as well as other clinical variables are associated with treatment decisions in children with newly diagnosed NF1-OPGs. METHODS Children with newly diagnosed NF1-OPG whose MRI included a T1-weighted volumetric sequence without significant artifact at their enrollment visit were eligible for inclusion. All subjects underwent a quantitative ophthalmic exam to determine if visual acuity (VA) was normal. The neuro-oncologist/NF1 expert determined whether the subject would be observed or undergo treatment at that baseline visit. Volumetric MRI analysis was automatically performed using a deep learning network that measured AVP volume (mm3). Non-parametric group comparisons and multivariable logistic regression models evaluated the impact of age at enrollment, sex, NF1 inheritance type, AVP volume, and VA on the decision for immediate treatment with chemotherapy versus observation. RESULTS One-hundred twenty-three subjects met inclusion criteria. Subjects assigned to observation (N=112, 44% female) and subjects immediately treated with chemotherapy (N=11, 80% female) at enrollment were of similar age (2.7 and 2.8 years, respectively) and inheritance (p &gt; 0.05). Abnormal VA was present more often in the treatment group (46%) compared to the observation group (17%, p &lt;0.001). AVP volume was significantly greater in the treatment group (4,181.1mm3) compared to the observation group (1,819.8mm3, p &lt;0.001). AVP volume, sex, and VA reached significance in univariable regression, however, in the multivariable regression model only the AVP volume (p &lt; 0.001) was significantly associated with treatment initiation. DISCUSSION Children with greater NF1-OPG AVP volumes are treated more often compared with those with lower volumes. Volumetric measures of NF1-OPGs are a valuable metric in understanding treatment patterns and are positioned to help inform clinical decision making.

3553 Background: Immuno-STATs are modular fusion proteins designed for the selective activation of tumor antigen specific CD8+ T cells. CUE-102, the second Immuno-STAT in clinical trials, is composed of a human leukocyte antigen (HLA) complex, HLA-A*0201, a peptide epitope derived from the Wilms Tumor 1 (WT1) protein, and 4 molecules of reduced affinity human interleukin-2 (IL-2). In preclinical studies CUE-102 binds, activates and expands WT1-specific CD8+ T cells with the potential to enhance anti-tumor immunity in patients with WT1+ cancers. Here we present the results of the dose-finding portion (Part A) of the CUE-102-01 study. Methods: CUE-102-01 is a 2 part phase 1 study. HLA-A*02:01 positive patients with WT1+ advanced colorectal (CRC), gastric (GA) and gastroesophageal junction (GEJ), pancreatic (PDAC) or ovarian (OvCa) tumors refractory to standard therapies were eligible for participation. WT1 status is determined by IHC via central testing. CUE-102 monotherapy was administered intravenously every three weeks in doses ranging from 1 mg/kg to 8 mg/kg following 3+3 design rules with a Bayesian Logistic Regression Model overlay. Dose levels that exhibit an immune or tumor response may be expanded to further characterize activity and toxicity as allowed by safety rules. Results: Dose escalation was successfully completed in 28 patients with CRC (17), PDAC (6), GA/GEJ (3) and OvCa (2). No DLTs were observed. Three dose levels (2, 4 and 8 mg/kg) exhibited evidence of immune activity and were expanded up to 9 patients each for further evaluation. CUE-102 was well-tolerated with > 96% of treatment-related adverse events (TRAEs) grade ≤2. The most common TRAEs, were fatigue, infusion reactions, nausea and vomiting. There were no cases of CRS Grade ≥ 2. Preliminary PK data demonstrate dose dependent increases in exposure across the dose range assessed. Preliminary analysis of patient samples demonstrates selective expansion of WT1-specific CD8+ T cells. Stable disease of ≥ 6 weeks (range 6-36 weeks), as determined by RECIST 1.1, has been observed in 10 of 23 patients (DCR 43.5%). Conclusions: CUE-102 is a novel T cell engager that demonstrates acceptable tolerability, favorable PK, and supportive preliminary PD readouts. No DLTs or drug-related SAEs have been observed in doses up to 8 mg/kg as of the data cut-off. Adverse events have been manageable and consistent with the CUE-102 mechanism of action and underlying disease. Early signs of disease stabilization and anti-tumor activity in late-stage patients are encouraging. Part B is a dose expansion that further evaluates safety, PK/PD, recommended phase 2 dose (RP2D), antitumor efficacy and is currently enrolling patients. Clinical trial information: NCT05360680 .