Citations

e13718 Background: Oncology has evolved in the cyber era of medicine. The 21 st Century Cures Act mandated patient access to medical data (tests, provider notes) via patient portals connected to EHRs in order to facilitate patient engagement. Furthermore, the COVID-19 pandemic rapidly transformed patients’ interactions with portals by increasing reliance on telehealth and portal messaging. This shift has been well-documented in primary care, and emerging research suggests similar trends in oncology. More information is needed regarding how this has evolved post-pandemic. We present single academic institution real-world data (RWD) describing ongoing changes in patient messages and telephone calls in oncology. Methods: We quantified the changes (2019-2024) within oncology at Mayo Clinic Rochester campus including all care team, provider, nursing, and pharmacist visits, patient portal medical advice requests, patient calls, and messages sent to patients per year using Epic's SlicerDicer™ tool. Results: Patient visits/year dipped (-0.2%) from 2019 to 2020, but increased steadily from 2021 forward (Table 1). Patient portal advice requests increased significantly faster (Table 1); from 2019 to 2024, visits /year increased by 40%, while the number of advice requests increased by 131%. Patient calls/year increased more modestly (64%), while the number of messages sent to patients increased by 163% over this time. Conclusions: The transparency allowed by the Cures Act coupled with the impact of the pandemic has empowered patients to engage in their oncology care more proactively through the EHR. Patient-initiated portal messaging is increasing, with messages sent to patients from the oncology department similarly rising. Patient call volumes are also growing despite EHR messaging. Further research is necessary to better understand patterns of EHR use in oncology and explore ways to reduce clinician burnout that may arise from responding to this increased communication volume, as well as to understand the impact on patient satisfaction and outcomes. Changes in patient volume compared to patient calls and EHR messaging over time. Year Total Patient Visits Change in Patient Visits from Prior Year (%) Total Patient Medical Advice Messages Change in Patient Medical Advice Message Volume from Prior Year (%) Total Patient Calls Change in Patient Call Volume from Prior Year (%) Messages Sent to Patients Change in Patient Messages Sent to Patients from Prior Year (%) 2019 62,440 n/a 173,177 n/a 195,143 n/a 99,974 n/a 2020 61,959 -0.7 218,976 +26.5 240,833 +23.4 135,044 +35.1 2021 70,950 +14.5 276,561 +26.3 267,395 +11.0 165,293 +22.4 2022 74,961 +5.7 325,580 +17.7 263,732 -1.4 206,043 +24.7 2023 80,672 +7.6 349,756 +7.4 274,446 +4.0 214,257 +4.0 2024 87,605 +8.6 399,740 +14.3 319,963 +16.6 263,271 +22.9

5515 Background: Clear cell ovarian carcinoma (CCOC) is a chemoresistant subtype of ovarian cancer. Immune checkpoint inhibitors have been reported to have clinical activity in CCOC. Additionally, CCOC harbors molecular alterations suggesting a role for anti-angiogenic agents. We therefore conducted a single-arm two-stage phase 2 trial to investigate the clinical activity of the combination of the PD-1 inhibitor pembrolizumab with the anti-angiogenic tyrosine kinase inhibitor lenvatinib in patients (pts) with CCOC. Methods: Pts with CCOC and measurable disease received pembrolizumab 200 mg IV every 3 weeks and lenvatinib 20 mg daily. Pts could have received an unlimited number of prior therapies; prior bevacizumab and immune checkpoint inhibitors were allowed, but prior lenvatinib was exclusionary. Malignant bowel involvement was not allowed. Co-primary endpoints were objective response rate (H 0 5%; H a 25%) and rate of PFS at 6 months (mo) per RECIST v1.1 (H 0 10%; H a 30%), restricting the probabilities of type I and type II errors to 10% and 10%, respectively. Two pts with objective responses or 3 pts progression-free and alive at 6 mos were needed to proceed from stage 1 (n=18) to stage 2 (n=13); 5 pts with objective responses or 6 pts progression-free and alive at 6 mos were needed to declare the combination worthy of further study. Results: Data cut-off occurred 22-Oct-2024. Of 30 enrolled pts, 83.3% were white; the mean age among all pts was 54.1 years. 30% of pts (9/30) experienced a confirmed response (2 CR, 7 PR); an additional 3 pts (10%) experienced unconfirmed PRs and 4 pts (13.3%) had SD ≥6 mo. As of data cut-off, 3 pts (10%) had not yet reached their first radiographic assessments, and 17 pts were still receiving study therapy. With a median of 9.72 mo of follow up, 16 pts were alive and progression-free at 6 months. The estimated 6-month PFS was 75.96% (95% CI 53.82-88.51%). Median PFS was 10.9 mo. The estimated 12-month PFS was 48.86% (95% CI 23.67-70.04%). The most common any-grade TRAEs were hypertension (71%), hypothyroidism (66%), and fatigue (60%). There were no unanticipated TRAEs. Conclusions: The combination of pembrolizumab/lenvatinib demonstrates encouraging evidence of clinical activity in CCOC, with 9 pts experiencing a confirmed response and 16 pts alive and progression-free at 6 months. As both co-primary endpoints of the study were met, enrollment closed with 30 pts. Updated data for all pts will be reported. There were no new safety signals. Clinical trial information: NCT05296512 .

3040 Background: EVEREST-2 is a first-in-human, phase 1/2 trial to assess the safety and efficacy of A2B694, an autologous, logic-gated Tmod CAR T therapy targeted to MSLN, which is normally expressed in the mesothelium and can be upregulated in many solid tumors. A2B694 is designed to overcome challenges of on-target, off-tumor toxicity that have limited other MSLN-targeted approaches by combining a CAR-activating receptor targeting MSLN with a blocker CAR that recognizes HLA-A*02, to distinguish between normal and tumor cells (Tokatlian, et al. J Immunother Cancer. 2022). Methods: Adults with recurrent unresectable, locally advanced, or metastatic cancers with MSLN expression who have progressed after standard-of-care therapy are eligible for EVEREST-2. Enrollment to EVEREST-2 and collection of T-cells occurs through the ongoing prescreening study BASECAMP-1 (NCT04981119). When clinically appropriate, A2B694 is manufactured from cryopreserved T cells, and patients undergo lymphodepletion before A2B694 infusion. The dose-escalation phase is evaluating the safety and tolerability of A2B694 to identify the recommended phase 2 dose (RP2D). Dose escalation was started at 1x10 8 Tmod positive cells (dose level [DL] 1) and will increase up to 14x10 8 in combination with low-dose IL-2 (DL 5). The dose-expansion phase will confirm RP2D and collect biomarker data to further characterize A2B694. Results: As of January 15, 2025, 5 participants (median age: 60 years; range, 50-84) have enrolled on EVEREST-2 and received A2B694 at DLs 1-2; participants had ovarian cancer (n = 3), pancreatic cancer (n = 1), and non-small cell lung cancer (n = 1) and had received a median of 4 prior lines of therapy (range, 1-7). Lymphodepleting chemotherapy was well tolerated with no significant cytopenias observed. The most common adverse events were lymphopenia (7 [14.6%]) and decreased appetite (6 [12.5%]). There were no dose-limiting toxicities, cytokine release syndrome, nor related neurotoxicity. One participant was admitted to the hospital for decreased appetite. No long-term toxicities have been noted up to 7.5 months post-infusion. Of the participants who have received A2B694, 5 were efficacy evaluable at DLs 1-2. A2B694 was detected post-infusion in the peripheral blood in all patients. Additionally, A2B694 was detected in an abdominal tumor biopsy from a patient with pancreatic cancer 42 days post-infusion. Conclusions: The logic-gated approach was successful at reducing toxicity seen with prior MSLN-targeted CAR T therapies, and A2B694 showed successful CAR T expansion and tumor infiltration. The maximum tolerated dose has not been reached, and results from the dose-escalation phase continue to determine the RP2D. Clinical trial information: NCT06051695 .

9578 Background: Anti-PD1 immunotherapy has shown improved clinical outcomes in patients (pts) with advanced cSCC, and recently, in the neoadjuvant setting for resectable disease. Pathological (path) response is predictive of recurrence in melanoma and recent NeoIT trials suggests the same in cSCC; however, an analysis of clinical outcomes in pts with resectable cSCC treated with intended anti-PD1-based NeoIT in larger datasets remains unknown. Methods: Pts with resectable cSCC treated with intended anti-PD1-based NeoIT from 17 cancer centres globally were included. Baseline patient and disease characteristics, treatment regimen, path response and recurrence-free survival (RFS) or progression-free survival (PFS) were collected and examined. Results: 134 pts with resectable cSCC were treated with intended anti-PD1-based NeoIT. Median age was 75 years old (range, 39-97), 72% (n=97) were male. One fifth (22%, n=29) were immunocompromised and 43% (n=58) had ECOG PS of ≥1. Of 125 (93%) pts with known primary cSCC, 82% (n=102) were from the head & neck. Most pts (79%, n=106) were stage III/IV. The majority had anti-PD1 monotherapy (91%, n=122) and 9% (n=12) had anti-PD1+/-investigational agent. Median follow-up from commencement of NeoIT was 10 months (95% CI, 9 - 12). Nearly half of the pts (49%, n=66) underwent surgery; 37 (56%) pts had major pathological response (MPR; ≤10% viable tumour cells at the surgical specimen; 31 [47%] had complete path response [0% of viable tumour cells] and 6 [9%] had near complete path response [1-10% of viable tumour cells]), 6 (9%) had partial path response (pPR; >10% and ≤50% of viable tumour cells), and 23 (35%) had path non-response (pNR; >50% of viable tumour cells). Of the 66 pts who underwent surgery, 11% (n=7) had recurrence (5 loco-regional and 2 distant recurrence), all non-MPR pts (1 pPR and 6 pNR). 12-months RFS was improved with MPR vs non-MPR (100% vs 79%, p=0.004). 52% (n=34) pts had adjuvant treatment (23 anti-PD1 alone, 7 anti-PD1+/-investigational agent, 2 platinum and 2 cetuximab). Within non-MPR pts, 12 had adjuvant treatment (3 recurred; 25%), while 17 did not have adjuvant treatment (4 recurred; 24%). Fifty-one percent (n=68) of pts did not have surgery; 9 (13%) due to progressive disease (PD) and 53 (78%) due to clinical response. Of the 53 pts with a clinical response, 5 (9%) subsequently progressed. Fourteen (10%) pts have died, 6 (4%) related to cSCC; 2 had surgery (non-MPR) and 4 did not have surgery (all due to PD). Conclusions: Anti-PD1-based NeoIT is an active regimen in resectable stage II-IV cSCC and is associated with high clinical response and MPR rates. No pts with MPR from NeoIT has recurred to date, however, 9% of pts who did not have surgery due to clinical response eventually progressed. These findings highlight the importance of further research to investigate the role of surgery in this subgroup of patients.

TPS3164 Background: TUB-030 is a novel antibody-drug conjugate (ADC) targeting 5T4, an oncofetal antigen expressed in various solid tumors with limited expression in healthy tissues. TUB-030 leverages optimized biophysical properties, an effector-silenced antibody, and an exatecan payload to maximize the therapeutic index and minimize off-target toxicities. Preclinical studies demonstrated potent anti-tumor activity, including long-lasting tumor regression at doses as low as 1 mg/kg and durable responses even in tumors with low 5T4 expression. Methods: 5-STAR 1-01 is a multicenter, first-in-human dose escalation and dose optimization Phase I/IIa clinical trial designed to investigate safety, tolerability, pharmacokinetics (PK), and efficacy of the anti-5T4 ADC TUB-030 in patients with advanced and metastatic solid tumors. Eligible patients have one of the following tumor types: head and neck squamous cell carcinomas (HNSCC), non-small-cell lung cancer (NSCLC), small cell lung cancer, pleural mesothelioma, triple-negative breast cancer, HR+/HER2- breast cancer, esophageal cancer, gastric cancer, pancreatic adenocarcinoma, colorectal cancer, bladder cancer, prostate cancer, cervical cancer, osteosarcoma, or soft tissue sarcomas and must have exhausted available standard-of-care therapies. Phase I is an open-label, single-arm dose escalation trial, with administration every 21 days. Dose escalation follows an accelerated titration design (ATD) transitioning to Bayesian optimal interval (BOIN) upon predefined toxicity thresholds. Backfill cohorts are planned in NSCLC and HNSCC to further evaluate the safety and efficacy profile at, or near, the maximum tolerated dose (MTD). Primary endpoints include safety and tolerability of TUB-030 as monotherapy, determination of the MTD and the recommended phase II doses; secondary endpoints assess pharmacokinetics, immunogenicity, and preliminary clinical activity using RECIST v1.1 criteria. Exploratory endpoints include analysis of circulating tumor DNA. In phase IIa, dose-optimization will evaluate two dose levels in select indications in order to identify the optimal dose for further development. Enrollment of approximately 130 patients across the US and Canada is planned, with dose escalation currently underway. This study investigates TUB-030, a novel 5T4 targeted ADC as a therapy for advanced/metastatic solid tumors. Clinical trial information: NCT06657222 .

Abstract Nearly half of premature deaths can be prevented with healthy lifestyle behaviours. However, most older adults do not adhere to established guidelines to promote a healthy lifestyle. We propose a tailored framework of lifestyle medicine that acknowledges the complex contexts and care needs of older adults. The proposed framework of lifestyle medicine for older adults integrates their lived experiences (e.g. social determinants of health, built environment), the 5 M framework of geriatric medicine (i.e. Mind, Mobility, Medications, Multicomplexity, Matters Most) and the six pillars of lifestyle medicine (i.e. nutrition/diet, physical activity/exercise, restorative sleep, stress management, avoidance of risky substances, positive social connections) through a novel transdisciplinary approach. Guided by the updated framework, key gaps and opportunities are presented to advance lifestyle medicine practice, research and policy with the goal of promoting sustained behaviour change and improving the healthspan of older adults.

Importance Nontraumatic subarachnoid hemorrhage (SAH) represents the third most common stroke type with unique etiologies, risk factors, diagnostics, and treatments. Nevertheless, epidemiological studies often cluster SAH with other stroke types leaving its distinct burden estimates obscure. Objective To estimate the worldwide burden of SAH. Design, Setting, and Participants Based on the repeated cross-sectional Global Burden of Disease (GBD) 2021 study, the global burden of SAH in 1990 to 2021 was estimated. Moreover, the SAH burden was compared with other diseases, and its associations with 14 individual risk factors were investigated with available data in the GBD 2021 study. The GBD study included the burden estimates of nontraumatic SAH among all ages in 204 countries and territories between 1990 and 2021. Exposures SAH and 14 modifiable risk factors. Main Outcomes and Measures Absolute numbers and age-standardized rates with 95% uncertainty intervals (UIs) of SAH incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) as well as risk factor–specific population attributable fractions (PAFs). Results In 2021, the global age-standardized SAH incidence was 8.3 (95% UI, 7.3-9.5), prevalence was 92.2 (95% UI, 84.1-100.6), mortality was 4.2 (95% UI, 3.7-4.8), and DALY rate was 125.2 (95% UI, 110.5-142.6) per 100 000 people. The highest burden estimates were found in Latin America, the Caribbean, Oceania, and high-income Asia Pacific. Although the absolute number of SAH cases increased, especially in regions with a low sociodemographic index, all age-standardized burden rates decreased between 1990 and 2021: the incidence by 28.8% (95% UI, 25.7%-31.6%), prevalence by 16.1% (95% UI, 14.8%-17.7%), mortality by 56.1% (95% UI, 40.7%-64.3%), and DALY rate by 54.6% (95% UI, 42.8%-61.9%). Of 300 diseases, SAH ranked as the 36th most common cause of death and 59th most common cause of DALY in the world. Of all worldwide SAH-related DALYs, 71.6% (95% UI, 63.8%-78.6%) were associated with the 14 modeled risk factors of which high systolic blood pressure (population attributable fraction [PAF] = 51.6%; 95% UI, 38.0%-62.6%) and smoking (PAF = 14.4%; 95% UI, 12.4%-16.5%) had the highest attribution. Conclusions and Relevance Although the global age-standardized burden rates of SAH more than halved over the last 3 decades, SAH remained one of the most common cardiovascular and neurological causes of death and disabilities in the world, with increasing absolute case numbers. These findings suggest evidence for the potential health benefits of proactive public health planning and resource allocation toward the prevention of SAH.

Background Endovascular therapy (EVT) for stroke due to distal or medium vessel occlusion (DMVO) is safe. Due to the distinct anatomical characteristics of DMVOs, further evaluation of EVT is crucial to determine which devices may yield better outcomes. Methods A retrospective analysis of adults with DMVO treated in 37 centers (11 countries) was queried. The primary outcome of favorable shift in 90-day modified Rankin Scale (mRS) was compared between patients treated with Trevo versus other devices on first pass using 1:1 propensity score matching (PSM) with multivariable adjustment. Secondary outcomes included the number of pass attempts, final thrombolysis in cerebral infarction (TICI) score 2b-3, symptomatic intracranial hemorrhage (sICH), improvement in National Institutes of Health Stroke Scale (NIHSS) at 24h, and 90-day mortality. Results Of the 1115 included patients, 264 (24%) were treated with Trevo (PSM cohort of 261 per group). Trevo use was not associated with a favorable 90-day mRS shift (proportional odds ratio [OR] 1.10, 95% confidence interval [CI] 0.80–1.51). Trevo was associated with fewer passes (adjusted β=-0.25, 95% CI −0.48 - −0.03), higher odds of TICI 2b-3 (adjusted OR 1.97, 95% CI 1.11–3.49), and a greater 24h NIHSS improvement (adjusted β= −1.74, 95% CI −3.11 - −0.36), with no difference in sICH or mortality (p>0.05). Results were similar in sensitivity analyses. Conclusions We observed no safety concerns with Trevo as compared to other EVT devices for DMVO recanalization. There was a signal of better technical efficacy and early clinical improvement.

BACKGROUND Treatment of tubo-ovarian high-grade serous carcinoma (HGSC) includes cytoreductive surgery, platinum-based chemotherapy, and often poly(ADP-ribose) polymerase (PARP) inhibitors. While homologous recombination (HR) deficiency is a well-established predictor of therapy sensitivity, over 50% of HR-proficient HGSCs also exhibit sensitivity. Currently, there are no biomarkers to identify which HR-proficient HGSCs will be sensitive to standard-of-care therapy. Replication stress may serve as a key determinant of response. METHODS We evaluated phospho–RPA2-T21 (p-RPA2) foci via immunofluorescence as a biomarker of replication stress in formalin-fixed, paraffin-embedded HGSC samples collected at diagnosis from patients treated with platinum chemotherapy (discovery cohort, n = 31; validation cohort, n = 244) or PARP inhibitors ( n = 63). Recurrent HGSCs ( n = 38) were also analyzed. p-RPA2 score was calculated using automated imaging analysis. RESULTS Samples were defined as p-RPA2-high if more than 16% of cells had ≥2 p-RPA2 foci on automated analysis. In the discovery cohort, HR-proficient, p-RPA2-high HGSCs demonstrated significantly higher rates of a chemotherapy response score of 3 to platinum chemotherapy than HR-proficient, p-RPA2-low HGSCs. In the validation cohort, patients with HR-proficient, p-RPA2-high HGSCs had significantly longer survival after platinum treatment than those with HR-proficient, p-RPA2-low HGSCs. Additionally, the p-RPA2 assay effectively predicted survival outcomes in patients treated with PARP inhibitors and in recurrent HGSC samples. CONCLUSION Our study underscores the importance of considering replication stress markers, such as p-RPA2, alongside HR status in therapeutic planning. This approach has the potential to increase the number of patients receiving effective therapy while reducing unnecessary toxicity. FUNDING The Reproductive Scientist Development Program, GOG Foundation, Pilot Translational and Clinical Studies function of the Washington University Institute of Clinical and Translational Sciences, the Foundation for Barnes-Jewish Hospital, Washington University School of Medicine Dean’s Scholar Program, The Cancer Biology Pathway Training Grant (5T32CA113275-17), The Lucy, Anarcha, and Betsey (L.A.B.) Award from the Department of Obstetrics and Gynecology at Washington University School of Medicine, and Veterans Affairs Office of Research and Development (I01BX006020).

AbstractStandard of care first‐line systemic treatment for advanced biliary tract cancer includes chemo‐immunotherapy with gemcitabine, cisplatin, and durvalumab, followed by maintenance durvalumab monotherapy. The present work aims to investigate the differences in baseline clinical and molecular characteristics between patients with early progression during chemo‐immunotherapy and those who reach durvalumab maintenance therapy. The study population included patients with unresectable, locally advanced, or metastatic BTC who received treatment at 38 clinical Institutions in 12 countries from July 2021 to December 2023. The primary objective of the study was to investigate whether baseline clinical and molecular characteristics differed between patients with early progression during chemo‐immunotherapy versus those reaching durvalumab maintenance therapy. Four hundred forty‐eight patients were included in this study. Two hundred twenty‐seven patients (50.7%) received maintenance with durvalumab monotherapy, whereas 221 (49.3%) did not receive maintenance therapy due to PD during first‐line chemo‐immunotherapy before completing 8 cycles. Results show that patients who received maintenance were more likely to be older (≥70 years), have an ECOG = 0, locally advanced disease, and a neutrophil‐to‐lymphocyte ratio (NLR) <3. A higher proportion of patients with BAP1 mutations received maintenance, while TP53 mutations were more common in those who progressed early. According to the present analysis, a substantial proportion of patients (50.7%) with advanced BTC who were treated with chemotherapy plus durvalumab proceeded to receive maintenance therapy with durvalumab monotherapy, with a median treatment duration of 4.4 cycles. Patients ≥70 years, with ECOG PS 0, with locally advanced disease, and with NLR <3 had a higher likelihood of receiving maintenance therapy.