Response Data Research Articles

Evaluating patient and family preferences for acute and preventive pediatric headache treatment.

To describe acute and preventive treatment preferences among youth with migraine and their parents/guardians, and to describe the degree of youth-parent/guardian preference agreement. Headache disorders are common in youth, but little is known about patient and family preferences for headache treatments and outcomes. In this cross-sectional survey, a headache treatment preferences questionnaire was co-created with stakeholders, piloted, and distributed to consenting youth with migraine aged 9-18 years and parents/guardians at a tertiary care headache clinic in western Canada. Response data were summarized for youth and parents/guardians separately, and agreement rates within a youth-parent/guardian pair were compared to a hypothesized agreement rate of 80% for the primary questionnaire items. Seventy-two youth and n = 94 parents/guardians participated, with n = 63 in youth-parent/guardian pairs. Freedom from pain and rapid relief, and reducing pain severity and headache frequency were top acute and preventive treatment priorities, respectively. More than 90% (69/72) agreed that ≥ 50% reduction in headache frequency was a good target. For both acute and preventive interventions, swallowed pill-based options were most often selected as the preferred first-line treatment, with neuromodulation selected as the preferred second-line treatment. The level of agreement within youth-parent/guardian pairs on preferred treatment modalities was lower than hypothesized for acute (63% [40/63], 95% confidence interval [CI] = 52-75%, χ2 = 10.73, p = 0.001) but not for preventive treatment (73% [46/63], 95% CI = 62-84%, χ2 = 1.92, p = 0.166). Regarding which treatment modalities were perceived as most effective, youth-parent agreement was lower than hypothesized for both acute (48% [30/63], 95% CI = 35-60%, χ2 = 41.29, p < 0.001) and preventive treatment (46% [29/63], 95% CI = 34-58%, χ2 = 45.43, p < 0.001). Youth and family preferences aligned qualitatively, but sometimes diverged quantitatively, from typical clinical trial outcomes. The level of agreement within youth-parent/guardian pairs on treatment preferences and perceptions was low. Clinicians should consider both perspectives as they may be divergent.

Strategy to expedite gas sensor calibration based on cyclic temperature operation and data augmentation

The gas sensor calibration using data-driven approach requires a large volume of training data. The conventional method demands numerous measurements of response data, consuming substantial manpower and time resources. To expedite and streamline the sensor calibration and model deployment, this study proposes a cost-effective and practical calibration strategy combining data augmentation and data preprocessing. This strategy aims to minimize both the collection time and amount of measurement data necessary while ensuring high identification accuracy and generalization performance. The random cropping technique based on sliding sampling window is developed to expand the sample size by randomly and consecutively resampling new data from the limited raw response data. This approach allows any fixed-length sequence from the raw response curve to serve as the training and test sample, facilitating fast and real-time measurement for online detection and dynamic analysis. Furthermore, data preprocessing techniques using sequence normalization and fast Fourier transform are employed to extract the species and concentration features, thereby mitigating drift-like effects in the response data. The effectiveness of this strategy is demonstrated with real measurement data, showcasing significant improvements in identification accuracy and generalization performance compared to conventional methods.

Fibrolamellar carcinoma registry: Opportunities and challenges.

e16384 Background: Fibrolamellar carcinoma (FLC) is a rare form of primary liver cancer which affects young adults and adolescents without underlying liver disease or cirrhosis. The tumors are typically well circumscribed masses characterized pathologically by well differentiated polygonal hepatic cells with eosinophilic and granular cytoplasm surrounded by fibrous bands. DNAJB1 and PRKACA fusion is perceived as a dominant recurrent genetic alteration in FLC. FLC affects patients worldwide and a continued lack of an international database remains a knowledge gap. Further, there remains a poor understanding of FLC etiology, and major unmet need for more effective therapy. Methods: A patient-centered multi time-points, dynamic registry was developed by Memorial Sloan Kettering (MSK) in collaboration with Google and Maven Wave. The effort was supported by the Fibrolamellar Cancer Foundation (FCF). The study was opened worldwide except for the European Union pending the acquisition of the requiredGeneral Data Protection Regulation (GDPR) of data control and processing. The latter were assigned to Trinity College Dublin (TCD); a partner in this study. Participants were required to have a Google account to access the study. Demographic, clinical and response data were collected at baseline and at selected time points (monthly for up to 18 months). The aim of the registry was to provide a longitudinal understanding of the biography and natural history of the disease and outcomes. Results: Between May 2021 and December 2023, the study was broadcasted publicly worldwide through different venues including MSK, FCF, websites and Google engine. Only 14 patients responded. Table 1 summarizes the study sequence and patients’ enrollment. On average, the participants completed 41% of the monthly surveys. Four responders out of 5 patients were female, with a median age of 32 years (range 21-53). Conclusions: The registry provided a unique opportunity to access a broad global community of patients with FLC. Poor participation was key main limiting factor. Barriers include: (1) the presence of competing registries or studies for FLC, (2) technical limitations such as the exclusivity to access the registry to Google account. Follow-up emails may have been received in spam or junk folders, (3) complexities posed by the GDPR in Europe, and (4) patient-related factors including preoccupation with treatments and symptom management of their illness add to the disinterest in or inability to fill the monthly surveys. Unifying efforts and collaborations among caring physicians and scientists, medical centers, foundations, and patient advocacy groups across the world can help overcome the current challenges and accelerate the buildup of resources for research and practice improvement for the rare FLC. [Table: see text]

Real-world outcomes of teclistamab for the treatment of relapsed/refractory multiple myeloma at UC San Diego Health: A single-institution experience.

e19504 Background: Bispecific antibodies (BsAb) are emerging as a promising class of cancer immunotherapy. Teclistamab, a BsAb targeting B-cell maturation antigen (BCMA) expressed on plasma cells, received FDA approval for the treatment of relapsed/refractory (R/R) multiple myeloma (MM) in 2022. Here we describe the real-world experience of teclistamab at a single institution. Methods: We retrospectively reviewed patients with R/R MM who received teclistamab at University of California San Diego and had at least 6 months of follow up. Baseline characteristics, efficacy outcomes, and safety outcomes were collected. Kaplan-Meier method was used to describe survival. Results: A total of 18 patients who received teclistamab between 01/01/2023 and 06/15/2023 were included in this analysis. The median age was 67 years old (range 50-83). Median prior lines of therapy was 6.5 (range 3-11). All patients had triple-refractory disease; all but one had penta-refractory disease. Approximately 44% of patients had extramedullary plasmacytomas at time of BsAb initiation; 39% had received prior BCMA therapy (2 belantamab, 5 ide-cel) before teclistamab. High-risk cytogenetics (t(4;14), t(14;16), t(14;20), Del17p, Gain1q) were characterized for 13 patients with data available. 6 had a single high-risk mutation, 4 had two, and 1 had three. Incidence of cytokine release syndrome (CRS) was 12 (67%); (4 (33%) grade 2, no grade 3-5). 6 (50%) received tocilizumab to treat CRS. Immune effector cell-associated neurotoxicity syndrome (ICANS) incidence was 2 (11%); (1 (50%) grade 2, no grade 3-5). Pain crisis occurred in 11% of patients. The incidence of infection was 67%; the majority were grade ≥ 3. The overall response rate (ORR) by IMWG criteria was 50%. All patients who responded had a very good partial response (VGPR) or better; further response data was not available due to the lack of restaging bone marrow biopsies during treatment. Median duration of response for the entire cohort was not reached. Median progression-free survival (PFS) was 12.5 months (95% CI 1.0 – not reached); median overall survival (OS) was not reached (95% CI 7.8 – not reached).Univariate analyses showed no statistically significant relationship between response and prior BCMA therapy (p=.91), response and presence of extramedullary disease (p=.31), or response and mSMART risk stratification (p=.13). Conclusions: Overall, the incidence and grades of CRS, ICANS, and infection in our cohort were similar to those observed in the phase I/II MajesTEC-1 trial. In contrast, the ORR and PFS in this study were lower compared to the MajesTEC-1 study. This difference may be due to a greater proportion of patients with high-risk cytogenetics and more aggressive disease, as depicted by the higher median prior lines of therapy and higher rates of extra-medullary plasmacytomas and triple-/penta-class refractory disease.

A phase 2 trial of IO102-IO103 and nivolumab-relatlimab fixed-dose combination in previously untreated, unresectable melanoma.

TPS9605 Background: One emerging strategy to augment immune checkpoint inhibitor efficacy is to eliminate immunosuppressive cell populations in the tumor microenvironment (TME) through vaccination. IO102-IO103 is an investigational cancer vaccine that targets both tumor and immune-suppressive cells in the TME. IO102-IO103 treatment promotes inflammation and potentiates anti-tumor activity via activation and expansion of T cells against IDO1 and/or PD-L1 positive cells. IO102-IO103 plus nivolumab demonstrated an impressive objective response rate (ORR) of 80% in the phase 1/2 MM1636 trial of 30 patients with previously untreated, unresectable melanoma, and a randomized phase 3 trial of pembrolizumab with or without IO102-IO103 (NCT05155254) is ongoing. No prior studies have evaluated IO102-IO103 in combination with dual PD-1 and LAG-3 blockade with nivolumab-relatlimab (nivo-rela), and to our knowledge there are no existing clinical data for other investigational agents in combination with nivo-rela. Methods: NCT05912244 is a single-arm, investigator-initiated trial testing IO102-IO103 in combination with nivo-rela in patients with previously untreated, unresectable melanoma. Twelve of forty-three planned patients have been enrolled. All patients will be treated with nivo-rela every four weeks for up to two years. IO102-IO103 will be administered subcutaneously every two weeks for the initial eight weeks, and then every four weeks for up to two years. An interim efficacy analysis for futility will be performed after response data are available for 21 patients. Eligible patients must have histologically confirmed, unresectable stage III or stage IV non-uveal melanoma, measurable disease by RECIST v1.1, an ECOG performance status of 0 or 1, and definitive treatment of any brain metastases. Prior systemic treatment in the neoadjuvant or adjuvant setting is allowed if completed at least six months prior to trial enrollment. Available pre-treatment melanoma tissue is required, and all patients will undergo an on-treatment study biopsy between the second and third dose of nivo-rela. Peripheral blood mononuclear cells will be collected prior to the first three doses of nivo-rela. The primary endpoint is ORR by RECIST v1.1, weighted by PD-L1 expression. Secondary endpoints include safety assessed by Common Terminology Criteria for Adverse Events v 5.0, progression-free survival (PFS) by RECIST v1.1, duration of disease response, and disease control rate. Exploratory correlative endpoints include assessment of changes in PD-L1 and IDO-expressing cells in the TME on paired tumor biopsies, identification of peripheral PD-L1 and IDO-reactive cells in the peripheral blood by ELISpot, and assessment of peripheral pre-treatment and on-treatment T cell clonality by TCR sequencing. Clinical trial information: NCT05912244 .

A first-in-human study of CRISPR/Cas9-engineered tumor infiltrating lymphocytes (TILs) product GT316 as monotherapy in advanced solid tumors.

2549 Background: A next-generation TIL product GT316 was engineered with CRISPR/Cas9 to genetically disrupt two key immunoregulatory targets identified from a genome-wide CRISPR screening platform and demonstrated significantly enhanced anti-tumor efficacy and persistence in pre-clinical animal studies with ameliorated TIL exhaustion profile. A first-in-human trial was initiated to evaluate the preliminary safety and efficacy of GT316 in advanced solid tumors. Methods: The first-in-class study is to enroll patients (pts) with advanced treatment-refractory solid tumors, especially gynecological tumors. Once the optimal biological dose (OBD) is identified, a monotherapy expansion phase will be initiated for pts with various solid tumors. Enrolled pts were preconditioned with a nonmyeloablative (NMA) lymphodepletion regimen and treated by infusion of the GMP-grade G316 product followed by IL-2 administration. Results: As of January 22, 2024, the dose escalation study enrolled 4 pts, all of whom were female with a median age of 58 years with 1 to 9 prior lines of systemic treatment. The median number of infused TIL cells was 1.0E+10. All pts experienced TRAEs with the majority being grade 1 or 2. Grade 3/4 TRAEs included lymphocyte count decreased, white blood cell count decreased, monocyte count decreased and neutrophil count decreased, which were related to the NMA regimen. No dose-limiting toxicities (DLTs) or TIL-related grade≥3 TRAEs were observed. Median time on study was 33.4 wks (8–35 wks). One pt with treatment-refractory cervical cancer experienced a confirmed complete response (CR) after 4 wks and the duration of response is 32 wks by now (RECIST 1.1). One ovarian cancer pt with 9 lines of previous systemic therapies experienced a confirmed partial response (PR) after 4 wks and the duration of response is 22 wks by now (RECIST 1.1). Response data will be continuously collected. The other two ovarian cancer pts experienced stable disease (SD) and progressive disease (PD), respectively. Despite varying doses of TILs (3.2E+09 to 1.90E+10) and IL-2 (up to 3.0E+05 IU/kg), all pts receiving GT316 showed robust TIL expansion post-infusion, which is positively correlated with administrated IL-2 doses. Enhanced IFN-γ secretion could be detected in the serum of the CR and PR pts compared to the SD and PD pts, indicating potential tumor antigen-specific response. Conclusions: The first-in-human study of GT316, a CRISPR/Cas9-dual KO anti-exhaustion TIL product, demonstrates good tolerability with encouraging preliminary anti-tumor efficacy as a monotherapy in pts with advanced solid cancers. The infusion of GT316 was associated with robust TIL expansion and IFN-γ secretion. Updated data with additional follow-up will be continuously collected, and OBD will be determined based on the overall data of safety and preliminary efficiency. Clinical trial information: NCT06145802 .

Optimizing the detection of emerging infections using mobility-based spatial sampling

Timely and precise detection of emerging infections is imperative for effective outbreak management and disease control. Human mobility significantly influences the spatial transmission dynamics of infectious diseases. Spatial sampling, integrating the spatial structure of the target, holds promise as an approach for testing allocation in detecting infections, and leveraging information on individuals’ movement and contact behavior can enhance targeting precision. This study introduces a spatial sampling framework informed by spatiotemporal analysis of human mobility data, aiming to optimize the allocation of testing resources for detecting emerging infections. Mobility patterns, derived from clustering point-of-interest and travel data, are integrated into four spatial sampling approaches at the community level. We evaluate the proposed mobility-based spatial sampling by analyzing both actual and simulated outbreaks, considering scenarios of transmissibility, intervention timing, and population density in cities. Results indicate that leveraging inter-community movement data and initial case locations, the proposed Case Flow Intensity (CFI) and Case Transmission Intensity (CTI)-informed spatial sampling enhances community-level testing efficiency by reducing the number of individuals screened while maintaining a high accuracy rate in infection identification. Furthermore, the prompt application of CFI and CTI within cities is crucial for effective detection, especially in highly contagious infections within densely populated areas. With the widespread use of human mobility data for infectious disease responses, the proposed theoretical framework extends spatiotemporal data analysis of mobility patterns into spatial sampling, providing a cost-effective solution to optimize testing resource deployment for containing emerging infectious diseases.

Updated safety and efficacy data of combined KRAS G12C inhibitor (glecirasib, JAB-21822) and SHP2 inhibitor (JAB-3312) in patients with KRAS p.G12C mutated solid tumors.

3008 Background: Resistance to KRAS G12C inhibitor in non-small cell lung cancer (NSCLC) can be overcome by SHP2 blockade. This concept was tested in Phase I study of glecirasib combined with JAB-3312 in patients (pts) with KRAS p.G12C mutated tumors. Promising preliminary data of safety and response were reported at the 2023 ESMO (653O). Here, we present the updated safety and efficacy data with treatment response and progression-free survival (PFS) of the combination therapy in front-line NSCLC. Methods: The phase 1/2a study [NCT05288205] evaluated glecirasib plus JAB-3312 in patients with KRAS p.G12C mutated solid tumors. The primary objective of the dose-escalation phase was to assess the safety and tolerability of the combination therapy, and the primary objective of the dose-expansion phase was to assess efficacy. Efficacy endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR), PFS by investigator per RECIST1.1 and overall survival. Glecirasib 400 mg or 800 mg daily was combined with various JAB-3312 doses and schedules. Results: As of December 1st, 2023, 179 pts were enrolled, including 157 with NSCLC, 17 with colorectal cancer, and five with other tumor types. Treatment-related adverse events (TRAE) ≥ grade 3 occurred in 41.9% of all pts. There were no treatment-related deaths. Discontinuation of either glecirasib or JAB-3312 due to TRAE occurred in 7.8% of all pts. The AE profile was unchanged from the last ESMO report. The most common ( &gt; 20%) TRAEs included anemia, ALT/AST increased, hypertriglyceridemia, bilirubin increased, neutropenia/leukopenia, creatine kinase increased, and edema. No overlapped toxicity was observed for this combination therapy. Amongst all pts enrolled, 88 had NSCLC and received the combination therapy as front-line treatment in seven dosing groups. The median follow-up duration was 6.1 (range:0.5-16.7) months. Eighty pts had at least once post-treatment efficacy assessment. The ORR was 72.5% (58/80) and DCR was 96.3% (77/80). In the group of glecirasib 800mg QD + JAB-3312 2mg one week on/one week off, the ORR was 77.8% (21/27) and DCR was 92.6% (25/27). The median PFS was not mature by the data cut-off date. The 6-month and 12-month PFS rate were 67.3% and 53.7%, respectively. Additional safety and efficacy data will be presented at the meeting. Conclusions: Glecirasib plus JAB-3312 has a manageable safety profile and a promising ORR and PFS as a front-line treatment for patients with KRAS p.G12C NSCLC. This combination will be further evaluated in a randomized phase III trial in NSCLC. Clinical trial information: NCT05288205 .

Long term outcomes in patients with recurrent/metastatic (R/M) salivary gland cancer (SGC) treated with immune checkpoint inhibitors (ICI).

e18063 Background: There is no standard of care systemic therapy in R/M SGC. Regimens containing ICIs are of interest, but overall response rates (ORRs) are low, and median duration of response (mDOR) and long term overall survival (OS) data are limited. We pooled mature data from two clinical trials evaluating the use of ICIs in SGC to evaluate long term outcomes. Methods: We combined the results of two phase I/II, open label, single arm trials utilizing ICIs in R/M SGC. NCT02538510 administered pembrolizumab 200 mg IV q3 weeks and vorinostat 400 mg PO 5 days on/2 days off. NCT03749460 administered nivolumab 3mg/kg IV q2 weeks x 12 doses, followed by 480 mg IV q4 weeks x 8 doses and ipilimumab 1 mg/kg IV q6 weeks x 4 doses with hypofractionated radiotherapy at 1-5 metastatic sites to a total dose of 24Gy/3 fractions over 1 week initiated 2 weeks after immunotherapy. All patients were ≥18 years with R/M disease, evidence of progression within 3 months of study entry, measurable disease per RECIST 1.1, EGOG PS 0-1, and adequate organ function at enrollment. PDL1 expression was not required for participation and prior ICI was not allowed. ORRs were evaluated by RECIST 1.1. OS and progression free survival (PFS) were estimated via the Kaplan-Meier method. Results: 45 patients were enrolled in the two studies from 11/2015-5/2022. The combined median age was 57 (IQR 46, 66). 26 (57.8%) were male; 33 (73.3%) were white and 10 (22.2%) were Asian. 27 (60.0%) had an ECOG PS of 0. Most common histology types were adenoid cystic carcinoma (21, 46.7%), acinic cell carcinoma (5, 11.1%), and salivary duct carcinoma (5, 11.1%). The ORR was 17.8% with all responders having a PR (n=8, histology types: 3 acinic cell, 2 adenoid cystic, 1 adenocarcinoma, 1 salivary duct, 1 lymphoepithelioma-like carcinoma). 20 (44.4%) had SD, with 16 (80.0%) of these responses lasting greater than 6 months. 16 (35.6%) had PD. One patient was not evaluable for RECIST due to rapid disease progression and death. At analysis, median follow up was 29.2 months (IQR 27.1-50.0) among survivors, mDOR was 26.7 months (range 7.1-69.5+), with three patients with ongoing response. Median OS and PFS were 25.4 (95% CI 14, 43.2) and 6.2 months (95% CI 3.9, 15.5) respectively. 23 (51.1%) patients received systemic therapy after trial ICI. Patients received: 4 additional ICI (3 PD-1 monotherapy, 1 ipi/nivo), 5 androgen deprivation therapy, 5 chemotherapy, 9 other treatments (dabrafenib/trametinib, everolimus, fam-trastuzumab deruxtecan, osimertinib, lenvatinib, investigational agents). Conclusions: Although SGC is heterogenous, responses to ICI were observed in multiple subtypes and were durable, similar to observations in other solid tumors. A significant proportion received subsequent lines of therapy post ICI, and exploration of ORR and PFS to next lines of therapy is of interest. Clinical trial information: NCT02538510 and NCT03749460 .

Exposure-response (ER) analyses of efficacy and safety of trastuzumab deruxtecan (T-DXd) to inform dosing recommendation in HER2-mutant non-small cell lung cancer (NSCLC).

e20545 Background: T-DXd, a novel human epidermal growth factor receptor 2 (HER2) targeting antibody drug conjugate, was evaluated at doses of 5.4 and 6.4 mg/kg every three weeks in Phase 1 or 2 trials in HER2 mutant (HER2m) NSCLC subjects, including Destiny-Lung01 (DL-01) and DL-02 trials1,2. ER analyses of key efficacy and safety endpoints were conducted to support the dosing recommendation of T-DXd in HER2m NSCLC. Methods: Exposure-efficacy (EE) analysis was performed using confirmed objective response (cORR) data from HER2m NSCLC in Phase 1-2 trials (N = 181). The dataset included primary analysis data cut from DL-011 and interim analysis data cut from DL-02. Exposure-safety (ES) analyses of T-DXd were performed, using pooled data from 11 Phase 1-3 trials (N = 1850) across tumor types, including DL-01 and DL-02, for safety endpoints of adverse events (AEs) associated with dose reduction or discontinuation, Grade3+ (G3+) AEs, serious AEs, G3+Anemia, G3+neutropenia, G3+thrombocytopenia, adjudicated any grade interstitial lung disease (ILD), and G3+ ILD. cORR and all safety endpoints, except ILD were analyzed by logistic regression; any grade ILD was analyzed by parametric time-to-event analysis. The T-DXd or DXd exposure metric and numerous patient-specific covariates were tested in the analysis. Results: T-DXd exposure had a positive but shallow relationship with cORR. The predicted cORR varied from 57% (95% credible interval (CrI): [36, 77]) to 65% (95% CrI: [41, 84]) across 5th and 95th percentile of T-DXd exposure respectively. No clinically meaningful difference in cORR was estimated across 5.4 and 6.4 mg/kg doses with predicted cORR values of 53% (95% CrI: [44, 60]) and 55% (95% CrI: [47, 62]) at T-DXd doses of 5.4 mg/kg and 6.4 mg/kg, respectively. ES relationships were consistent with previous T-DXd ES analyses in breast cancer (BC). Model-predicted AE rates were lower (up to 9%) in 5.4 mg/kg compared to the 6.4 mg/kg dose. Model-predicted safety at 5.4 mg/kg dose in HER2m NSCLC was similar to the approved dose of 5.4 mg/kg in BC. Conclusions: The ER analyses showed no clinically meaningful difference in efficacy between 5.4 and 6.4 mg/kg doses of T-DXd; and safety events were lower in 5.4 mg/kg, thus supporting the 5.4 mg/kg recommended dose for HER2m NSCLC. These findings were later confirmed based on primary analysis in DL-022 and support the utility of ER analyses in dosing recommendation. Reference: Li BT et al. N Engl J Med 2022;386:241-51 Goto K et al. J Clin Oncol 41:4852-4863. Clinical trial information: NCT03505710 , NCT04644237 .

A novel MRI-based tumor-targeting theragnostic agent: Magnetoelectric nanoparticles in an in vivo murine KRAS/P53 pancreatic flank tumor model.

3075 Background: Magnetoelectric nanoparticles (MENPs) are a novel material with a magnetoelectric (ME) property that allows for conversion of an external magnetic field to a local electric field (EF) that can be exploited to generate a Coulomb force to target and electroporate the relatively non-polarized tumor cell walls. We hypothesized that their local EF and superparamagnetic cores can be exploited as an MRI-based anti-cancer theragnostic agent for solid tumors. Methods: 35 immunocompetent C57BL/6 mice were inoculated with KPC961 pancreatic adenocarcinoma cells in their flank. The 27 mice with the largest tumors at 4 weeks were randomized into 5 cohorts based on treatment: 300 µg of MENP (300; n=6), 600 µg of MENP (600; n=6), 300 µg of low-ME coefficient MENP (LM; n=5), 300 µg of MENP without M1 MRI (NM; MRI field control, n=5), and normal saline (NS; MENP causal effect control; n=5). The 300, 600, LM, and NS cohorts had T2 MRI maps (M0) on a 7T MRI. NM had T2 weighted MRIs at M0. All mice had a neodymium magnet placed over their tumors for 12 hours after tail vein injections (300 µl for all mice) for targeting. The 300, 600, LM, and NS cohorts then underwent MRI mapping (M1) after magnet removal (No M1 MRI for NM). MRI mapping was repeated 5 days after (M2). NM had a T2 weighted MRIs at M2. M1 and M2 data were used to assess relaxation time (contrast effect) and tumor volume from M0, respectively. Student t and ANOVA tests were used to compare differences for tumor volume and relaxation time data and one-sided Fisher’s exact test was used for complete response (CR) data. Results: The median M0 tumor volume was 109.6 mm3 for all mice, and there were no differences between any cohort ( p = 0.978; Table). The 300 and 600 MENP cohorts demonstrated a 102.7% reduction in volume (M2/M0; 56.7% vs. 159.4% for NS and NM controls, p = &lt;0.001) and a 7.2% T2 negative contrast effect (M1/M0; 94.2% vs. 101.3% for NS, p = 0.046) compared to controls. Six mice in 300, 600, and LM (2 each) achieved a clinical CR (between 1 to 2 weeks after M1) vs. none in the NS and NM control cohorts ( p = 0.0418), without any recurrences until end of study (6 weeks after M2). Conclusions: This is the first report demonstrating the theragnostic effects of MENPs having both T2 contrast and locally ablative therapy properties as an in vivo tumor targeting agent. These results confirm prior pilot study and point towards irreversible electroporation as the likely mechanism of action (MOA) since the antitumor effect is not seen within the NM cohort. Additional studies characterizing the MOA, dose-response relationships, and immunomodulatory effects are needed to better understand their full clinical potential.[Table: see text]

Evaluation and refinement of Self-Directed Learning Readiness Scale for medical students.

This study evaluated the underlying subdomain structure of the Self-Directed Learning Readiness Scale (SDLRS) for medical students and refined the instrument to measure the subdomains to provide evidence for construct validity. Developing self-directed learners is a well-recognized goal amongst medical educators. The SDLRS has been frequently used, however, lack of construct validity makes it difficult to interpret results. To identify the valid subdomains of the SDLRS, items were calibrated with the graded response model (GRM) and results were used to construct a 30-item short form. Short-form validity was evaluated by examining the correspondence between the total scores from the short form and the original instrument for individual students. A five-subdomain model explained the SDLRS item response data reasonably well. These included: (1) initiative and independence in learning, (2) self-concept as an effective learner, (3) openness to learning opportunity, (4) love of learning, and (5) acceptance for one's own learning. The unidimensional GRM for each subdomain fits the data better than multi-dimensional models. The total scores from the refined short form and the original form were correlated at 0.98 and the mean difference was 1.33, providing evidence for validation. Nearly 91% of 179 respondents were accurately classified within the low, average, and high readiness groups. Sufficient evidence was obtained for the validity and reliability of the refined 30-item short-form targeting five subdomains to measure medical students' readiness to engage in self-directed learning.

A method for assessing the predictivity of drug-specific biomarkers before interventional clinical data is available.

e15170 Background: A key goal in precision oncology is to develop predictive biomarkers that can identify patients likely to benefit from a given treatment. The main hurdle for generating such biomarkers is the availability of datasets that match predictive features for each patient (clinical, omics etc.) with treatment and individual outcome data. Such datasets are hard to obtain for approved drugs, and nonexistent for drugs in development. In contrast, there is ample data matching predictive features with survival data, but methods that use such data to develop and validate drug-specific predictive biomarkers are lacking. Here, we introduce a method termed the Surrogate Clinical Outcome Test (SCOT), which assesses, using non-interventional data, whether a drug-specific biomarker will be beneficial in clinical settings. Together with our previously published ENLIGHT platform, this enables early development and validation of predictive biomarkers. Methods: The SCOT test assumes that a patient population that exhibits low expression of the drug target(s) can serve as a surrogate for patients receiving the investigated drug, in the sense that survival dependency on the biomarker score would be similar to that of patients with the same features who actually receive the drug. Hence, a good predictive marker will be characterized by a negative hazard ratio in this population. To ensure that the marker is drug-specific and not merely prognostic, cases for which the same is true also in the population with high target expression should not pass the test. We studied 6 targeted drugs for which interventional clinical data is available. We used SCOT to classify two known prognostic biomarkers, as well as drug-specific transcriptomic biomarkers developed by our ENLIGHT algorithm, and compared the classifications to marker predictivities on the interventional clinical datasets. Results: Of the 6 drug-specific biomarkers developed by ENLIGHT, SCOT classified 4 as predictive of response to the respective drug, one as prognostic, and one as neither. The classification of 4 of these 6 biomarkers was confirmed by the interventional data (67% accuracy). The two prognostic markers - KI67 and Proliferation Index - were identified by SCOT as such. That is, SCOT found an association between these two markers and survival, regardless of target expression, for targets of the 6 drugs tested. Conclusions: Our work presents a novel method to test predictive markers for virtually any targeted cancer drug using big non-interventional clinical data. A key feature of this method is that it offers an independent validation of predictive markers for drugs, based on human clinical data, even before the drug enters clinical development. Combined with our ENLIGHT platform for generating predictive biomarkers in the absence of direct response data, this creates a powerful pipeline for early biomarker development and validation.

Feasibility study utilizing a combinatorial functional precision medicine platform, Optim.AI, to help guide treatment for pancreatic cancer.

e13614 Background: Functional screening methods are increasingly applied to guide patient treatment and could be beneficial in indications with poor survival and response rates, such as pancreatic cancer. However, challenges faced when implementing ex vivo testing include complexities in obtaining sufficient tumor cells for different cancer types and maximizing the number of treatments tested with limited sample material. The latter is especially significant in informing clinical decision making as combination therapies are common with cancer, exponentially increasing the number of regimens to select from. To address this hurdle, we developed Optim.AI, a combinatorial functional precision medicine platform, which utilizes efficiently designed experiments and small data AI to expand to over 530,000 phenotypic response data points and predictively rank all actionable treatments within a 12-drug panel. In this feasibility study, we explored the application of Optim.AI on patient-derived tumor cells in pancreatic cancer. Methods: We established a procedure to run Optim.AI with isolated tumor cells from pancreatic cancer patients. After dissociation, these cells were then incubated to allow for 3D organoid formation within the following week. Upon organoid formation, the cells were treated with an FDA-approved panel of chemotherapy and targeted drugs. Cell viability was quantified post-drug treatment for analysis with Optim.AI software to rank all possible single to 4-drug combinatorial therapies for report generation. Results: The viability of the cells post-processing was high (mean = 97.4% live cells), passing the quality check of having at least 60% live cells before proceeding with Optim.AI testing. The success rate of organoid formation was 100% within 1 week of sample processing. The turnaround time from the receipt of samples to dissemination of the reports to clinicians was approximately a week (mean = 7.67 days). Z’ factor, a measurement of statistical effect size for high throughput screening, was demonstrated to be more than 0.5 for the reports generated, indicative of very good assays. The top ranked drug combinations were sensitive, with their normalized cell viability reported to be under 0.2, while the prior line of treatment was shown to be resistant, 100% concordant with previously observed clinical outcomes. Notably, Gemcitabine with either a HDAC or PI3K inhibitor was ranked high amongst the reports generated. Conclusions: Optim.AI had a high success rate in generating reports within a very short timeframe for pancreatic cancer. Comparing the top ranked therapies against the prior lines of treatment allows the clinicians to better evaluate the alternative treatments. Based on this initial feasibility study, Optim.AI could potentially be viable in guiding clinicians in managing treatment options for pancreatic cancer patients.

Advanced signal processing methodology of vibration response data toward Structural Health Monitoring purposes

Advanced signal processing methodology of vibration response data toward Structural Health Monitoring purposes

Neoadjuvant HPV16-specific arenavirus-based immunotherapy HB-200 plus chemotherapy followed by response-stratified de-intensification in HPV16+ oropharyngeal cancer: TARGET-HPV.

6017 Background: The role of immunotherapy in curative viral-mediated oropharyngeal cancer (OPC) remains undefined. Human papillomavirus (HPV) 16 positive (+) OPC constitutively expresses viral epitopes that drive antigen-specific anti-tumor immunity, supporting rationale for evaluating neoadjuvant HPV16 directed therapeutics in non-metastatic OPC. HB-200 is an arenavirus-based vector therapy derived from LCMV (HB-201) and Pichinde virus (HB-202) each expressing a non-oncogenic HPV16 E7E6 fusion protein to induce HPV16 specific CD8+ T-cell responses. Building on our OPTIMA II results demonstrating that neoadjuvant chemotherapy/nivolumab led to deep responses in 71% of patients who went on to receive reduced radiation (RT), we hypothesized that adding HB-200 to chemotherapy to drive HPV16-specific anti-tumor immunity would be safe and effective to further deepen responses and facilitate more de-escalation. Methods: In this Phase 1 dose escalation investigator-initiated study, patients with non-metastatic HPV16+ OPC were treated with escalating doses of HB-201 single vector (Arm A) or HB-202/201 alternating vector (Arm B) x3 with neoadjuvant carboplatin AUC5 on day 1 and paclitaxel 100mg/m2 on days 1/8/15 of a 21-day cycle for 3 cycles. Deep responders (≥50% tumor shrinkage) received transoral robotic surgery (TORS) alone or RT to 50Gy +/- cisplatin, while non-responders (&lt;50% shrinkage) received 50 or 70Gy of RT with cisplatin. Primary objective was safety/tolerability and recommended phase 2 dose of HB-200 with chemotherapy. Additional objectives included deep response rate, circulating tumor (ct) HPV-DNA dynamics, and HPV16-specific T-cell response. Results: Twenty-one patients with HPV16+ OPC were enrolled and treated (Arm A, n=9, 43%; Arm B, n=12, 57%). Median age 57, 91% male, 75% base of tongue, 52% non-smokers, and 33% stage II/III (AJCC 8th edition). ≥Grade 3 treatment-emergent adverse events (AEs) occurred in 13 (62%) of patients overall and 3 (14%) non-hematologic during neoadjuvant. There were no Grade 4 AEs reported. All patients completed neoadjuvant HB-200/chemotherapy and response-stratified locoregional treatment. Deep responses following HB-200/chemotherapy were observed in 17/21 (81%) of patients, and in 14/15 (93%) treated on higher dose levels 1 or 2 ( p=0.05). All three patients who underwent TORS had no viable tumor at time of surgery. Two patients (9%) had persistent disease following CRT and underwent salvage surgery with no evidence of disease at last follow-up. ctHPV-DNA and HPV16-specific T-cell response data will be presented at the meeting. Conclusions: Neoadjuvant HB-200/chemotherapy is safe and feasible with early efficacy signal in this setting warranting further study. Enrollment to the subsequent randomized phase II part is ongoing (NCT05108870). Clinical trial information: NCT05108870 .

A meta-analysis analyzing the efficacy of trastuzumab-deruxtecan (T-DXd) on central nervous system (CNS) disease in patients with metastatic breast cancer (mBC).

e14012 Background: CNS metastasis from mBC portends a poor prognosis. We sought to analyze CNS activity of T-DXd through a meta-analysis. Methods: A systematic search with terms encompassing BC and T-DXd was conducted in PubMed, Embase, Scopus, and Cochrane on November 23 2023. There were no search restrictions. A total of 2318 records were identified, and duplicates were removed using Mendeley. 1189 records that remained were imported into Rayyan, and the titles were screened independently by 2 reviewers. 47/75 full texts were relevant, of which 12 [7 clinical trials and 5 retrospective study] were included for analysis. Only studies that provided stratified CNS response data for mBC were included. RevMan was used to analyze the Risk Ratio (RR) and Odds Ratio (OR) with 95% Confidence Interval (CI), derived from Random Effects (RE) model with Mantel-Haenszel (MH) method. Binary RE Pooled Proportions (PP) using DerSimonian-Laird method were determined using OpenMeta. Visual inspection of our funnel plots revealed no bias. Results: The T-DXd cohort had a total of 377 patients with a median age of 54.2 years (42.5-69). Control group (T-DM1-1, Chemotherapy-2 studies) had 86 patients with a median age of 54.5 years (54.2-54.7). All studies had previously treated patients and most of the patients received local therapy. PP with T-DXd for CNS Complete Response (CR) was 4.8% (2-7.6%). Partial Response (PR) was 50.1% (32.4-67.7%) and Stable Disease (SD) was 28.9 (20.5-37.3%). PP of Objective Response Rate (ORR) (CR+PR) was 60.9% (48.3-73.5%). Drug discontinuation rate was 18% (12.2-23.9%) and pneumonitis rate was 14.5% (9.4-19.6%). RR for Event/Progressive Disease (PD) comparing T-DXd and control group was not significant [0.96 (0.77,1.2) p=0.74, I²=0%], nor was OR for Disease Control Rate (DCR) (CR+PR+SD) [1.11 (0.63,1.96) p=0.64, I²=0%] (Table). The median Progression Free Survival (PFS) was 14.1 (8.5-18.1) months for the T-DXd and 4.3 (3-5.6) months for the control group. Conclusions: Although direct comparison between the pooled T-DXd and control group failed to reveal a difference, the pooled ORR from 10/12 studies was clinically significant at 60.9%. The median PFS for T-DXd was also longer. T-DXd could be a viable treatment option for pretreated HER2+ and low mBC with CNS metastasis. Limitation of our study is the heterogeneity between the studies, entailing the need for future clinical trials in this setting. [Table: see text]

Beacon: A phase II study of bevacizumab, atezolizumab, and cobimetinib in patients with recurrent, platinum resistant, high grade serous ovarian cancer.

5565 Background: Platinum resistant high grade serous ovarian cancer (HGSC) is associated with a poor prognosis and limited treatment options. Immune checkpoint inhibitors have failed to show significant impact in treatment of HGSC to date. Bevacizumab (anti-VEGF) and atezolizumab (anti-PDL1) have shown synergy in multiple cancer types. Cobimetinib (MEK inhibitor) may also potentiate immune responses, particularly by altering the tumour microenvironment. We sought to evaluate the efficacy of cobimetinib, bevacizumab and atezolizumab in women with platinum resistant HGSC. Methods: BEACON is a Phase II single arm study of cobimetinib (60mg oral D1-21 q 28-days), bevacizumab (5mg/kg IV q2w) and atezolizumab (840mg IV q2w from Cycle 2) in patients with platinum-resistant recurrent HGSC. Patients continued therapy until progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR) according to RECIST 1.1 at 24 weeks. Secondary endpoints included best overall response (BOR), safety, progression free survival, and response duration. Correlative studies on paired tumor biopsy and blood samples will explore molecular characteristics/subtypes and potential biomarkers of response as exploratory objectives. This study has now completed accrual and we present the 24-week response data, with a data cut off 21st December 2023. Results: Twenty-nine patients were enrolled between September 2018 and June 2023. Median age was 62 years (range 37 - 79) and 97% had received ≥ 2 prior lines of chemotherapy. The median number of cycles received was 3 cycles of atezolizumab and cobimetinib, and 4 cycles of bevacizumab. The ORR at 24 weeks was 21% [95% CI: 8-40], and a further 28% had stable disease as assessed per RECIST. Five patients (17%) have remained on study treatment for ≥ 52 weeks to date, suggesting that in some patients there was durable disease control. In terms of safety, 22 patients (76%) required a dose reduction in cobimetinib, mainly due to gastrointestinal and skin toxicity. Seventeen patients (59%) experienced a ≥Grade 3 treatment related adverse event, most commonly hypertension (6 patients, 21%). Two patients (7%) discontinued all study treatments due to toxicity. Conclusions: Preliminary results from this study show promising efficacy with the combination of atezolizumab, bevacizumab and cobimetinib in platinum resistant HGSC. Duration of response, progression free survival data and translational data exploring molecular characteristics will be presented as data matures. Clinical trial information: NCT03363867 . [Table: see text]

A rapid assessment tool for systemic treatment outcomes in colorectal cancer with deep bidirectional transformers.

e15567 Background: Retrospective investigations involving cancer treatment encounter the challenge of manually reviewing voluminous imaging reports to identify the best responses and the timing of disease progression. Here, we employed natural language processing, specifically deep bidirectional transformers, to automate the extraction of treatment response data. Methods: Data were sourced from the Yonsei Cancer Data Library database, focusing on patients with stage II-IV colorectal cancer at the Yonsei Cancer Center from Jan 1, 2010, to Dec 31, 2020. Imaging reports from 6,574 patients were gathered, amounting to 97,119 CT readings. Among these, 9,000 CT reports corresponding to 2,859 patients were randomly subjected to multilabel manual labeling by four radiology experts, based on the RECIST version 1.1 classification (CR/NED, PR, SD, PD). The pretrained BERT-base-uncased model was employed and fine-tuned for the downstream tasks of multilabel classification. 6,765 reports were used for training, while the remaining 1,000 reports were divided equally between the validation and test sets. Additionally, an algorithm for integrating and extracting treatment response data was also implemented. Clinical data were meticulously collected for 47 patients with stage IV early-onset colorectal cancer (EOCRC) receiving palliative first-line chemotherapy. The primary objective was to evaluate the model’s accuracy in predicting the timing of disease progression events within a ±30-day window. Secondary objectives focused on the model’s ability to identify the best response and its timing within a ±45-day window. Results: The evaluation of the classification accuracy across 1,000 individual CT reports, categorized as CR/NED (319), PR (86), SD (272), and PD (298), revealed accuracy with an AUROC of 0.956 and an F1 score of 0.823. All EOCRC patients were initially diagnosed with stage IV disease, and 45 out of 47 (95.7%) underwent metastasectomy either before initiating chemotherapy or during the first-line chemotherapy treatment. In clinical evaluation, the model demonstrated 72.3% (95% Confidence Interval [CI], 59.5-85.1) accuracy in predicting the day of disease progression within a ±30-day window. It achieved 55.3% (95% CI, 41.1-69.5) accuracy in predicting the best response category and its timing within ±45-days. Notably, the model was more accurate in predicting CR/NED at 72% compared to SD and PR, which had accuracy of 27.3% and 15.4%, respectively. Conclusions: Our model demonstrated high performance in classifying CT reports, which is expected to provide rapid insights into patient progress and improve clinical decision-making. However, the complexity involved in integrating and extracting data result in slight constraints in performance. This emphasizes the need for further research into multimodal large language models that can integrate a wider variety of clinical data.

Using Machine Learning to Determine a Functional Classifier of Retaliation and Its Association With Aggression

ObjectiveMethods to determine integrity of integrated neural systems engaged in functional processes have proven elusive. This study sought to determine the extent to which: (i) a machine learning retaliation classifier (retaliation vs. unfair offer) developed from a sample of typically developing (TD) adolescents could be applied to an independent sample of clinically concerning (CC) youth; and (ii) the classifier-determined functional integrity for retaliation was associated with antisocial behavior, proactive and reactive aggression. MethodBOLD response data were collected from 82 TD and 120 CC adolescents whilst they performed a retaliation task. The Support Vector Machine (SVM) algorithm was applied on the TD sample and tested on the CC sample (adolescents with externalizing and internalizing diagnoses). ResultsThe SVM was able to distinguish the offer from the retaliation phase after training in the TD sample (accuracy=92.48%, sensitivity=89.47% and specificity=93.18%) that was comparably successful in distinguishing function in the test sample. Increasing retaliation distance from the hyperplane was associated with decreasing conduct problems and proactive aggression. ConclusionsThe current study provides preliminary data of the importance of a retaliation endophenotype whose functional integrity is associated with reported levels of conduct problems and proactive aggression.