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Can overall survival (OS) benefit be predicted from improvements in progression-free survival (PFS) for previously untreated metastatic colorectal cancer (mCRC)?

222 Background: With improvements in treatment of mCRC, OS maintains its gold standard efficacy measure but takes longer to mature than intermediate endpoints. This study analyzed the association between treatment effects on PFS and OS using aggregate-level data from RCTs in previously untreated mCRC patients. Methods: A systematic literature review identified RCTs in previously untreated mCRC patients published from 2010–2021 reporting hazard ratios on PFS (HR PFS ) and OS (HR OS ). All treatments in comparison to chemotherapy alone or chemotherapy with anti-VEGF (bevacizumab) or anti-EGFR (cetuximab) targeted therapy were considered. Correlation between HR PFS and HR OS was evaluated using bivariate random-effects meta-analysis (BRMA) and weighted linear regression (WLR). Predictive performance of the surrogacy equations from WLR was assessed using leave-one-out cross-validation (LOOCV). Surrogate threshold effects (STE), defined as the minimum PFS benefit that would translate into a statistically significant OS benefit with 95% probability, were also derived to gauge the practical utility of the models. Primary analysis consisted of all included trials. Sensitivity analyses omitted trials that (I) had anti-EGFR medications, (II) had anti-VEGF medications, (III) violated proportional hazards assumptions, and (IV) permitted treatment crossover. Results: In the primary analysis 47 trials were included. The estimated correlation between PFS and OS was 0.67 (95% CI: 0.48–0.80) using BRMA and 0.70 (95% CI: 0.48–0.84) using WLR. The surrogacy equation derived from WLR was log(HR OS ) = −0.03 + 0.56 log(HR PFS ) with a statistically insignificant intercept and significant slope. Estimated STEs corresponding to sample sizes of 200 and 300 patients were 0.55 and 0.62, respectively. Observed HR OS ’s were within their 95% prediction intervals predicted from HR PFS for 93.6% of studies in LOOCV. Sensitivity analyses produced moderate correlations with >90% coverage in LOOCV (Table). Conclusions: Moderate correlations were found between HR PFS and HR OS using both modeling approaches, highlighting the stability of the findings. Cross-validations of surrogacy equations indicated promising predictive value of PFS benefit for OS benefit in previously untreated mCRC. Analysis Set​ # of Studies​ Correlation (95% CI) STE LOOCV​Coverage Rate​ BRMA WLR N = 200 N = 300 Sensitivity Analysis I​ 34​ 0.75 ​(0.57, 0.86)​ 0.78 ​(0.55, 0.90)​ 0.55​ 0.61​ 94.1​% Sensitivity Analysis II​ 14​ 0.44 ​(-0.08, 0.77)​ 0.62 ​(-0.05, 0.90)​ 0.44​ 0.52​ 92.9​% Sensitivity Analysis III​ 36​ 0.61 ​(0.36, 0.77)​ 0.59 ​(0.26, 0.80)​ 0.46​ 0.55​ 94.4​% Sensitivity Analysis IV 43​ 0.68 ​(0.48, 0.81)​ 0.67​(0.41, 0.83)​ 0.52​ 0.60​ 93.0​%

Comparative analysis of racial disparities in social determinants of health among patients with GI cancer in the All of Us dataset.

804 Background: Social Determinants of Health (SDoH) are key factors in understanding disparities in cancer treatment and outcomes. Examining SDoH across racial and ethnic groups helps uncover the mechanisms behind disparities and identify solutions. This study compared SDoH factors between White (non-Hispanic) and Non-White (Asian, African American, Hispanic) patients diagnosed with Gastrointestinal (GI) cancers using a national dataset. Methods: We analyzed data from the All of Us Research Program. Adult patients with GI cancers, identified via ICD-10 and SNOMED codes, who had completed the SoDH surveys were included. Comparative analyses were performed between White and Non-White participants across SDoH constructs, including social/community construct, neighborhood environment, economic stability, and healthcare access using Chi-squared, T-test, and Mann-Whitney U tests as appropriate. Results: Of the 6,620 GI cancer patients identified, 1,831 completed the SDoH survey, of which 13.9% were Non-White. The most common cancers were colon and liver, with pancreatic, stomach, rectal, esophageal, and biliary tract cancers also included. White participants were older than Non-White participants (71.0 vs. 64.2 years, SD = 10.7 and 11.4) and reported higher levels of social cohesion (Mean (SD) = 3.92 (0.70) vs. 3.64 (0.76), p < 0.001) and social support (Mean (SD) = 3.92 (1.00) vs. 3.68 (1.11), p < 0.001). Non-White participants experienced greater perceived discrimination (Mean (SD) = 1.73 (0.80) vs. 1.54 (0.57), p = 0.016) and reported more neighborhood physical disorder (p < 0.001). Food insecurity (23.6% vs. 5.8%, p < 0.001) and housing quality issues (41.8% vs. 21.8%, p < 0.001) were more common among Non-White participants, who also faced more delayed medical care (45.9% vs. 32.5%, p < 0.001). Conclusions: This study highlights racial disparities in SDoH among GI cancer patients. Non-White participants experienced greater economic instability and neighborhood disorder compared to White participants. The All of Us dataset offers valuable data for examining SDoH in this population, though it may not fully represent the broader US population. As the dataset expands, it will provide more opportunities for comparative analyses among cancer patients across racial and demographic groups. Construct White Non-Hispanic (n = 1489) Non-White (n = 255) P-Value Gender: Female, n (%) 827 (55.5) 167 (65.5) p = 0.010 Social Disorder; mean (SD) 2.10 (0.22) 2.17 (0.28) p = 0.002 Perceived Stress; mean (SD) 11.36 (7.12) 12.85 (7.99) p = 0.003 Global Physical Health T-score (SD) 37.16 (1.89) 36.26 (2.08) p < 0.001 Global Mental Health T-score (SD) 38.30 (1.76) 38.22 (1.86) p = 0.520 Food Insecurity; n (%) 170 (5.8) 117 (23.6) p < 0.001 Poor Housing Quality; n (%) 326 (21.8) 127 (41.8) p < 0.001 Delayed Medical Care; n (%) 484 (32.5) 117 (45.9) p < 0.001 Cannot afford specialist; n (%) 47 (4.2) 20 (11.9) p < 0.001

Use of molecular residual disease (MRD) testing with measurement of circulating tumor DNA (ctDNA) post-operatively in stage II colon cancer (SIICC) in the community-based setting.

53 Background: 80% of adult oncology patients (pts) are treated in the community-based setting. Data on the implementation of emerging technologies such as ctDNA testing is scant in this population. Use of adjuvant chemotherapy in SIICC pts historically was based on clinical/pathological risk factors however new data presented in mid 2022 utilizes the presence or absence of ctDNA 6-8 weeks post operatively to help risk stratify pts. The absence of ctDNA predicts a high chance of disease-free survival. Use of ctDNA was incorporated into the NCCN Colon Cancer guidelines as of 2023. In a private practice setting, we retrospectively looked at the use of ctDNA assay for adjuvant chemotherapy decision-making in SIICC pts. Methods: We conducted a retrospective study to quantify ctDNA testing frequency in SIICC pts in our community based oncology practice. The historical cohort was comprised of pts diagnosed prior to the NCCN guideline inclusion of ctDNA; the current cohort included pts diagnosed after the NCCN guideline change. For all pts, we reviewed clinicopathologic risk factors deemed to be high risk (positive margin, < 12 LN removed, tumor budding, lymphovascular invasion, poorly differentiated features; perforation or obstruction) and used this for stratification. Low-risk pts had no high risk features. Medical record data (office notes, pathology, molecular testing) was evaluated to determine ctDNA results including timing and use of adjuvant chemotherapy. Primary endpoint was the percent (%) of current pts who were low-risk with ctDNA testing sent compared to historical control. Secondary endpoint was the % of ctDNA testing sent within 8 weeks of curative surgery in both cohorts. Results: In a private practice setting, we identified low-risk SIICC pts spanning a 36-month period and categorized them into two groups: the historic cohort (A) pts were diagnosed between July 2021-Dec 2022, and the active cohort (B) pts were diagnosed between Jan 2023-July 2024. 26 pts were identified in cohort A and 36 pts were identified in cohort B to have SIICC. Out of 26 pts in cohort A, we identified 13 low risk SIICC pts; for cohort B, out of 36 pts, we identified 25 low-risk SIICC pts. The percentage of pts in each group that had ctDNA testing sent was 79.6% (10/13 pts) in cohort A and 92% (23/25 pts) in cohort B. In cohort A, 80% (8/10 pts) and in cohort B, 90.9% (20/22 pts) had ctDNA sent within 8 weeks of surgery. Conclusions: Incorporation of ctDNA testing in low-risk SIICC pts in a community-based setting occurred quickly. As ctDNA testing was implemented into practice, a majority of pts had the testing sent in the appropriate time frame. Future best practices, especially in the community, should incorporate tumor specific clinician oversight with use of updated pathways to ensure any recent changes to standard of care are followed.

Optimizing AI models to predict esophageal squamous cell carcinoma risk by incorporating small datasets of soft palate images

Automated radiomics model for preoperative pancreatic neuroendocrine tumor grade prediction.

655 Background: Pancreatic neuroendocrine tumors (PNETs) have varying biologic behavior based on factors including tumor grade. Many prognostic factors can only be determined post-pancreatectomy; thus, are unable to guide clinical decision making preoperatively. This is particularly relevant in small, non-functional (NF)-PNETs. Imaging analysis with radiomics may be able to elucidate biologic data such as tumor grade, without the need for tissue sampling. Our study aims to create an automatic pipeline from segmentation to radiomics-signature building to preoperatively predict tumor grade. Methods: Patients that underwent resection between 2003-21 with adequate preoperative arterial phase CT scans were divided into training and validation cohorts. In the training cohort, the pancreas and tumor region were manually segmented and used to train an auto-segmentation model. The validation cohort then underwent automatic segmentation. A total of 255 radiomics features were extracted from the tumor region. Correlated features were removed, and the minimum redundancy maximum relevance (mRMR) method was used to select the final feature set. These features were used to train a Support Vector Machine (SVM)-based classifier through the training cohort to predict grade, which was dichotomized into grade I versus II/III. The radiomic based prediction model was then evaluated in the automatically segmented validation cohort. Results: A total of 186 patients were identified and divided into training (n = 140) and validation (n = 46) cohorts. Median age was 57 (27, 85) and 52% were male. 113 (62%) and 70 (38%) patients were grades I and II/III, respectively. Median tumor size was 24 mm (6, 200) and 43 (26%) patients had positive nodal disease. The auto-segmentation model was able to accurately segment the tumor region in 33 (72%) patients of the validation cohort. In the training cohort (n = 140), the radiomics-signature produced an area under the curve (AUC) of 0.87 (0.81, 0.93). Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were 0.94 (0.9, 0.98), 0.74 (0.66, 0.81), 0.72 (0.65, 0.80) and 0.97 (0.94, 1.00) respectively. In the auto-segmented validation cohort (n = 33), the radiomics model produced an AUC of 0.75 (0.61, 0.90). Sensitivity, specificity, PPV and NPV were 0.88 (0.77, 0.99), 0.62 (0.46, 0.79), 0.71 (0.56, 0.87) and 0.83 (0.71, 0.96), respectively. Conclusions: The proposed auto-segmentation model was able to automatically identify tumor regions with a high degree of accuracy. Similarly, the subsequent radiomics-signature was also able to strongly discern PNET grade. This automatic pipeline bypasses manual segmentation and could help incorporate a radiomics-signature into preoperative clinical decision-making for PNETs.

Expression of Trop2, Nectin-4, and FOLR1 cell surface markers in biliary tract cancers: Is it time to repurpose drugs?

637 Background: Biliary tract cancers (BTC), including gall bladder cancer, intrahepatic and extrahepatic cholangiocarcinoma are aggressive malignancies, with poor prognosis. Despite advances in frontline setting, and in biomarker selected population (IDH1, FGFR2, Her2, BRAF, HRD), there is a dire need to advance therapy in subsequent lines. Methods: We identified BTC patients (pts) at Roswell Park Cancer Center who underwent curative intent surgery between 01/2006-01/2020. After excluding duplicate samples and those with insufficient tissue, we found 78 pts with adequate follow up for analysis. Expression of trophoblast cell surface antigen 2 (Trop2), nectin4, folate receptor alpha (FOLR1) was assessed by immunohistochemistry and correlated with clinical outcomes. H score, a weighted index score that factor in, the % of cells across different intensity was calculated. H scores were classified as negative (0) and positive (>1). Positive H scores were grouped as weak (1-100), intermediate (101-200) and strong (201-300). Descriptive statistics were conducted, and multivariate analyses performed (R studio) to study any correlation between expression of markers and survival outcomes. Results: The median age of our cohort was 67.5 years (range 40-87) with 58% male; 24.4%, 30.8%, 20.5%, 7.7% had stages I, II, III, IV disease. Staging information was missing in 16.7% of pts. Of 73 analyzable samples for Trop2, all were positive for Trop2, with a mean H score of 86, SD of 68.9. 56.4% of patients had a weak H score, 30.8% had an intermediate H score and 6.4% had a strong H score for Trop2. Median overall survival (mOS) among low, intermediate and high expressing group of pts with Trop2 was 48.9 months (m), 23.9 m, and 41.9 m with median Progression Free Survival (mPFS) of 37.8m, 15.3 m, and 37.4 m, respectively. Of 75 analyzable samples for FOLR1 and Nectin4, FOLR1 was expressed in 51.3% with a mean H score of 6.97 (SD 21.9). Nectin4 was expressed in 78.2%, with a mean H score of 13.7 (SD 26.3). Pts with Trop2 expression had a mOS of 39.5 m and a mPFS of 28.7 m. There were no significant differences in mOS (48.9 m vs 33.3 m, p =0.14) and mPFS (37.8 m vs 26.2 m, p =0.35) among patients with positive vs negative FOLR1 respectively. There was no difference in mOS (41.6 m vs 38.3 m, p=0.92) and mPFS (32.8 vs 26.4 m, p-value=0.5) in patients with positive vs negative Nectin4. Multivariate analyses showed that pts with intermediate Trop2 (H score=101-200) had a high risk of death (HR 21.44, CI 2.81-163.4, p= 0.003). Conclusions: Though no difference was seen in clinical outcomes in pts with strong Trop2 expression, FOLR1, and Nectin4 expression, this could be explained by the small sample size. Trop2 is frequently expressed in BTCs and patients with Intermediate Trop2 H score had lower mOS and mPFS, with a higher risk of mortality. This warrants further investigation into potential use of Antibody Drug conjugates against Trop2 in BTC.

Updated results from ALTER-H004 study: Anlotinib combined with TACE as adjuvant therapy in patients with hepatocellular carcinoma (HCC) at high risk of recurrence after surgery—A single arm, multi-center, phase II clinical trial.

588 Background: High recurrence rate after curative resection significantly compromised the long-term survival of patients with HCC patients (pts). TACE as adjuvant therapy was proved to improve clinical outcomes for pts with high recurrence risk factors after hepatectomy. However, the prognosis of TACE reminded unsatisfactory and controversial. Therefore, this study aimed to identify the efficacy and safety of anlotinib as maintenance adjuvant treatment following inductional TACE in pts with HCC. The preliminary results had been reported in 2024 ASCO GI (Poster 513) and the update results were reported here with longer follow-up duration. Methods: HCC pts with one of the following high risk factors after hepatectomy: ≥5 cm and <10 cm of tumor diameter, tumor number ≥3, tumor microvascular invasion M1 or M2, portal vein tumor thrombus resection (Cheng's classification I/II) were recruited. Eligible pts received cTACE treatment within 1-2 months after hepatectomy, on the 3-5th day after cTACE, oral anlotinib (12mg, qd, d1-d14, q3w) was given until disease recurrence or unacceptable toxicity. The predefined sample size was 30. The primary endpoint was disease free survival (DFS). Secondary endpoints included 1-year DFS rate, time to recurrence and safety. Results: The data cut-off date was April 2024, 29 pts were enrolled and 27 pts received at least once tumor assessment. The median follow-up was 34.1 (IQR, 32.0-40.9) months. Of 27 with assessable efficacy, mDFS was 40.9 (95% CI, 11.4-70.3) months, with 1-, 2-, and 3-year DFS rates of 72.1% (95% CI, 50.2%-85.6%), 63.0% (95% CI, 40.7%-78.9%), and 56.7% (95% CI, 33.6%-74.5%), respectively. 21 of 27 pts (77.8%) experienced treatment-related adverse events (TRAEs). Grade 3 TRAEs occurred in 5 pts (18.5%) included hypertension (7.4%), leukocytopenia (7.4%) and ascites (3.7%), and blood bilirubin increased (3.7%). No grade 4 or 5 TRAEs occurred. Conclusions: Anlotinib combined with TACE as adjuvant therapy in HCC pts at high recurrence risk exhibited encouraging efficacy and tolerable safety profile. And the conclusions needed to be confirmed in large scale clinical trials subsequently. Clinical trial information: NCT04213118 .

MFIEN: multi-scale feature interactive enhancement network for seismic data denoising in desert areas

Trastuzumab emtansine as second-line therapy in HER2 positive advanced biliary tract cancers: Single arm prospective phase II clinical trial (TAB-3 trial).

584 Background: HER2 overexpression or amplification is a therapeutic target of interest in advanced BTC, especially gallbladder cancers (GBC). Limited studies evaluate the role of T-DM1 in these groups of cancers. Methods: This study was an investigator-initiated, open-label, single-arm, phase II trial in patients (pts) aged 18 years or older with HER2-positive (defined as IHC 3+ or IHC 2+, and FISH positive), advanced BTCs who had previously received systemic therapy (irrespective of prior additional HER2 targeted therapy). Pts received T-DM1 at 3.6mg/kg q 3 -weekly till disease progression (PD), unacceptable toxicities, or patient choice. The primary end-point of the study was an improvement in 3-month progression-free survival (PFS) from 50% (historical cohort) to 70% in the study arm. Secondary endpoints included overall response rates (ORR), disease control rate (DCR), overall survival (OS), and incidence of grade 3 and 4 treatment-related adverse events (TRAE). Results: From July 2023 to July 2024, ‘52’ pts with HER2-positive BTC were screened, and 40 enrolled in the study. A majority of patients had GBC (95%) and most commonly received combination chemotherapy with gemcitabine-cisplatin, with or without nab-Paclitaxel (78%). Six patients (15%) had previously received trastuzumab in combination with chemotherapy. A majority of patients (n=24; 60%) had rapid progression (within 3 months) on prior systemic therapy. With a median follow-up of 7.1 months [95% confidence interval (CI): 5.1-9.1] , 24 patients had disease progression with a 3-month PFS of 51.2% (95% CI: 33.4 - 69) and median PFS of 3.1 months (95% CI: 2.3-3.8); median OS was 7.1 months (95% CI: 5.1-9.1). Partial responses (PR) were seen in 5 patients (12.5 %) and 8 had stable disease (20 %) for a disease control rate of 32.5 %. Patients without rapid disease progression on prior therapy (n=16; 40%) had a 3-month PFS of 70% (95% CI: 44.8 - 95.2) and median PFS of 4.9 months (95% CI: 2.9-6.9). Grade 3 and grade 4 TRAE in the overall cohort were noted in 11 patients (28%), with the commonest being grade 2 fatigue in 6 patients and grade 3 thrombocytopenia in 2 patients. Conclusions: T-DM1 was well tolerated in pre-treated HER2 positive advanced BTCs, but did not statistically improve PFS in comparison to historical data. Patients who did not have rapid progression on prior systemic therapy appeared to have a more favorable survival in comparison to rapid progressors and the role of T-DM1 in such favorable cohorts can be explored in larger studies. Clinical trial information: CTRI/2023/07/055785.

Galeterone monotherapy in advanced pancreatic ductal adenocarcinoma: Results from a phase two trial.

744 Background: Advanced pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with limited treatment options. Dysregulated MAPK and PI3K signaling in PDAC activates the eukaryotic translational initiation complex, promoting cell growth, chemoresistance and metastatic spread (PMID 25593033). Galeterone, a novel steroidal anti-androgen, downregulates critical mediators of this complex including Mnk1/2 and phosphorylated eIF4E, thereby blocking epithelial-to-mesenchymal transition and NF-kB activity. In-vitro, galeterone exhibits anti-tumor activity both alone and in combination with gemcitabine and slows tumor growth in a MiaPaCa-2 xenograft murine model (PMID 28881737). We present results of the monotherapy arm from an ongoing phase two trial evaluating galeterone +/- gemcitabine for patients with advanced PDAC. Methods: Patients with locally advanced or metastatic PDAC, an ECOG performance status of 0-2 and adequate organ function, who progressed on two prior lines of systemic therapy were eligible. Galeterone was administered orally at 2550mg daily and gemcitabine intravenously at 1000mg/m 2 weekly for three weeks on 28-day cycle. The primary endpoint was radiographic response rate per RECIST v1.1 and secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. We used a Simon’s optimal two-stage design with a null hypothesis of p 0 =0.05 and one-sided alternative of p 1 =0.20 with an early stopping rule for futility in each arm. Due to poor accrual and no signal of activity, the galeterone alone arm closed after enrollment of four patients. Results: Four patients were evaluable for the primary endpoint. Ages ranged from 43 to 68. Two patients were male and two were female. Two patients were white and two were black; one patient was Hispanic/Latino. All patients had ECOG PS of 1. No patients had a radiographic response; the best response was progressive disease (PD). PFS from cycle 1 day 1 ranged from 0.9 – 1.7 months and overall survival between 1.8 – 3.6 months. The only treatment-related adverse events (TRAEs) were grade 1 dizziness and grade 3 fatigue in one patient each. There were no treatment-related serious adverse events. No patients required dose modification or discontinued due to TRAEs. Conclusions: Galeterone showed no clinical activity, but with a favorable safety profile, as a single-agent in heavily pre-treated patients with advanced PDAC. Activation of the Mnk-eIF4E axis mediates chemoresistance in PDAC and galeterone may prove more efficacious with gemcitabine. This combination arm is currently open to enrollment. Clinical trial information: NCT04098081 . Clinical outcomes with galeterone monotherapy in PDAC. Pt # Age Prior lines of Therapy Time on Treatment (days) Best Response PFS (months) OS(months) 1 68 4 46 PD 1.5 3.6 2 59 2 54 PD 1.7 3.8 3 55 2 47 PD 1.4 2 4 43 2 35 PD 0.9 1.8

A multi-institutional retrospective study evaluating clinical outcomes and prognostic factors in patients with metastatic appendiceal adenocarcinoma.

69 Background: Appendiceal adenocarcinoma (AA), a rare cancer, has been reported to have high incidences of mucinous type histology, peritoneal metastasis, and relatively good prognosis. However, its chemotherapeutic efficacy and prognostic factors is not well known. Methods: We collected patients with metastatic AA treated with chemotherapy between February 2005 and March 2023 in two high volume cancer centers in Japan. We retrospectively analyzed the clinical outcomes of the chemotherapy of patients with metastatic AA and the clinical factors associated with treatment efficacy and prognosis by multivariate analysis. Results: A total of 66 patients with a median age of 54 years, were enrolled. 40 patients (60.6%) received an oxaliplatin-based regimen in combination with bevacizumab. The response rate was 22.0% and the disease control rate was 87.8%. With median follow-up period was 15.5 months [1.9-103.1], median progression-free survival (PFS) was 10.9 months [95% CI: 7.2-15.2] and median overall survival (OS) was 23.0 months [95% CI: 19.6-35.8]. 77.4% of patients received subsequent chemotherapy. In multivariate analysis, pretreatment carcinoembryonic antigen (CEA) and/or carbohydrate antigen 19-9 (CA19-9) were associated with significantly shorter PFS (HR: 2.93, P = 0.0049). Presence of primary tumor (HR:2.50, P = 0.015), ECOG performance status (PS) ≥1 (HR: 2.67, P = 0.0091), moderate to massive ascites (HR: 3.06, P = 0.0043) and high tumor marker levels (HR: 2.46, P = 0.026) were associated with significantly shorter OS. Classifying the patients by number of these prognostic factors for OS into three groups (0, 1-2, and 3-4), the group with prognostic factors (1-2 or 3-4) had a significantly shorter prognosis compared to the group without any these factors (0 vs 1-2: HR: 4.70, P = 0.038, 0 vs 3-4: HR: 17.6, P < 0.01). In addition, the group with 3-4 prognostic factors had relatively lower rate of subsequent chemotherapy ratio than the group without these factors (66.7% vs 100%, P = 0.25). Conclusions: We confirmed our treatment outcomes were consistent with previous studies and elevation of tumor markers presence of primary tumor, ECOG PS ≥1, moderate to massive ascites were significantly associated with survival in patients with metastatic AA.

Immunotherapy engagement in pancreatic adenocarcinoma: Provisional results of iLSTA study— Durvalumab, LSTA1 (certepetide), gemcitabine, and nab-paclitaxel for locally advanced pancreatic ductal adenocarcinoma.

746 Background: Pancreatic ductal adenocarcinoma (PDAC) is characterised by a dense, extracellular matrix-rich stroma, which creates a physical barrier against drug penetration. Evidence suggests that the iRGD peptide, LSTA-1, can increase the penetration of anti-cancer drugs to tumours through selective targeting of tumour endothelial cell receptors. Additionally, LSTA-1 administration promotes CD8+ immune cell tumour infiltration, potentially enabling immunotherapy as a treatment modality. iLSTA examined safety, tolerability and effect of the combination. Methods: Participants diagnosed with locally advanced PDAC were divided into 3 cohorts in a 1:1:4 ratio. Cohort 1 (n=5) received gemcitabine (1000mg/m 2 ), nab-paclitaxel (125mg/m 2 ), placebo LSTA-1 (3.2mg/kg) and placebo durvalumab (750mg). Cohort 2 (n=5) received gemcitabine, nab-paclitaxel, active and placebo LSTA-1, and placebo durvalumab. Cohort 3 (n=20) received gemcitabine, nab-paclitaxel, LSTA-1 and durvalumab. Tissue biopsies via endoscopic ultrasound were obtained pre-treatment and between weeks 12 and 16 for analysis of tumour infiltrating lymphocytes (TILs). Patient tumour sizes were assessed every 8 weeks using radiological imaging according to RECIST v1.1, and serum CA19-9 levels were analysed monthly. Results: 6/17 patients showed significant RECIST partial response after 2 cycles of treatment (5 patients in cohort 3), with the remaining 11 patients exhibiting stable disease. After 4 cycles of treatment, 10/17 patients demonstrated partial response (9 patients in cohort 3). Of the remaining 7 patients, 6 demonstrated stable disease, and 1 patient (cohort 2) exhibited a RECIST complete response. 13/17 patients who completed 4 treatment cycles showed a decrease in CA19-9 levels. 6 patients demonstrated >90% reduction in CA19-9 (5 in cohort 3), with the remaining 7 patients showing a >50% reduction in CA19-9 levels (5 in cohort 3). 12 patients underwent repeat biopsies 12-16 weeks post-treatment to assess TILs. 10 patients showed immune cell infiltration (5% to 50% stroma infiltration), 2 had no tumour found (Cohort 3). The combination was safe with no unexpected toxicities. Conclusions: The preliminary results of this study suggest that the combination of gemcitabine and nab-paclitaxel with LSTA-1 and durvalumab is safe and potentially induces tumour infiltrating lymphocytes and RECIST response in locally advanced pancreatic adenocarcinomas. Clinical trial information: ACTRN12623000223639 .

Real-world experience with atezolizumab plus bevacizumab (A+/-B) in Hispanic patients with advanced hepatocellular carcinoma (HCC) at a Hispanic-majority cancer center.

549 Background: Combination of atezolizumab (A), a programmed death-ligand 1 (PD-L1) inhibitor, and bevacizumab (B), a vascular endothelial growth factor (VEGF) inhibitor, has demonstrated efficacy for first-line treatment for HCC. However, real-world data on the outcomes of this combination therapy in diverse patient populations, particularly in Hispanic U.S. patients, remains limited. This study aims to evaluate the clinical outcomes of patients intended to treat with A+/-B at a Hispanic-majority U.S. cancer center. Methods: This retrospective study of patients diagnosed with advanced unresectable HCC who received treatment with A+B at a Hispanic-serving NCI-designated cancer center. Patients were included if they received at least one dose of A, either as monotherapy or in combination with B, between January 2019 and April 2022. Demographic and clinical data, including age, gender, ethnicity, liver disease etiology, Child-Pugh (CP) classification, comorbidities, and treatment details, were collected. The primary endpoints were the overall response rate (ORR) and complete response (CR) rate. Statistical analyses were conducted to evaluate the association between baseline characteristics and clinical outcomes. The median overall survival (mOS) evaluated by Kaplan-Meier Method. Results: 38 patients received at least A (84% A+B, 6 patients had B held due to bleeding risk after consent). Median age 65 years (45-90). 32 (84%) patients were male. 22 (58%) patients were Hispanic. 45% had HCV-related liver disease. 32% had CP B with no statistically significant association between CP Class and ethnicity. 53% had concurrent diabetes. 26% patients had obesity. The median time on treatment was 7.5 mo (1- 24 mo) with no statistical difference between Hispanics and non-Hispanics (9 vs 6 mo, p 0.70). CR 37% with ORR of 42%. Using Fisher’s exact test, no association was noted between obesity, ethnicity, treatment option or CP class to occurrence of complete or partial response. mOS was 19 mo. There was no statistical difference in mOS between CP A and CP B (19 vs 10 mo, p value 0.6) and no difference between Hispanics (14 mo) vs non-Hispanics (19 mo) (p 0.5), using log rank test. Conclusions: This real-world analysis of a Hispanic-majority U.S. cohort of patients with advanced HCC shows 42% ORR and 37% CR. The findings suggest that this regimen is effective across a diverse patient population, including those with comorbid conditions, such as liver dysfunction (CP B 32%), HCV (45%), diabetes (53%, and obesity (26%). Limitations are the small study population and retrospective nature of the study. Evaluation of toxicity data is ongoing. Further prospective studies are needed to identify biomarkers of outcomes in Hispanic patients with HCC, which is ongoing at our cancer center (NCT03894917).

Long-term follow-up of the randomized trial on open versus laparoscopic surgery for primary tumor resection in patients with non-curable stage IV colon cancer (JCOG1107).

55 Background: The Japan Clinical Oncology Group (JCOG) 1107 (UMIN-CTR: UMIN000009715) was a non-inferiority phase III trial to compare laparoscopic surgery (LAP) with open surgery (OP) for symptomatic, non-curable stage IV colon cancer, using progression-free survival (PFS) as the primary endpoint based on the intention-to-treat principle. The planned primary analysis confirmed the non-inferiority of the LAP over the OP. Additionally, the present study aimed to compare the LAP and OP using long-term 3-year follow-up data from the JCOG1107. Methods: Eligibility criteria included pathologically proven adenocarcinoma or adenosquamous carcinoma; primary tumor located at the cecum, ascending, transverse, descending, sigmoid, and rectosigmoid colon; primary tumor with bowel stenosis and/or bleeding; and having at least one to three non-curable factors. The sample size was 194 with a power of 70%, one-sided alpha of 5%, and non-inferiority margin of the hazard ratio (HR) of 1.38. Results: In total, 195 patients were randomized (OP 95, LAP 100) between January 2013 and January 2021. OP was performed in 92 and LAP in 98 patients. Postoperative chemotherapy was administered in 82 OP and 86 LAP patients. As the data cut-off date of Feb 2024, 93 (98%) and 100 (100%) PFS event occurred in OP and LAP. The 3-year PFS were 5.3% (95% CI, 2.0-11.0) and 3.0% (0.8-7.8) for OP and LAP arms, respectively (HR: 1.028, 95% confidence interval [CI]: 0.772–1.370; P for non-inferiority = 0.0222). Regarding OS, 87 (92%) and 90 (90%) death occurred in OP and LAP. The 3-year OS were 31.5% (22.5-41.0) and 28.5% (20.0-37.6) for OP and LAP arms, respectively (HR: 1.048; 95% CI: 0.780–1.410). Conclusions: Long-term follow-up data supported the non-inferiority of LAP over OP for primary tumor resection in patients with non-curable stage IV colon cancer. Our study findings indicate that LAP is acceptable as a standard treatment for symptomatic, non-curable stage IV colon cancer. Clinical trial information: UMIN000009715 .

Novel Magnetic‐Field‐Free Switching Behavior in vdW‐Magnet/Oxide Heterostructure

Abstract Magnetization switching by charge current without a magnetic field is essential for device applications and information technology. It generally requires a current‐induced out‐of‐plane spin polarization beyond the capability of conventional ferromagnet/heavy‐metal systems, where the current‐induced spin polarization aligns in‐plane orthogonal to the in‐plane charge current and out‐of‐plane spin current. Here, a new approach is demonstrated for magnetic‐field‐free switching by fabricating a van‐der‐Waals magnet and oxide Fe 3 GeTe 2 /SrTiO 3 heterostructure. This new magnetic‐field‐free switching is possible because the current‐driven accumulated spins at the Rashba interface precess around an emergent interface magnetism, eventually producing an ultimate out‐of‐plane spin polarization. This interpretation is further confirmed by the switching polarity change controlled by the in‐plane initialization magnetic fields with clear hysteresis. Van‐der‐Waals magnet and oxide are successfully combined for the first time, especially taking advantage of spin‐orbit torque on the SrTiO 3 oxide. This allows this study to establish a new way of magnetic field‐free switching. This work demonstrates an unusual perpendicular switching application of large spin Hall angle materials and precession of accumulated spins, and in doing so, opens up a new field and opportunities for van‐der‐Waals magnets and oxide spintronics.

Update of phase 1b/2 study of muzastotug (ADG126, an anti-CTLA-4 SAFEbody) in combination with pembrolizumab in advanced/metastatic MSS CRC.

193 Background: ADG126 is an anti-CTLA-4 IgG1 masked antibody with cleavable masking peptides that is preferentially activated in the tumor microenvironment, which in turn binds to a unique epitope to block CTLA-4 function, prime T cells and deplete Tregs. We previously reported that repeated dosing of the IO doublet therapy ADG126 plus pembrolizumab (Pembro) was well-tolerated with promising clinical efficacy in 3L MSS CRC patients (pts) free of liver metastasis (NCT05405595) 1,2 . Here we update clinical safety and efficacy of the study as result of continued dose optimization for the IO doublet therapy. Methods: This is a Phase 1b/2, open-label, multicenter dose escalation (DE) and expansion (EXP) study. Primary endpoints were safety and tolerability. Secondary endpoints were PK, ADA, ORR, DCR, DOR, PFS and OS. Results: A total of 72 pts were dosed with ADG126/Pembro (Table). 27.8% pts had ≥ 3 prior therapies and 6.9% pts had prior IO therapies. There was no Grade 4/5 TRAE, and MTD was not reached. Grade 3 TRAEs were 5.9% (1/17), 16.2% (6/37), 33% (4/12) for 10 mg/kg Q6W, 10 mg/kg Q3W and 20 mg/kg loading dose (LD) & cohorts, respectively. Repeated dosing of ADG126 at 20 mg/kg (Q3W)/Pembro was not well-tolerated. In MSS CRC EXP cohorts, ADG126 of 10 mg/kg Q3W/Pembro treatment resulted in 4 confirmed PRs (n=24 EE), 17% ORR (95% CI: 5-37%), 75% DCR, 4.7-mon mPFS and OS rate of 88% (6 mons) and 75% (9 mons). Subgroup analysis revealed that in pts without liver and peritoneal metastasis (NLPM), ADG126 of 10 mg/kg Q6W/Pembro (10 EE) showed 70% SD and ~ 100% OS (6 and 9 mons); ADG126 of 10 mg/kg Q3W/Pembro (17 EE) showed 24% ORR (4 PR (95% CI: 7-50%)), 88% DCR, 47% CBR, 8.5-mon mPFS and OS rate of 89% (6 mons) and 83% (9 mons). Detailed safety and efficacy results, including those from ADG126 20 mg/kg LD cohort, will be reported. Conclusions: Extensive effort on ADG126 dose optimization, aided by PK-informed dosing strategy, suggested that ADG126 10 mg/kg Q6W and Q3W are appropriate dose/regimen for the IO doublet; this is supported by the well-balanced safety and efficacy (ORR, PFS and OS) profile observed in MSS CRC. ADG126 20 mg/kg Q3W appears to have reached safety ceiling for the IO doublet. The totality of the data further verifies that ADG126 possesses potential best-in-class therapeutic index, and provides basis for continued development of the IO doublet in MSS CRC and for additional exploration of the IO doublet in combination with SOCs/other anti-cancer agents in broader patient populations. Clinical trial information: NCT05405595 . Patient number for safety and efficacy evaluation. Evaluated for ADG126 Dose/Pembro* 10 mg/kg Q6W 10 mg/kg Q3W 20 mg/kg Q3W 20 mg/kg LD & Overall Safety (all pts of DE & EXP) 17 37 6 12 72 Efficacy (MSS CRC NLM, EXP) 10 24 / 5 39 *200mg, Q3W, IV; & 20 mg/kg LD: 20 mg/kg x1 cycle followed by 10 mg/kg Q3W. NLM: liver metastasis-free; DE: Dose Escalation; EXP: Dose Expansion; EE: efficacy evaluable. Data cut date: Aug 30, 2024.

A novel immune-based score and its immune contexture exploration in colorectal cancer.

234 Background: The majority of currently available biomarkers in colorectal cancer (CRC) perform poorly with respect to prognostication and prediction of response. Immunoscore (IS) has been proposed as a signature of host immune cancer response reflecting a favorable prognosis. Next, through AtezoTRIBE, ‘Immunoscore immune checkpoint’ (IS-IC) was introduced, indicating its potential predictive value for immune checkpoint blockade (ICB) in pMMR metastatic CRC. IS-IC is computed through quantitative and spatial variables related to density and proximity of CD8 cells and programmed cell death-ligand 1 (PD-L1) cells in the tumor core (TC). There are little confirmatory studies. In this work we test the application of IS-IC through multiplex immunofluorescence (mIF) on our own cohort of patients. Next we explore immune contexture differences through subgroup analysis. Methods: 15 prospectively collected, treatment naïve, primary CRC samples (9 dMMR/MSI-H, 6 pMMR/MSS) where analyzed with mIF. Cell density, proximity between cells, cell clustering and spatial distribution of selected mIF biomarkers (CD3, CD20, CD11c, CD163, CD15, CD4, CD8, Foxp3, CD56, Granzyme B, PD-L1, programmed cell death protein 1 (PD-1), pan-cytokeratin (CK) and Ki67) were analyzed both at the invasive margin (IM) and TC using digital pathology. All slides subjected to digital image analysis met predefined quality control criteria. Results: Serial mIF showed PD-L1 was enriched in stromal cells (CK - ) within IM ( p =0.0148) and confirmed its co-localization with macrophages (CD163 + ) ( p =0.0092). Hence, both TC and IM were included to quantify the densities of CD8, PD-L1 and the proximity between them, as a suggested novel IS-IC TC+IM . During exploration of the immune context we found that both IS-IC and IS-IC TC+IM high groups exhibited significantly increased infiltration of PD-1 + cells ( p =0.0074 and p =0.0058, respectively) and CD8 + PD-1 + cells ( p =0.0101 and p =0.0062, respectively), compared to the corresponding low groups. Whereas only the IS-IC TC+IM high group showed increased natural killer (NK) cells (CD56 + ) ( p =0.0192), found mainly at IM ( p =0.0167) in contrast to TC ( p =0.0824). The novel IS-IC TC+IM scoring system captures the immunosuppressive and immune responsive interaction among PD-1 + cells, PD-L1 + cells, NK cells and CD8 + cells in TC and IM from the cell numbers and cell-cell proximity. A validation cohort is underway. Conclusions: In this study we confirm the ease of replicating IS-IC and the presence of ICB sensitive stroma in the high score group. This study further explored the immune context in both TC and IM, emphasizing the importance of regional differences. Additionally it was found that NK cells were only increased at IM. Altogether we suggests adding dual quantification in TC and IM as a novel IS-IC TC+IM , which may be a more sufficient reflection of the tumor micro environment.

SOX/FOLFOX+nivolumab followed by conversion surgery for HER2 negative primary gastric or gastroesophageal junction cancer with oligo-metastasis or borderline resectable tumors: Early results of a consecutive 41 cases.

487 Background: Gastric or gastroesophageal junction cancer with oligo-metastasis or borderline resectable tumors could be cured by conversion surgery after primary chemotherapy. Because SOX/FOLFOX plus Nivolumab showed high clinical response regardless of CPS score, this nivolumab-based chemotherapy followed by surgery may be promising strategy for these tumors. Methods: The study examined the patients who had HER2 negative primary gastric or gastroesophageal junction cancer with synchronous oligo-metastasis or borderline resectable tumors. Oligo-metastasis was defined as peritoneal dissemination localized to the upper abdomen, para-aortic lymph node metastasis, liver metastasis limited up to 3 segments, mediastinal lymph node metastasis, ovarian metastasis, or esophageal intramural metastasis. Borderline resectable tumors were defined as regional lymph node metastasis forming bulky mass or primary tumors invading adjacent organs. The patients with these tumors were treated with primary chemotherapy with SOX/FOLFOX plus Nivolumab for 3 to 22 months, then were proceeded to conversion surgery in case the tumors are responded to chemotherapy and are considered to achieve R0 resection based on the MDT conference. Results: During November 2021 and February 2024, 41 consecutive patients were included in the study. Disease status was peritoneal dissemination in 1, para-aortic lymph node metastasis in 26, liver metastasis in 5, mediastinal lymph node metastasis in 1, ovarian metastasis in 1, esophageal intramural metastasis in 2, bulky nodal metastasis in 6, and primary tumors invading pancreas in 1 (distant oligo-metastasis in 34 patients and borderline resectable in 7). CPS score was >5 in 13, 5> and >1 in 23, and >1 in 5 patients. Chemotherapy regimen was SOX+Nivo in 38 and FOLFOX+Nivo in 3. Of 41 patients, 33 (80.5%) (SOX+Nivo: 30, FOLFOX+Nivo: 3) were proceeded to the conversion surgery, and 32 patients achieved R0 resection. 6 patients showed disease progression and 2 patients were judged as unresectable. Major pathological response (disappearance more than 80% of the primary tumor) rate was 54.5% (18/33) and pCR rate was 33.3% (11/33). Conclusions: SOX/FOLFOX plus Nivolumab for HER2 negative gastric or gastroesophageal junction cancer with oligo-metastasis or borderline resectable tumors achieved a high R0-conversion surgery rate and pathological response rate.

Phase II study of mFOLFIRINOX efficacy as first and subsequent lines of advanced gastrointestinal neuroendocrine tumors G3 and neuroendocrine carcinomas therapy.

659 Background: Gastrointestinal (GI) neuroendocrine carcinomas (NEC) are rare tumors and account for 3% of all NECs. Despite the differences in genetic characteristics, treatment principles of GI NECs are extrapolated from lung NECs. The standard first-line therapy is platinum and etoposide-containing regimens, which allow to achieve a median PFS of 5-6 months. A small retrospective study demonstrated the potential effectiveness of the mFOLFIRINOX regimen with a median PFS of 5.4 months, despite that the majority of patients (pts) received this regimen as second or subsequent lines. The aim of this study is to evaluate mFOLFIRINOX +/- somatostatin analogues (SA) efficacy in GI NEC subgroup. Methods: This prospective, single center phase II study used a two-stage Simon design. The primary endpoint is disease control rate (DCR) ≥ 6 months. Statistical hypothesis: investigated therapy improves DCR compared with historical control from 50 to 70%. Secondary endpoints are progression-free survival (PFS), overall survival (OS), objective response. At the first stage, enrollment of 16 pts was planned (α=0.05, power 80%). If a disease control ≥ 6 months was achieved in at least 9 of the 16 pts, it was planned to continue enrollment up to 39 pts. Here we present results of the first stage of this study. Inclusion criteria: pts ≥18 y.o. with histologically confirmed advanced GI NEC or neuroendocrine tumor (NET) G3 ki67≥55%; ECOG 0-2. Recruitment of pts was carried from 2019 to February 2024. Results: The study included 16 pts, 12 male and 4 female. The most common sites of primary tumor are stomach (N=8, 50%) and pancreas (N=5, 31.3%). 10 (62.5%) pts had large cell carcinoma, 1 – small cell carcinoma (6.3%), 5 (31.3%) – NET G3. The median ki-67 was 70% (40-95%). 15 pts (93.7%) had IV stage, 1 (6.3%) – III. The most common site of metastases is liver – 11 (68.8%), more than half of pts have isolated metastases in liver (N=9, 56.3%). ECOG status was evaluated as 0-1 in 15 (93.7%) cases. Majority of pts (N=14, 87.5%) received mFOLFIRINOX as first line therapy. 7 pts (46.7%) had positive expression of SSTR-2A or -5 and received concurrent treatment with SA. ORR was 62.5% (N=10/16), stable disease – 37.5% (N=6/16). DCR ≥ 6 months was 93.7% (N=15). With a median follow-up of 13.2 months, median PFS was 10.8 months (95% CI 7.57-14.1). One pts had serious adverse event - myocardial infarction, no grade 5 toxicity was observed. Conclusions: Chemotherapy with mFOLFIRINOX showed promising results in GI NECs or NETs G3 ki67≥55% treatment. Primary endpoint was met, enrollment of patients in the study continues.

Alternative dosing regimens of tislelizumab proposed using modeling and simulation.

394 Background: Tislelizumab (TIS; BGB-A317) is approved for the treatment of multiple solid tumors, administered at 200 mg every 3 weeks (Q3W), and has demonstrated a flat exposure–response relationship across a wide range of doses. We evaluated alternative dosing regimens of TIS at 150 mg every 2 weeks (Q2W), 300 mg every 4 weeks (Q4W), and 400 mg every 6 weeks (Q6W) using a model-based approach with the aim of alleviating patient burden by providing longer dosing intervals and/or treatment flexibility compatible with background chemotherapy to meet the needs of patients and healthcare practitioners. Methods: A previously developed population pharmacokinetic (PK) model was used for simulating PK exposure of the alternative regimens, which were selected by exposure-matching to the reference dose of 200 mg Q3W. PK-based criteria (peak concentration [C max ] within 25% and trough concentration [C trough ] within 20% of the reference dose) were also used. Alternative dosing regimen exposures in the first least common time interval and at steady state were compared with the reference. Deviations from PK-based criteria were bridged using appropriate safety and efficacy references and exposure–response analyses using data from four phase 1, 2, and 3 clinical trials of TIS in patients with solid tumors, including gastric cancer and esophageal squamous cell carcinoma. Results: Simulations at steady state shown here demonstrate that the TIS alternative dosing regimens of 150 mg Q2W, 300 mg Q4W, and 400 mg Q6W produce comparable exposures to the 200 mg Q3W reference regimen. Although the simulated C max at 300 mg Q4W and 400 mg Q6W were higher than with the 200 mg Q3W reference dose, these were below the C max of the 5 mg/kg Q3W safety reference (Table). And while the C trough for the 400 mg Q6W dosing regimen was lower than with the 200 mg Q3W reference dose, it was 10.7% higher compared with the 2 mg/kg efficacy reference dose; therefore, it was within the concentration range where a flat exposure–efficacy relationship of TIS has previously been established. Conclusions: TIS alternative dosing regimens of 150 mg Q2W, 300 mg Q4W, and 400 mg Q6W are expected to result in similar safety and efficacy profiles as the 200 mg Q3W reference dosing regimen and may be used interchangeably for indications where 200 mg Q3W is approved. Clinical trial information: NCT04716634 , NCT05014828 , NCT04379635 , NCT02407990 , NCT04068519 , NCT03430843 and NCT03358875 . Steady-state PK exposure metrics for alternative TIS doses vs reference doses. Parameter 150 mg Q2W vs 200 mg Q3W 300 mg Q4Wvs 200 mg Q3W 300 mg Q4Wvs 5 mg/kg Q3W a 400 mg Q6Wvs 200 mg Q3W 400 mg Q6Wvs 5 mg/kg Q3W a 400 mg Q6Wvs 2 mg/kg Q3W b C max −5.8 (Yes) 31.4 (No) −18.7 (Yes) 52.2 (No) −5.8 (Yes) – C average 12.3 (Yes) 12.6 (Yes) – 0.4 (Yes) – – C trough 27.2 (Yes) 0.1 (Yes) – −28.4 (No) – 10.7 (Yes) Data are presented as difference (% = [GM test − GM reference /GM reference ] × 100) vs the 200 mg Q3W reference, a safety reference, or b efficacy reference (meets regulatory criteria, Yes/No). C average , average concentration; GM, geometric mean.