bluuebunny/crossref_metadata_2025 huggingface dataset:
Short interval circulating tumor DNA (ctDNA) kinetics as a predictor of tumor response in patients with gastrointestinal (GI) cancer receiving immune checkpoint inhibitor (ICI)-based treatment.
Authors: Chakrabarti Sakti , Bajor David L. , Lumish Melissa Amy , Conces Madison , Mohamed AMR , Mahipal Amit , Selfridge J. Eva
Published: January 2025

836

Background:
Circulating tumor DNA (ctDNA) has a short half-life (<2 hours) which may permit real-time monitoring of tumor status. This single-institution study aimed to assess the feasibility of rapid treatment response evaluation through serial short-interval ctDNA testing.
Methods:
Patients with gastrointestinal (GI) cancer undergoing immune checkpoint inhibitor (ICI)-based therapy were included. A personalized, tumor-informed ctDNA assay (Signatera, Natera, Inc.) was used in this study. We collected samples to measure the baseline ctDNA levels on cycle 1, day 1 (C1D1) of treatment or within 14 days prior to C1D1. A second ctDNA sample was obtained after 14-21 days depending on the cycle length of the treatment regimen employed (on cycle 2, day 1 [C2D1]). Changes in ctDNA levels between baseline and C2D1 were recorded, as well as the tumor response at the first radiographic assessment. Patients achieving partial response (PR) or better, or stable disease (SD) with tumor shrinkage supporting continuation of same treatment were considered responders.
Results:
The study cohort consisted of 14 patients aged 36-89 years (median age 66); 5 patients were female. Tumor types included advanced colorectal (n=5) and gastroesophageal (n=9) cancers. Treatments consisted of pembrolizumab alone (n=5), ICI + chemotherapy combinations (n=8), and regorafenib plus nivolumab (n=1). Baseline ctDNA levels were obtained on C1D1 in 9 patients, with the remaining 5 patients having baseline measurements within 14 days before C1D1. All patients had the second ctDNA level drawn on C2D1. The median interval between C1D1 and the first radiographic response assessment was 61 days (range, 45-84). A reduction in ctDNA levels by 50% or more (range: 66-100%) was observed in 9 patients (64%) after one cycle of treatment. All 9 patients were classified as responders at the time of first radiographic assessment: 7 with PR and 2 with SD but significant tumor shrinkage leading to continuation of the same treatment. In 3 patients (21%), ctDNA levels increased (range: 20-500%), correlating with progressive disease (PD) on first assessment scan. Two patients showed increased ctDNA levels of 82% and 22% after one cycle of treatment but achieved PR and SD, respectively. In both patients, however, the 3rd ctDNA level drawn before the first assessment scan dropped by >90%. Overall, short-interval ctDNA kinetics correlated with treatment response in 12 of 14 patients (86%), with a binomial test p = 0.0065.
Conclusions:
Short-interval ctDNA kinetics demonstrates a strong correlation with radiographic tumor response and clinical benefit in GI cancer patients receiving ICI-based treatments, providing early signal of tumor response. This approach has the potential to guide treatment decisions if validated in larger prospective studies.
Trends in utilization of colorectal cancer screening modalities among patients with average risk in the United States from 2017 to 2023.
Authors: Stieber Brad , Greene Mallik , Le Quang Anh , Mou Joshua , Sakthisivabalan Lakshya , Lynch Danielle , Ozbay A Burak , LeMaster Joseph , Dore Michael , Fendrick A. Mark , Limburg Paul J.
Published: January 2025

98

Background:
Colorectal cancer (CRC) is the second leading cause of cancer mortality in the US. The national CRC screening rate (58%) is still below 80%, which is the goal set by the National Colorectal Cancer Roundtable. National guidelines recommend multiple strategies for CRC screening including colonoscopy, sigmoidoscopy, CT colonography, fecal occult blood test (FOBT), fecal immunochemical tests (FIT), or multi-target stool DNA (mt-sDNA) test. To provide updated insights regarding proportional utilization of different CRC screening strategies, we analyzed modality-specific CRC screening rates across demographic subgroups between 2017 and 2023.
Methods:
A retrospective review was conducted using a large national claims database that covers over 165 million lives and is representative of the US population for the study period from 2017 to 2023. Individuals were included if they were aged 45-75 years, at average CRC risk in the baseline period of 1 year before the index date and continuously enrolled in a health plan for at least 1 year after the index date. The index date was defined as date of the first claim for a CRC screening test. CRC screening uptake by modality and newly screened individuals each calendar year were examined among the entire eligible population and across demographic subgroups.
Results:
Overall rates of CRC screening were relatively stable across the study years (approximately 20%) with the lowest annual proportion of screen eligible patients in 2020 (16.6%) and highest in 2023 (24.4%). For CRC-screened individuals, colonoscopy was the most commonly used screening modality, increasing from 1,943,733 (53%) in 2017 to 2,319,695 (58.7%) in 2023. The mt-sDNA test use increased significantly from 87,769 (2.4%) in 2017 to 807,227 (20.4%) in 2023; while FIT/FOBT use declined from 1,611,730 (44%) in 2017 to 805,150 (20.4%) in 2023. Utilization of colonoscopy and mt-sDNA tests increased notably among the 45–49 age group starting in 2021, while FIT/FOBT use simultaneously declined in this age group. Observed trends were similar to the above findings across additional subgroups defined by gender, race/ethnicity, payer type, and geographic region.
Conclusions:
Data from this large study of national claims data provides updated results for overall and proportional utilization of guideline-endorsed CRC screening strategies. While colonoscopy usage remained stable , the use of the non-invasive mt-sDNA test has increased significantly as FIT/FOBT usage declined over time, reflecting growing interest in this noninvasive, home-based option.
Multi-target stool DNA test adherence in average-risk African Americans from 2017-2024.
Authors: Johnson William K , Camardo Mark , Greene Mallik , Ozbay A Burak , Limburg Paul J. , Lovelace Jerry
Published: January 2025

99

Background:
Colorectal cancer (CRC) stands as the second most common cause of cancer-related mortality in the United States, while being the third most common cancer in the country. African Americans (AA) are disproportionately affected with CRC (incidence and mortality), yet the disease can be prevented through screening and early detection. Data reveals that only 59% of AA between ages 45-75 were up to date with CRC screening as of 2021. Broad availability of the navigation-supported, at home multi-target stool DNA (mt-sDNA) test may help mitigate barriers to screening adherence in this population. We examined multi-target stool-DNA (mt-sDNA) test adherence rates in a nationally representative AA population.
Methods:
Using a national claims database of over 165 million individuals linked with Exact Sciences Laboratories data, mt-sDNA orders for AA patients were retrospectively identified from 2016 to 2024. Average CRC risk individuals aged ≥45 years, and new to mt-sDNA, were included in this analysis. Primary outcome of interest was adherence, defined as mt-sDNA kit return rate within 365-days from shipment. Time to test return was examined as the secondary outcome. Demographics were age, sex, ordering provider, residential geography, payor, and outreach preference. Covariates on adherence were examined using logistic regression.
Results:
Among 434,951 mt-sDNA orders from 2017-2024, the overall adherence rate was 62%, and the average time to test return was 27.6 days. The cohort included higher percentages of women (61.7%), ages 50-64 years (57.8%), located in Southern US (51.4%), and metro areas (90.9%). Most patients were also commercially insured (56.1%) and received their mt-sDNA order from their primary care provider (65.4%). Digital SMS was the most preferred outreach option (47%). Patients ages ≥76 years demonstrated the highest adherence (70.3%), with all age categories near or above 60% (45-49 yrs [59.4%]; 50-64 yrs [60.8%], 65-75 yrs [64.3%]). Across payors, patients with Medicare had the highest adherence rates (66.5%). Across outreach, highest adherence was among those who preferred ‘Digital SMS + Email’ outreach (64.3%). Men were quicker to return their test than women (26.8 days vs 28 days, p<0.001). Those ages ≥76 years and with tests ordered by GIs had the shortest time to test return (21.3 and 22.2 days, respectively). Adjusted analyses revealed multiple factors were associated with increased odds of adherence, including older age (≥76 years; OR=1.54; p<0.001), ‘Digital SMS + Email’ outreach (OR=1.25; p<0.001), rural residence (OR=1.23; p<0.001), and males (OR=1.05; p<0.001).
Conclusions:
Mt-sDNA adherence was higher for AA patients in this large, national cohort as compared to previously reported overall CRC screening adherence data for this population group. Findings suggest mt-sDNA utilization, with its included patient navigation, may help reduce screening disparities among AA patients.
Combining low-dose regorafenib with pembrolizumab for patients with MSI-H colorectal cancer: REGPEM-CRC-01.
Authors: Sahin Ibrahim Halil , Hsieh Ronan Wenhan , Gorantla Vikram , Cohen Stacey A. , Rhee John C. , Safyan Rachael A. , Tatsuoka Curtis , Chiorean E. Gabriela , Tejani Mohamedtaki Abdulaziz , Benson Al B. , Boland Patrick M , Kim Richard D. , Saeed Anwaar
Published: January 2025

TPS313

Background:
Currently, pembrolizumab is one of the front-line therapies for patients with MSI-H CRC. However, approximately 40% of patients who received pembrolizumab experienced disease progression early in the course of disease (KEYNOTE 177). Therefore, there is still an unmet need to enhance the efficacy of checkpoint inhibitors in MSI-H CRC. MSI-H CRC has a higher level of expression of VEGF in blood compared to patients compared to its MSS counterpart (Hansen et al. Colorectal Dis. 2011). Consistently, exploratory analysis of CALBG-80405 and PARADIGM trial showed that patients with MSI-H CRC were more likely to benefit from anti-VEGF therapy than anti-EGFR therapy regardless of the side of the tumor. NSABP C-08 also suggested that anti-VEGF therapy may have biological activity even in as adjuvant therapy for patients with MSI-H colon cancer. Regorafenib is a potent VEGF inhibitor, with preclinical evidence showing its immune modulatory effect in the tumor microenvironment. In this trial, we hypothesize that adding low-dose regorafenib to pembrolizumab may induce synergistic activity beyond their independent clinical efficacy and create deep and durable responses for patients with MSI-H CRC.
Methods:
In the lead arm of this prospective randomized study, 22 patients will be enrolled through Hoosier Cancer Research Network (HCRN-GI23-643). Patients with treatment naïve MSI-H CRC will be enrolled in this front-line trial. One cycle of pembrolizumab and up to 3 cycles of chemotherapy prior to determination of MMR-D/MSI-H is allowed. Patients will receive regorafenib 60 mg daily in combination with pembrolizumab 200mg IV in cycle 1, followed by regorafenib 90mg in subsequent cycles to improve treatment tolerance. The primary outcome that will be measured is ORR, defined as the percentage of partial or complete response to the treatment within 12 months. ORR will be measured using RECIST 1.1. criteria. A formal one-sided hypothesis test will be conducted for futility, assuming that we will reject the null hypothesis of a target ORR only if we have strong evidence. In this study, we assume a null hypothesis that ORR is 0.60, which would reflect significant clinical improvement over the current standard of ORR = 0.43 from KEYNOTE 177. The alternative hypothesis is that ORR is less than 0.60. For the lead-in phase of the study, the emphasis is on controlling Type I error to be small, approximately 0.05. The test statistic will be the number of ORRs in the 22 patients, which we assume to follow a binomial distribution.
Clinical trial information: NCT06006923
.
A phase II, randomized study of JMT101 in combination with irinotecan and SG001 versus regorafenib in patients with metastatic colorectal adenocarcinoma (mCRC).
Authors: Xu Jianmin , Tang Wentao , Yang Xiugao , Yang Yang , Chen Qiwen , Cheng Jianhong , Wan Xuechao , Song Yane , Li Mengke
Published: January 2025

TPS314

Background:
Epidermal growth factor receptor (EGFR) inhibitorcombined withchemotherapy based on5-FU with oxaliplatin and irinotecanis the first-line treatment of wild-type RAS mCRC.JMT101 is a humanized monoclonal IgG1 antibody targeting EGFR. Previous trials showed that JMT101 monotherapy or in combination with chemotherapy had demonstrated a promising anti-tumor activity in advanced solid tumors with good safety profiles. EGFR inhibitor might have a synergetic effect with immunocheckpoint inhibitor (ICI) by activating innate and adaptive immune response. SG001 is a fully humanized and high-affinity immunoglobulin G4 monoclonal antibody that targets programmed death-1 (PD-1), which also had encouraging efficacy in advanced solid tumors. Therefore, EGFR antibody in combination with chemotherapy plus ICI is worthy exploration in patients with mCRC.
Methods:
This is a phase II, multicenter, open-label, two-part study. Part I is a safety run-in, followed by part II randomized treatment. Eligible patients are histologically confirmed mCRC without MSI-H/dMMR, wild-type RAS and BRAF, who progressed on at least 2 prior systemic therapy with chemotherapy based on 5-FU with oxaliplatin and irinotecan, with or without cetuximab and bevacizumab (both parts); no prior treatment with regorafenib, fruquintinib, or TAS-102 (part II). Safety run-in data will be analyzed after 3-6 patients have received JMT101 6 mg/kg plus irinotecan 180 mg/m
2
plus SG001 240 mg Q2W. Upon dose confirmation, 90 patients with mCRC will be randomized into three arms (1:1:1) to receive JMT101 plus irinotecan plus SG001, or JMT101 plus irinotecan, or regorafenib monotherapy. Primary endpoints include incidence of dose limiting toxicities (DLT) and adverse events (part I) and objective response rate (ORR) as per RECIST v1.1 by investigator (part II). Secondary endpoints include JMT101 and SG001 pharmacokinetic profile, antidrug antibodies (ADA) (both parts), disease control rate (DCR), duration of response (DOR), progression free survival (PFS), and overall survival (OS), as well as safety (part II). Prespecified goal for safety run-in part was met; randomized treatment part accrual began in February 2024.
Clinical trial information: NCT06089330
.
Cetuximab and vemurafenib plus liposomal irinotecan (II), leucovorin and fluorouracil for BRAF
V600E
-mutated advanced colorectal cancer (IMPROVEMENT2): A multicenter, open-label, randomized controlled trial.
Authors: Wang Zhan , Ye Chen-Yang , Jiao Xiao-Dong , Liu Ke , Qin Bao-Dong , Zhai Wen-Xin , Yang Biao-Long , Sun Li , Dai Wei-Ping , Ling Yan , Wu Ying , Chen Shi-Qi , Zhang Ying-Fu , Shi Dong-Min , Duan Xiao-Peng , Zhong Xue , He Xi , Jia Cheng-Hao , Zang Yuan-Sheng
Published: January 2025

TPS316

Background:
Current first-line treatment regimen for advanced colorectal cancer with BRAF
V600E
gene mutation is chemotherapy combined with anti-angiogenic drug, but the efficacy is somewhat limited. Theoretically, targeting BRAF
V600E
mutation is an effective treatment strategy and has achieved success in lung cancer and melanoma. However, the objective response rate (ORR) is below 5% in colorectal cancer, suggesting that BRAF
V600E
mutation in colorectal cancer may have different feedback regulation mechanisms compared to other cancer types. Combining chemotherapy (such as 5-fluorouracil plus irinotecan) with BRAF/EGFR targeted therapy may potentially achieve good efficacy. Subsequently, we conducted the IMPROVEMENT (NCT03727763) study, which showed an objective response rate (ORR) of 85% and a disease control rate of 100% with this regimen, significantly higher than those with chemotherapy combined with anti-angiogenic drug. The recent BREAKWATER study showed similar trends. To further validate the efficacy and safety of this regimen, we designed a randomized controlled trial.
Methods:
IMPROVEMENT2 (NCT06603376) is a multicenter, open-label, randomized controlled trial in patients with histologically or cytologically confirmed advanced colorectal cancer. Adult patients who are previously untreated in the metastatic setting, have a confirmed BRAF
V600E
mutation, measurable disease per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1, and Eastern Cooperative Oncology Group performance status of 0-1 are eligible. Patients who received previous treatment in the adjuvant setting but experienced metastasis or recurrence within 12 months are permitted. A total of 75 eligible patients will be randomly assigned (2:1) to receive liposomal irinotecan(Ⅱ) 60 mg/m
2
, leucovorin 400 mg/m
2
, fluorouracil 2800 mg/m
2
, and cetuximab 500 mg/m
2
on day 1 of each 14-day cycle plus oral vemurafenib 720 mg twice daily, or liposomal irinotecan(Ⅱ) 60 mg/m
2
, leucovorin 400 mg/m
2
, fluorouracil 2800 mg/m
2
, and bevacizumab 5 mg/kg on day 1 of each 14-day cycle. Treatment will be continued until disease progression or unacceptable toxicity. The primary endpoint is ORR per RECIST 1.1 by blinded independent central review (BICR). Key secondary endpoints are depth of response, progression-free survival per RECIST 1.1 by BICR, overall survival, and safety. The study is actively enrolling patients.
Clinical trial information: NCT06603376
.
A phase 2 study of intravenous pembrolizumab and intratumorally injected autologous dendritic cells (DCs) in refractory colorectal cancer (CRC).
Authors: Mukherjee Sarbajit , Fujiwara Yu , Connors Eoghan , Basse Per , Huck Connor , Vujcic Marija , Stanson Joanna , Kokolus Kathleen , Kalinski Pawel
Published: January 2025

TPS319

Background:
Immune checkpoint inhibitors (ICIs) have shown limited benefit in CRC outside the microsatellite instability high (MSI-H) population. Deficient cytotoxic T lymphocyte (CTL) trafficking to the tumor microenvironment (TME) and excess pro-tumorigenic cytokines and immunosuppressive cells may contribute to primary ICI resistance in microsatellite stable (MSS) CRC. Selective enrichment of T cells with specific chemokine receptors may enhance antitumor immunity. Studies highlight the role of IL-12 in improving progression-free survival (PFS) and overall survival (OS) in patients on DC therapies. Our group developed ST-aDC1s, optimized for high production of high levels of IL-12 and CTL-attracting chemokines when injected intratumorally. In preclinical models, ST-aDC1s combined with anti-PD-1/PD-L1 therapy showed therapeutic synergy, suggesting ST-aDC1s as a promising alternative to traditional DC vaccines for inducing CTL entry into tumors.
Methods:
We designed an open-label, non-randomized, phase 2 study of intratumoral autologous ST-αDC1 combined with pembrolizumab in recurrent/metastatic unresectable MSS CRC. Eligible patients must have prior treatment with, or contraindication to fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF, and anti-EGFR therapy (if RAS wild type), be anti-PD-1/PD-L1 therapy naïve, have ECOG PS ≤1, and have at least two target lesions, one amendable to biopsy and injection. Leukapheresis will collect monocytes for ST-αDC1 generation. Patients will receive intratumoral ST-αDC1s (6 million) on days 1 and 8 with biopsies, and an optional dose on day 50 before a third pembrolizumab dose. Pembrolizumab 200 mg IV will start on day 8, given every 3 weeks for 4 doses during the study period. Pembrolizumab will continue as conventional care afterwards. CT scans will occur after 2 and 4 doses of pembrolizumab. A safety lead-in cohort will include six patients, with up to 17 patients enrolled. The primary endpoint is objective response rate (ORR) at 12 weeks per RECIST 1.1. Secondary endpoints are safety, PFS, OS, and ORR per iRECIST. Correlative analysis will assess baseline levels and post-treatment changes in infiltrating T cells, CD4/CD8 ratios, FoxP3+ Tregs, and Teff-attracting and Treg-favoring chemokines from biopsy specimens, and immune cell subsets and cytokine levels from peripheral blood. With an expected ORR under 5% for standard treatment, 17 patients are required to show at least a 25% ORR with 81.2% power and a one-sided type I error rate of 0.05. A Simon two-stage Optimal design will enroll 9 patients in stage 1, and if ≥1 response occurs, 8 more patients will be added in stage 2. If ≥3 responses are observed, the treatment will be deemed promising for further study.
Clinical trial information: NCT05518032
.
Phase 1/2 study of the HER3-directed antibody-drug conjugate patritumab deruxtecan (MK-1022) as monotherapy in patients with gastrointestinal cancers.
Authors: Oh Do-Youn , Kim Tae Won , Aguilo Ariel , Jing Naimin , Jain Rishi , Adelberg David E. , Pishvaian Michael J.
Published: January 2025

TPS321

Background:
A significant medical need exists for more effective and tolerable therapeutic options for patients with advanced gastrointestinal cancers (colorectal cancer [CRC], biliary tract cancer [BTC], and hepatocellular carcinoma [HCC]). Human epidermal growth factor receptor (HER3) expression is high in CRC and BTC, and low-to-intermediate in HCC. Patritumab deruxtecan (HER3-DXd; U3-1402/MK-1022) is a HER3-directed antibody-drug conjugate (ADC) comprising a fully human anti-HER3 immunoglobulin G1 monoclonal antibody (patritumab), which includes a plasma-stable, selectively cleavable linker, and a potent topoisomerase I inhibitor payload (DXd; released payload) that leverages the clinically validated deruxtecan (a derivative of exatecan) technology. DXd is cell membrane permeable and enables a bystander antitumor effect after DXd ADC internalization and linker cleavage, resulting in elimination of both target and neighboring tumor cells. Patritumab deruxtecan has shown antitumor activity in phase 1 and 2 studies of EGFR-mutated advanced non–small cell lung cancer and advanced breast cancer and in preclinical studies of CRC. This nonrandomized, open-label, phase 1/2 study (NCT06596694) will examine the safety and efficacy of patritumab deruxtecan in select gastrointestinal cancers.
Methods:
Approximately 130 adults (aged ≥18 years) will be allocated to 1 of 3 cohorts based on their disease. Patients in cohort 1 (CRC; n = 40) must have previously treated unresectable or metastatic colorectal adenocarcinoma. Patients in cohort 2 (BTC; n = 40) must have previously treated locally advanced or metastatic BTC. Patients in cohort 3 (HCC; n ≤50) must have previously treated advanced HCC. Prior topoisomerase I inhibitor therapy is not allowed. Patients in cohorts 1 and 2 will receive patritumab deruxtecan intravenously (IV) as monotherapy. Cohort 3 includes a dose-escalation phase to determine the recommended phase 2 dose of patritumab deruxtecan monotherapy and an efficacy phase. In the efficacy phase, patients will receive the recommended phase 2 dose of patritumab deruxtecan. The primary objectives are to evaluate safety and tolerability of patritumab deruxtecan and to evaluate the confirmed objective response rate per RECIST v1.1 assessed by blinded independent central review (BICR) for each cohort. Secondary objectives are to evaluate duration of response and progression-free survival per RECIST v1.1 by BICR and overall survival, and to characterize the pharmacokinetics of patritumab deruxtecan.
Clinical trial information: NCT06596694
.
A phase 3 study of first-line sotorasib, panitumumab, and FOLFIRI versus FOLFIRI with or without bevacizumab-awwb for patients with
KRAS
G12C–mutated metastatic colorectal cancer (CodeBreaK 301).
Authors: Kim Tae Won , Price Timothy , Grasselli Julieta , Strickler John H , Masuishi Toshiki , Kwok Gin Wai , Yalcin Suayib , Obiozor Cynthia Chinedu , Chan Emily , Gokani Priya , Sunakawa Yu
Published: January 2025

TPS326

Background:
CodeBreaK 300 (NCT05198934) evaluated sotorasib, a selective inhibitor that irreversibly binds to the Kirsten rat sarcoma (
KRAS
) G12C mutant protein, in combination with panitumumab, an anti–epidermal growth factor receptor inhibitor, and showed that 960 mg sotorasib + panitumumab provided a statistically and clinically significant improvement in progression-free survival compared with trifluridine/tipiracil or regorafenib in patients with chemorefractory metastatic colorectal cancer (mCRC) (1). In CodeBreaK 101 (NCT04185883) subprotocol H expansion cohort 2F, the addition of folinic acid, fluorouracil, and irinotecan (FOLFIRI) to this combination in the first-line setting demonstrated a manageable safety profile and promising response rate of 78% in patients with
KRAS
G12C–mutated mCRC (2). The current study aims to evaluate whether the combination of sotorasib, panitumumab, and FOLFIRI is superior to FOLFIRI with or without bevacizumab-awwb, a VEGF inhibitor, in the first-line setting for mCRC.
Methods:
CodeBreaK 301 (NCT06252649) is a phase 3, multicenter, randomized, open-label, active-controlled study of sotorasib, panitumumab, and FOLFIRI versus FOLFIRI with or without bevacizumab-awwb as first-line therapy for patients with
KRAS
G12C–mutated mCRC. Key eligibility criteria include mCRC with
KRAS
G12C mutation confirmed by central molecular testing, and no prior therapy for metastatic disease. Approximately 450 patients will be randomized 1:1 to receive either sotorasib, panitumumab, and FOLFIRI, or FOLFIRI with or without bevacizumab-awwb. The primary endpoint is progression-free survival assessed by a blinded independent central review of disease response per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1). The key secondary endpoint is overall survival, and additional secondary endpoints include objective response rate and depth of response. Global enrollment is ongoing. 1. Fakih, NEJM 2023. 2. Siena, ESMO 2024.
Clinical trial information: NCT06252649
.
A safety trial of antibiotic fecal microbiota transplantation for esophageal and gastric cancer patients treated with immune checkpoint inhibitors (Biorich2 trial).
Authors: Yoshinami Yuri , Shoji Hirokazu , Okita Natsuko Tsuda , Takamaru Hiroyuki , Hirose Toshiharu , Imazeki Hiroshi , Yamamoto Shun , Hirano Hidekazu , Takashima Atsuo , Tanaka Kazuki , Ogawa Kana , Koyama Shohei , Ishikawa Dai , Kato Ken
Published: January 2025

TPS510

Background:
The development of immune checkpoint inhibitors (ICIs) has improved the prognosis of unresectable advanced or recurrent esophageal and gastric cancer. However, the prognosis remains poor. The human intestinal microbiota plays various roles in digestion, immunomodulation, and metabolism and is known to influence tumor suppression. Previous studies reported that intestinal microbiota can impact immune responses and the effectiveness of ICIs. Therefore, this study investigates the safety and efficacy of antibiotic fecal microbiota transplantation (A-FMT) in patients with unresectable advanced or recurrent esophageal or gastric cancer.
Methods:
Eligible patients are diagnosed with unresectable advanced or recurrent esophageal squamous cell carcinoma or gastric adenocarcinoma. The primary endpoint is to examine the dose-limiting toxicity (DLT) of A-FMT. Secondary endpoints include response rate, disease control rate, progression-free survival, overall survival, and biomarkers of efficacy and adverse events. This trial consists of two parts: safety confirmation, which assesses DLT incidence, and an expansion part, which examines efficacy and safety. The safety confirmation part will enroll 3-6 patients in cohort 1 (combination therapy with ICIs and chemotherapy) and cohort 2 (combination of anti-PD-1 and anti-CTLA4 antibodies). The expansion part will enroll untreated patients: 10 for esophageal cancer (ICIs + chemotherapy), 10 for anti-PD-1 + anti-CTLA4 antibodies, and 11 for gastric cancer (ICIs + chemotherapy). After enrollment, patients receive antibacterial agents for 1 week before FMT. Patients then undergo total colonoscopy after bowel cleaning with polyethylene glycol plus ascorbic acid. A 200 mL fecal suspension from a healthy donor is transferred to the patient's cecum, and ICIs with/without chemotherapy are initiated thereafter. Biomarker analysis explores diagnostic or surrogate biomarkers, aiming to identify molecular targets, cell populations, microbial species, and functions involved in efficacy by analyzing the effects of A-FMT and ICIs on the tumor microenvironment and intestinal microbiota using methods such as proteome analysis. This trial is registered in the Japan Registry of Clinical Trials as jRCTs031240170 and was initiated in August 2024, with enrollment ongoing. Clinical trial information: jRCTs031240170.
A phase II study of neratinib (Nera) in combination with chemotherapy/trastuzumab/pembrolizumab (C/T/P) in HER2 overexpressing gastroesophageal cancers (GECs).
Authors: Kim Dae Won , Ponto Lauren , Pereira Allan Andresson Lima , Kim Richard D. , Kracht Chandler , Lauwers Gregory , Pimiento Jose Mario , Biachi de Castria Tiago , Strosberg Jonathan R. , Haider Mintallah , Imanirad Iman , Avriett Trenton A , Costello James , Hoffe Sarah E. , Chen Dung-Tsa , Mukherjee Sarbajit , Mehta Rutika
Published: January 2025

TPS514

Background:
Human epidermal growth factor receptor 2 (HER2) is overexpressed in about 15-20% of GECs and is tested using immunohistochemistry and/or in-situ hybridization. Per 3
rd
interim analysis of KN-811 study, addition of P to C/T improved overall response rate (ORR) and overall survival (OS) in patients with HER2 positive tumors. HER2 heterogeneity and activation of other signaling pathways ultimately leading to T resistance limits its potential to have a durable response. Nera is an anilinoqiunoline derivative intracellular oral kinase inhibitor that irreversibly binds to epidermal growth factor receptor (EGFR), HER2 and HER4. In this study, we hypothesize that targeting other oncogenic pathways with Nera may help derive additional therapeutic benefit in HER2 positive GECs when combined with C/T/P.
Methods:
This is an open-label, single arm, multi-institutional Phase II study of Nera in combination with C/T/P in HER2 overexpressing GECs as 1
st
line treatment. The first 6 pts as a lead-in phase will be evaluated for toxicity. If no dose limiting toxicity (DLT), a total of 30 patients (include the first 6pts in the lead-in phase) will be used to evaluate efficacy in the phase II portion. All pts will receive standard dose mFOLFOX/trastuzumab q2w along with pembrolizumab 400 mg q6w. Nera will be dosed at 240 mg daily. In case of DLTs observed with this dose, a dose of 160 mg/day for Nera will be considered. Estimated sample size is 30-36 pts using Simon 2 stage design. Primary endpoint in ORR. The null hypothesis will be rejected if 26 or more responses are observed in 30 patients. Key inclusion criteria include: HER2 positive GECs (as determined by local testing), treatment naïve for stage IV disease, measurable disease, ECOG 0-1, preserved cardiac function. Uncontrolled brain metastases or impaired organ function that poses risk with treatment are key exclusion criteria. Primary endpoint is ORR and secondary endpoints include safety, duration of response, clinical benefit rate and OS. The trial is registered on clinicaltrials.gov under NCT06109467.
Clinical trial information: NCT06109467
.
A phase II double window of opportunity trial evaluating the oral TGF-beta receptor I inhibitor vactosertib in patients undergoing standard of care preoperative therapy for locally advanced esophageal adenocarcinoma.
Authors: Patell Kanchi , Henke Lauren E. , Dorth Jennifer Anne , Lumish Melissa Amy , Conces Madison , Mohamed AMR , Chakrabarti Sakti , Mahipal Amit , Bajor David L. , Blum Andrew , Guda Kishore , Selfridge J. Eva
Published: January 2025

TPS516

Background:
Esophageal adenocarcinoma (EAC) is the seventh most common cancer globally and ranks sixth in overall mortality. Despite improvements in pre-operative therapy, EAC has a high recurrence rate, especially among patients whose tumors do not achieve pathologic complete response (pCR), thus there is a critical need to enhance pCR rate and improve long-term outcomes. We recently discovered that a subset of EACs are driven by tumor-intrinsic oncogenic TGFβ signaling and have identified two potential biomarkers to predict response to anti-TGFβ therapy. One of these biomarkers is enriched in poorly differentiated EAC. We hypothesize that TGFβ signaling blockade will exert a tumor-inhibitory effect in patients with EAC and propose a double window-of-opportunity trial to test if TGFβ receptor I inhibitor vactosertib can improve pCR and induce tumor metabolic response in patients undergoing neoadjuvant therapy for localized EAC.
Methods:
This phase II double window of opportunity study assesses the efficacy and pharmacodynamics of the oral TGFβ Receptor I inhibitor vactosertib in patients with locally advanced esophageal adenocarcinoma (EAC). Patients will be treated with single-agent vactosertib in two windows of opportunity: the first will be prior to initiation of standard of care neoadjuvant therapy and the second after completion of neoadjuvant therapy prior to surgery. Patients will be eligible if they have poorly differentiated EAC and are appropriate for neoadjuvant therapy followed by resection as per standard of care. The primary objectives are improvement in pCR compared to historical controls and metabolic response (decrease in fluorodeoxyglucose uptake by PET CT) in the primary tumor after the first window. Secondary objectives will evaluate biomarkers of response identified in preclinical studies. Pre- and post-first window of opportunity treatment biopsies will be obtained for correlative and exploratory analyses.
Clinical trial information: NCT06044311
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HERIZON-BTC-302: A phase 3 study of zanidatamab with standard-of-care (SOC) therapy vs SOC alone for first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive advanced/metastatic biliary tract cancer (BTC).
Authors: Harding James J. , Macarulla Teresa , Pant Shubham , Wu Xiaotian , Garfin Phillip M. , Okusaka Takuji
Published: January 2025

TPS648

Background:
Zanidatamab is a humanized, IgG1-like, HER2-targeted bispecific antibody that simultaneously binds to 2 non-overlapping domains on HER2. Zanidatamab is being investigated for the treatment of HER2-expressing solid tumors, including BTC. In the phase 2 HERIZON-BTC-01 trial, zanidatamab monotherapy demonstrated promising antitumor activity in 80 patients with previously treated HER2-positive BTC. Confirmed objective response rate (cORR) was 41.3% with rapid and durable responses and a manageable safety profile. This phase 3 trial is assessing zanidatamab + SOC therapy vs SOC alone for first-line treatment of HER2-positive advanced/metastatic BTC.
Methods:
This ongoing, global, phase 3, randomized, open-label trial (NCT06282575) is investigating the efficacy and safety of zanidatamab with cisplatin and gemcitabine (CisGem) vs CisGem alone ± a programmed cell death protein-1/ligand 1 (PD-1/L1) inhibitor (pembrolizumab or durvalumab at physician’s discretion if locally approved) as first-line treatment for patients with advanced HER2-positive BTC. Eligibility criteria include ≥18 years of age; locally advanced, unresectable, or metastatic HER2-positive BTC by immunohistochemistry and in situ hybridization assay (IHC 3+ or IHC 2+/ISH+); and Eastern Cooperative Oncology Group performance status ≤1. Patients may have received ≤2 cycles of a gemcitabine-based regimen ± pembrolizumab or durvalumab. Prior HER2-targeted therapy is not allowed except for patients who completed it for breast cancer >5 years prior to BTC diagnosis. Eligible patients will be randomized to receive zanidatamab (flat 2-tiered dosing: 1800 mg intravenous [IV; body weight <70 kg] or 2400 mg IV [body weight ≥70 kg] every 3 weeks) + a standard dose of CisGem ± a PD1/L1 inhibitor or CisGem alone ± a PD1/L1 inhibitor (≤8 cycles). The primary endpoint is progression-free survival (PFS) in patients with IHC 3+ tumors. Secondary/exploratory endpoints include overall survival (IHC 3+ subgroup; overall population), PFS (overall population), cORR, incidence and severity of adverse events, and patient-reported outcomes. The study is currently recruiting patients.
Clinical trial information: NCT06282575
.
A phase I, single-center, open label, dose de-escalation and expansion study of Ivosidenib + mFOLFIRINOX in patients with resectable pancreatic adenocarcinoma.
Authors: Lee Ho Jun , Henke Lauren E. , Dorth Jennifer Anne , Lumish Melissa Amy , Conces Madison , Mohamed AMR , Chakrabarti Sakti , Mahipal Amit , Selfridge J. Eva , Ammori John Brian , Hardacre Jeffrey , Winter Jordan Michael , Bajor David L.
Published: January 2025

TPS794

Background:
Pancreatic ductal adenocarcinoma (PDA) carries a dismal prognosis, with a 34% 5-year survival rate for patients with localized disease. Guidelines recommend consideration of neoadjuvant approaches in localized PDA with the goals of controlling microscopic metastatic disease and increasing rates of microscopically margin-negative resections. One of the hallmark characteristics of PDA is a micronutrient poor, highly stromal microenvironment. Surviving in this environment requires enhanced mitochondrial function, which utilizes isocitrate dehydrogenase 1 (IDH1). In pre-clinical studies, ivosidenib, an FDA approved medication for IDH1 mutant AML, induced high levels of reactive oxygen species in PDA cells with wild-type IDH1, and caused tumor regressions and extended survival in implanted KPC mouse models. Here, we investigate the addition of ivosidenib to standard of care neoadjuvant mFOLFIRINOX in patients with resectable PDA to determine safety, pharmacodynamics, and early efficacy signals.
Methods:
This is a phase I, single-center, open label, dose de-escalation and expansion study in patients with resectable PDA. Eligible patients must have histologically confirmed and resectable right-sided PDA based on CT or MRI imaging. Patients receive approximately 10 weeks of neoadjuvant treatment composed of 2 weeks of ivosidenib monotherapy, followed by 6 weeks (3 cycles) of mFOLFIRINOX with ivosidenib, followed by up to 4 weeks of ivosidenib monotherapy until the day of surgery. Ivosidenib is administered once daily at 500mg; it is to be de-escalated to 250mg based on Bayesian Optimal Interval Design with Informative Prior and a target dose limiting toxicity (DLT) rate of 30%. The primary endpoint is to determine the safety and tolerability of ivosidenib in combination with mFOLFIRINOX. Secondary endpoints include RECIST version 1.1 response rates, major pathologic response rates, and biochemical (CA19-9, CEA) response rates. Correlative studies will be performed on surgical samples to evaluate metabolomic profiles. At the time of submission, 10 out of 16 planned patients have been enrolled. There have been no DLT at 500mg of ivosidenib.
Clinical trial information: NCT05209074
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A phase II study of peri-operative NovoTTF-200T(P) in combination with gemcitabine and nab-paclitaxel for resectable pancreatic adenocarcinoma: Big Ten Cancer Research Consortium (BTCRC-GI21-500).
Authors: Khorasanchi Adam , Noonan Anne M. , Jin Ning , Hays John L. , Roychowdhury Sameek , Malalur Pannaga , Rahman Shafia , Cloyd Jordan M. , Dillhoff Mary , Tsai Susan , Mittra Arjun , Manne Ashish
Published: January 2025

TPS795

Background:
The recurrence rates and outcomes in resectable pancreatic ductal adenocarcinoma (R-PDA) is concerningly high. The benefit of neoadjuvant chemotherapy over traditional upfront surgery followed by adjuvant therapy is not clear. Electromagnetic fields generate bi-directional forces on highly polar intracellular components, causing abnormal microtubule polymerization during spindle formation and irregular cleavage furrow formation. We will leverage these anti-proliferative effects in managing R-PDA by tumor treating fields (TTF) with chemotherapy backed by strong in vitro and in vivo evidence. The PANOVA phase II trial (n=40) gave us safety and efficacy data of this combination in advanced PDA. No systemic effects were associated with TTF. The only notable safety issue was a small incidence of grade 3 device-related dermatitis.
Methods:
Our phase II single arm study will investigate perioperative use of TTF with gemcitabine and nab-paclitaxel (G-NP) combination. Eligible patients R-PDA (visible pancreatic mass, measurable disease, absence of arterial interface, venous interface ≤ 180°, patent portal splenic confluence, and no metastatic disease, including lymphadenopathy outside the surgical area) will wear TTF and receive three cycles of G-NP before restaging. Patients are expected to wear TTF for > 80% of the time during this period. If they proceed with resection, additional 3 cycles of Gem-NP with TTF will be given to the patient. This study employs a Bayesian Optimal Phase 2 (BOP2) design with primary endpoints of overall survival (OS) at 2 years and resection rate. The null hypothesis posits a 40% OS rate compared to a target of 60%, and a resection rate null hypothesis of 60% versus a target of 75%. The trial aims to enroll 30 patients, with an interim futility analysis planned after 15 participants. Enrollment will be terminated early if 8 or fewer patients undergo resection in the initial stage, providing 83% power and a type I error rate of 10%. Secondary endpoints include adverse events, overall response rate, TTFields compliance rate, relative dose intensity, and overall survival. The trial started actively recruiting patients in April 2024. The accrual goal is 38 patients. At the time of submission, one patient was enrolled.
Clinical trial information: NCT05624918
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Endocrine Alterations in Patients With Pachydermoperiostosis
Authors: Stelmachowska-Banaś Maria , Barry Sayka , Angurala Ishita , Rice Tom , Magid Kesson , Carreira Ana , Rai Ashutosh , Evans Amy , Bollington Mark , Kaur Vaishali , Singhmar Shallu , Silaghi Cristina Alina , Mandisodza Kudakwashe , McGregor Alan , Sahoo Jayaprakash , Gupta Rahul , Behera Kishore Kumar , Roy Ayan , Carr Ian M , Loughrey Paul Benjamin , Dutta Pinaki , Korbonits Márta
Published: January 2025

Context

Pachydermoperiostosis (primary hypertrophic osteoarthropathy, PHO), usually due to biallelic loss of function variants in HPGD and SLCO2A1, has some features overlapping with acromegaly and is often referred to endocrinologists. A detailed endocrine assessment is not available for these patients.

Objective

To assess the genetic and endocrine characteristics of patients with PHO referred to endocrine centers with a possible diagnosis of acromegaly.

Methods

Seventeen patients from 14 families in which acromegaly was excluded based on lack of elevated insulin-like growth factor (IGF)-1 levels and/or growth hormone suppression on an oral glucose tolerance test were assessed for HPGD and SLCO2A1 variants.

Results

Age at diagnosis was 26.2 ± 9.0 years (mean ± SD, range 9-43). Digital clubbing was present in all patients. Periostosis (94%), arthralgia (88%), periarticular edema (77%), pachydermia (82%), and coarsened facial features resembling acromegaly (71%) were present in the vast majority of the patients, while eyelash trichomegaly, blepharoptosis, high-arched palate, gingival hypertrophy, gastrointestinal symptoms, and marfanoid habitus were seen in some. Nine patients (53%) had low IGF-1 levels; the rest of the patients had IGF-1 levels in the lowest quartile of the reference range. Estradiol concentration was increased above the normal range in 8 male patients (62%) with normal testosterone and prolactin levels. Biallelic HPGD (2/14 kindreds) or SLCO2A1 (8 novel) variants (12/14 kindreds) were found. Two patients had no identifiable pathogenic/likely pathogenic variant in HPGD or SLCO2A1. Their phenotype was not different from the other patients.

Conclusion

We establish that low IGF-1 and elevated estradiol levels are frequent features of PHO. Nine novel and 5 known pathogenic/likely pathogenic genetic variants were identified.
O-06 CUSHING’S SYNDROME DUE TO BILATERAL IMMUNHISTOCHEMICALLY-PROVEN ACTH POSITIVE ADRENAL NEOPLASMS
Authors: Ekşi Haydardedeoğlu Filiz , Bağır Gülay Şimşek , Kırbıyık Özgür , Emrah Koçer Nazım , Ertörer Melek Eda
Published: January 2025

Introduction

Ectopic ACTH secretion is a rare cause of endogenous hypercortisolism. Herein, a case of Cushing’s syndrome due to bilateral immunhistochemically-proven ACTH positive adrenal neoplasms is presented.

Clinical Case

A 60 year old women was admitted with acute-onset severe hypokalemia and hyperglycemia. She had severe metabolic alkalosis and her serum K levels kept being below 1.5 mmol/L, if left untreated. Physical examination demonstrated facial and upper body flushing, but was otherwise normal. Laboratory analyses were; early morning plasma ACTH: 211 pg/ml, early morning serum cortisol: 88.9 mcg/dl, late night serum cortisol: 58.8 mcg/dl, late night plasma ACTH:42.3 pg/ml, total testosterone: 1.79 ng/ml (0.120-0.350), DHEAS: 377.8 mcg/dl (29.7-182.2), 24 H urine free cortisol (UFC): 6696 mcg/24 h (urinary volume:2.7L), plazma aldosterone: 1.43 ng/dl, PRA<0.1 ng/ml/saat, 17-OH-progesterone: 2.91 ng/ml, calcitonin <2.0 pg/ml. Relying on rapid-onset of severe findings and very high UFC, our prediagnosis was Ectopic ACTH Syndrome. Thorax CT, 18-FDG-PET and Ga-68-PET scans did not exhibit any source. Abdominal CT scan revealed diffuse enlargement of both adrenal glands. Then Desmopressin test was performed and demonstrated central gradient (Table 1). However, pituitary MRI demonstrated no lesion, but thinning of the global gland. Accordingly inferior petrosal sinus sampling (IPSS) was compatible with ectopic ACTH syndrome (Table 2). Due to life-threatening hypercortisolemia of unknown origin, a decision was made in favor of bilateral adrenalectomy. Fluconazole 2x200mg/day iv was started, and after 48 hours, serum cortisol dropped significantly. The operation was performed safely, the patient’s general condition and serum potassium improved rapidly. Pathological specimen was reported as bilateral adrenocortical oncocytic neoplasms, and Ki-67 index was <1%. Immunohistochemistry (IHC) showed strong staining for ACTH in both lesions (Figure).

Conclusion

Although very rare, adrenals should be kept in mind as a source of ectopic ACTH syndrome.Figure:Immunohistochemical (IHC) staining demonstrating ACTH-secreting adrenal tumors (original magnification x100)  Table 1:Plasma ACTH levels following 10 mcg desmopressin given intravenously  Table 2:Plasma ACTH levels during Inferior Petrosal Sinus Sampling test performed with desmopressin