Trials In Colorectal Cancer Research Articles

Roles of Necroptosis, Apoptosis, and Inflammation in Colorectal Carcinogenesis: A Longitudinal Human Study.

Necroptosis triggers an inflammatory cascade associated with antimicrobial defense. No prospective human study has yet explored the role of necroptosis in colorectal cancer (CRC) development. We conducted quantitative analysis of biomarkers for necroptosis (transient receptor potential melastatin 7 (TRPM7) and phosphorylated mixed lineage kinase-like protein (pMLKL)), inflammation (cyclooxygenase-2, COX-2), apoptosis (BAX and TUNEL), and cell proliferation (Ki67). This was done using tissue microarray biospecimens from the Cooperative Human Tissue Network and rectal biopsies from a longitudinal study within the Personalized Prevention of Colorectal Cancer Trial. In the human colorectal adenoma-carcinoma sequence, we observed an inverse expression trend between BAX and TRPM7; TRPM7 decreased from normal mucosa to small and large adenomas but significantly increased in early CRC stages (Ptrend=0.004). It maintained high levels through all cancer stages. An increased COX-2 intensity in the epithelium was noted during tumorigenesis (Ptrend=0.02) and was significantly associated with an elevated risk of metachronous polyps (odds ratio =3.04, 95% confidence interval:1.07-8.61, Ptrend=0.02). The combined composite index scores of TRPM7 and COX-2 were strongly linked to 6- to 47-fold increased risks for metachronous adenoma/serrated polyps while combined scores of pMLKL or TRPM7 with BAX were associated with an 11.5- or 13.3-fold elevated risk for metachronous serrated polyps. In conclusion, our findings suggest that COX-2 expression within normal-looking colorectal mucosa is significantly associated with an increased risk of metachronous colorectal polyp. Furthermore, our results propose the hypothesis that synergistic interactions among necroptosis, inflammation, and apoptosis could play a pivotal role in human colorectal tumorigenesis.

Generalizability of lesion detection and segmentation when ScaleNAS is trained on a large multi-organ dataset and validated in the liver.

Tumor assessment through imaging is crucial for diagnosing and treating cancer. Lesions in the liver, a common site for metastatic disease, are particularly challenging to accurately detect and segment. This labor-intensive task is subject to individual variation, which drives interest in automation using artificial intelligence (AI). Evaluate AI for lesion detection and lesion segmentation using CT in the context of human performance on the same task. Use internal testing to determine how an AI-developed model (ScaleNAS) trained on lesions in multiple organs performs when tested specifically on liver lesions in a dataset integrating real-world and clinical trial data. Use external testing to evaluate whether ScaleNAS's performance generalizes to publicly available colorectal liver metastases (CRLM) from The Cancer Imaging Archive (TCIA). The CUPA study dataset included patients whose CT scan of chest, abdomen, or pelvis at Columbia University between 2010-2020 indicated solid tumors (CUIMC, n=5011) and from two clinical trials in metastatic colorectal cancer, PRIME (n=1183) and Amgen (n=463). Inclusion required ≥1 measurable lesion; exclusion criteria eliminated 1566 patients. Data were divided at the patient level into training (n=3996), validation (n=570), and testing (n=1529) sets. To create the reference standard for training and validation, each case was annotated by one of six radiologists, randomly assigned, who marked the CUPA lesions without access to any previous annotations. For internal testing we refined the CUPA test set to contain only patients who had liver lesions (n=525) and formed an enhanced reference standard through expert consensus reviewing prior annotations. For external testing, TCIA-CRLM (n=197) formed the test set. The reference standard for TCIA-CRLM was formed by consensus review of the original annotation and contours by two new radiologists. Metrics for lesion detection were sensitivity and false positives. Lesion segmentation was assessed with median Dice coefficient, under-segmentation ratio (USR), and over-segmentation ratio (OSR). Subgroup analysis examined the influence of lesion size ≥ 10mm (measurable by RECIST1.1) versus all lesions (important for early identification of disease progression). ScaleNAS trained on all lesions achieved sensitivity of 71.4% and Dice of 70.2% for liver lesions in the CUPA internal test set (3,495 lesions) and sensitivity of 68.2% and Dice 64.2% in the TCIA-CRLM external test set (638 lesions). Human radiologists had mean sensitivity of 53.5% and Dice of 73.9% in CUPA and sensitivity of 84.1% and Dice of 88.4% in TCIA-CRLM. Performance improved for ScaleNAS and radiologists in the subgroup of lesions that excluded sub-centimeter lesions. Our study presents the first evaluation of ScaleNAS in medical imaging, demonstrating its liver lesion detection and segmentation performance across diverse datasets. Using consensus reference standards from multiple radiologists, we addressed inter-observer variability and contributed to consistency in lesion annotation. While ScaleNAS does not surpass radiologists in performance, it offers fast and reliable results with potential utility in providing initial contours for radiologists. Future work will extend this model to lung and lymph node lesions, ultimately aiming to enhance clinical applications by generalizing detection and segmentation across tissue types.

Assessing the Contribution of Duffy Null Phenotype to Disparities in Eligibility Criteria for Clinical Trials for Newly-Diagnosed Colorectal Cancer

Assessing the Contribution of Duffy Null Phenotype to Disparities in Eligibility Criteria for Clinical Trials for Newly-Diagnosed Colorectal Cancer

Primary tumour resection in metastasised adrenocortical carcinoma: a systematic review.

Up to 30% of adrenocortical carcinoma (ACC) patients have metastasised disease upon initial presentation and systemic treatments currently fail to sufficiently improve survival. Palliative primary tumour resection can be considered for symptomatic relief, but its potential survival benefit remains a topic of debate. This systematic review therefore aims to assess the effect of primary tumour resection on overall survival in patients with metastatic ACC. A systematic review was performed using Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. Relevant databases were searched from 2000-2024 for studies on primary tumour resection in metastatic ACC. Overall survival data were analysed. A total of thirteen studies on primary tumour resection for metastatic ACC were included. All studies were retrospective and assessed as having a high risk of bias. Data regarding adequate patient characteristics and indications for surgery were missing in all studies. Hence, current literature is hampered by both indication and selection bias to draw any conclusions on the survival benefit of primary tumour resection in patients with metastasised ACC. However, twelve out of thirteen studies (92%) demonstrated longer overall survival after primary tumour resection compared to no surgery. Whereas this is in line with retrospective data on other cancers, randomised controlled trials in other tumours, like breast and colorectal cancer, have failed to display survival benefits of primary tumour resection. These cancers are however relatively chemo-sensitive, unlike ACC. Primary tumour resection could therefore only be considered on individual patient basis.

Evaluating time-to-event surrogates for time-to-event true endpoints: an information-theoretic approach based on causal inference.

Putative surrogate endpoints must undergo a rigorous statistical evaluation before they can be used in clinical trials. Numerous frameworks have been introduced for this purpose. In this study, we extend the scope of the information-theoretic causal-inference approach to encompass scenarios where both outcomes are time-to-event endpoints, using the flexibility provided by D-vine copulas. We evaluate the quality of the putative surrogate using the individual causal association (ICA)-a measure based on the mutual information between the individual causal treatment effects. However, in spite of its appealing mathematical properties, the ICA may be ill defined for composite endpoints. Therefore, we also propose an alternative rank-based metric for assessing the ICA. Due to the fundamental problem of causal inference, the joint distribution of all potential outcomes is only partially identifiable and, consequently, the ICA cannot be estimated without strong unverifiable assumptions. This is addressed by a formal sensitivity analysis that is summarized by the so-called intervals of ignorance and uncertainty. The frequentist properties of these intervals are discussed in detail. Finally, the proposed methods are illustrated with an analysis of pooled data from two advanced colorectal cancer trials. The newly developed techniques have been implemented in the R package Surrogate.

An RNA damage response network mediates the lethality of 5-FU in colorectal cancer

5-fluorouracil (5-FU), a major anti-cancer therapeutic, is believed to function primarily by inhibiting thymidylate synthase, depleting deoxythymidine triphosphate (dTTP), and causing DNA damage. Here, we show that clinical combinations of 5-FU with oxaliplatin or irinotecan show no synergy in human colorectal cancer (CRC) trials and sub-additive killing in CRC cell lines. Using selective 5-FU metabolites, phospho- and ubiquitin proteomics, and primary human CRC organoids, we demonstrate that 5-FU-mediated CRC cell killing primarily involves an RNA damage response during ribosome biogenesis, causing lysosomal degradation of damaged rRNAs and proteasomal degradation of ubiquitinated ribosomal proteins. Tumor types clinically responsive to 5-FU treatment show upregulated rRNA biogenesis while 5-FU clinically non-responsive tumor types do not, instead showing greater sensitivity to 5-FU's DNA damage effects. Finally, we show that treatments upregulating ribosome biogenesis, including KDM2A inhibition, promote RNA-dependent cell killing by 5-FU, demonstrating the potential for combinatorial targeting of this ribosomal RNA damage response for improved cancer therapy.

Efficacy and safety in early-phase clinical trials for refractory colorectal cancer: A meta-analysis

BackgroundDespite recent metastatic colorectal cancer (mCRC) therapeutic innovations a comprehensive synthesis of patient outcome and risk-benefit assessment of phase 1/2 trials is missing. The aim of this meta-analysis is to assess efficacy, safety, and trends over time for phase 1 and 2 mCRC trials by examining clinical benefit rate (CBR), overall response rate (ORR), grade 3 or higher adverse events (AE), and discontinuation due to AE. MethodsThe PRISMA guidelines were followed. We searched PubMed and Embase for publications of phase 1/2 trials between 2010–2021. Trials reporting on new therapies for treatment-refractory mCRC were included. ResultsThe search strategy yielded 4175 unique reports, of which 258 publications were eligible. These publications report data of 277 unique treatment arms. Overall ORR was 6 %, CBR was 27 % in phase 1 and 36 % in phase 2 trials. CBR increased from 23 % in 2010–2012 to 42 % in 2019–2021. Compared to 2010–2012, trials in 2019–2021 more often tested immunomodulators (4 % vs 23 %), included molecularly preselected populations (4 % vs 38 %) and younger patients (median age<60 44 % vs 66 %). Grade 3 + AE occurred in 35 % of patients, most frequently in trials investigating targeted treatments. ConclusionsTreatment efficacy in phase 1/2 trials is modest but improved from 2010 to 2021. This improvement is accompanied by a shift towards testing in a younger, fitter, and more strictly molecularly preselected population, as well as an increased focus on targeted and immunotherapies.

Abstract B109: Results from colorectal cancer and clinical trials health education in racially/ethnically diverse populations

Abstract Introduction: The University of California, San Francisco (UCSF), a National Cancer Institute (NCI) designated comprehensive cancer center implemented NCI’s Colorectal cancer (CRC) and Clinical Trials (CT) Education Initiative to foster awareness, knowledge and intent to uptake CRC screening or participate in CT. Racial/ethnic groups have higher death rates and shorter survival rates for most cancers and face additional disparities and inequities. CRC is the third most commonly diagnosed cancer. CRC screening reduces incidence and mortality, however, it is underutilized. CT are studies that evaluate methods to understand prevent, find and treat cancer plus assess safety &amp; effectiveness. Racial/ethnic populations CT participation is low. More diverse enrollment is needed to guide future cancer prevention, control, care and improve health equity. Methods: UCSF Community Health Educators engaged with community partners and the public to conduct CRC &amp; CT education. The education topics included understanding the colon and rectum, colorectal health promotion, risk factors, what is CRC and screening, access to screening, what are clinical trials, how they advance medical progress, diversity &amp; inclusion, types and phases of CT, informed consent, myths and facts, mistrust/other concerns, barriers, and how to find and enroll in CT. Education sessions included administering pre/post surveys- 19-item for CRC and 17-item for CT to measure knowledge and intention to get screened for CRC or participate in CT. Results: There were 772 total surveys (N=411 CRC completed pre/post, 361 completed CT pre/post). CRC respondents: 70% female, 30% male; 54 average age; 53% African American, 0.3% American Indian, 23% Asian, 13% Latino, 4% Pacific Islander, 3% White &amp; 3% Multiracial. Overall (from pre to post education) CRC knowledge significantly increased, as well as intent to get screened, and to ask healthcare provider about CRC. Knowledge improved pre to post by 14% (76% vs 91%). Post-education intent, respondents strongly agreed or agreed: 91% talk to healthcare provider, 92% get screened for CRC, 89% talk about CRC with family/friends, 95% eat healthier, 95% increase physical activity. CT respondents: 77% female, 23% male; 51 average age; 64% African American, 1.2% American Indian, 10% Asian, 17% Latino, 2% Pacific Islander, 4% White &amp; 2% Multiracial. Post CT education knowledge, intent to seek out CT information and intent to join significantly increased. CT knowledge improved pre to post by 7% (83% vs 90%). Post-education intent respondents strongly agreed or agreed: 69% seek out CT information, 59% search for CT, 75% talk to a healthcare provider about CT; 78% importance of people of color CT participation; 48% intent to join a CT and 70% talk to family/friends about joining a CT. Conclusion: CRC and CT education demonstrated efficacy in increasing awareness and knowledge and advanced intent to get colorectal cancer screening and enroll in clinical trials. Citation Format: Michelle Moseley, Eva Pardo, Kim Rhoads, Ghila Andemeskel, Nanci Bocanegra, Tontantzin Rodriguez, Yushan Zhang. Results from colorectal cancer and clinical trials health education in racially/ethnically diverse populations [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr B109.

Abstract B001: Engaging patient advocates in the battle against cancer directly in their communities in culturally and language specific ways

Abstract Background: Patient advocates from diverse communities are at the forefront of informing on the latest scientific findings to different audiences; and connecting to resources to help battle cancer. However, disparities exists that exacerbate barriers to the delivery of cancer information. These disparities are the result of impactful socio-determinants of health that range from language barriers to food insecurity, mental health challenges and a lack of connection to support services and clinical trials. Lazarex Cancer Foundation has established Pop-up Hubs that go directly into the community to alleviate barriers while empowering patient advocates from varied cultural and racial/ethnic groups to deliver cancer information that account for culture, race/ethnicity literacy and numeracy levels, and delivered in multiple languages. Patient advocates are cancer-care ambassadors that help reduce the cancer burden, provide referrals, follow-up with needed information or care, and enroll patients into clinical trials. Methods: With community participation, patient advocates have helped develop culturally and language specific educational materials, approach communities in their own neighborhoods, and help connect to support services, such as free food distribution, mental health services, and raise awareness on environmental and lifestyle factors that can influence a cancer trajectory. Our patient advocates follow up with community members seeking resolution to their cancer concerns. Patient advocates promote screenings and help link individuals and their families. Patient advocates also work with community coalitions, testify before local decision-makers, and promote early detection, screening, tobacco cessation, weight management, nutritious culturally specific meals, and advise on exercise. Results: Working with patient advocates in a participatory manner, we have developed and disseminated educational materials on prostate cancer, breast cancer, colorectal cancer, cervical cancer, and clinical trials. Patient advocates have provided cancer information to 5,000 individuals of Latino/a (Spanish speaking), Black/African American, and Asian (Korean and Mandarin speaking) heritage). 3,773 have received cancer information, have connected 260 individuals to support groups; provided 112 community members with individualized follow-up increasing knowledge and access to services. Reached over 3 million people via various media and between 2018-2024 supported the passing with our partners of 31 tobacco laws in California. Conclusion: Patient advocates have created knowledgeable inviting environments for community members directly in the diverse communities of Los Angeles. The information provided includes screening guidelines, the importance of diversity participation in clinical trials, self or patient advocacy, and accessing trustworthy, reliable sources. Patient advocates are opening new ways to reach communities in a participatory manner in their own backyard; enhancing our ongoing effort to reduce cancer disparities. Citation Format: Lourdes Baezconde-Garbanati, Elena Nieves, Carolina Aristizabal1, Yaneth L. Rodriguez, Rosa Barahona, Marya Shego, Dana Dornsife. Engaging patient advocates in the battle against cancer directly in their communities in culturally and language specific ways [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr B001.

Quality of Reporting on Anastomotic Leaks in Colorectal Cancer Trials: A Systematic Review.

Although attempts have been made in the past to establish consensus regarding the definitions and grading of the severity of colorectal anastomotic leakage, widespread adoption has remained limited. A systematic review of the literature was conducted to examine the various elements used to report and define anastomotic leakage in colorectal cancer resections. A systematic review was conducted using the PubMed, Embase, and Cochrane Library Database. All published randomized controlled trials, systematic reviews, and meta-analyses containing data related to adult patients undergoing colorectal cancer surgery and reporting anastomotic leakage as a primary or secondary outcome, with a definition of anastomotic leakage were included. Definitions of anastomotic leakage, clinical symptoms, radiological modalities and findings, findings at reoperation, and grading terminology or classifications for anastomotic leakage. Of the 471 articles reporting anastomotic leakage as a primary or secondary outcome, a definition was reported in 95 studies (45 randomized controlled trials, 13 systematic reviews, and 37 meta-analyses) involving a total of 346,140 patients. Of these 95 articles, 68% reported clinical signs and symptoms of anastomotic leakage, 26% biochemical criteria, 63% radiological modalities, 62% radiological findings, and 13% findings at reintervention. Only 45% (n = 43) of included studies reported grading of anastomotic leakage severity or leak classification, and 41% (n = 39) included a time frame for reporting. There was a high level of heterogeneity between the included studies. This evidence synthesis confirmed incomplete and inconsistent reporting of anastomotic leakage across the published colorectal cancer literature. There is a great need to develop and implement a consensus framework for defining, grading, and reporting anastomotic leakage. Prospectively registered at PROSPERO (ID 454660).

Research Perspective on Quality of Reporting on Anastomotic Leaks in Colorectal Cancer Trials: A Systematic Review.

Research Perspective on Quality of Reporting on Anastomotic Leaks in Colorectal Cancer Trials: A Systematic Review.

Futility Interim Analysis Based on Probability of Success Using a Surrogate Endpoint.

In clinical trials with time-to-event data, the evaluation of treatment efficacy can be a long and complex process, especially when considering long-term primary endpoints. Using surrogate endpoints to correlate the primary endpoint has become a common practice to accelerate decision-making. Moreover, the ethical need to minimize sample size and the practical need to optimize available resources have encouraged the scientific community to develop methodologies that leverage historical data. Relying on the general theory of group sequential design and using a Bayesian framework, the methodology described in this paper exploits a documented historical relationship between a clinical "final" endpoint and a surrogate endpoint to build an informative prior for the primary endpoint, using surrogate data from an early interim analysis of the clinical trial. The predictive probability of success of the trial is then used to define a futility-stopping rule. The methodology demonstrates substantial enhancements in trial operating characteristics when there is a good agreement between current and historical data. Furthermore, incorporating a robust approach that combines the surrogate prior with a vague component mitigates the impact of the minor prior-data conflicts while maintaining acceptable performance even in the presence of significant prior-data conflicts. The proposed methodology was applied to design a Phase III clinical trial in metastatic colorectal cancer, with overall survival as the primary endpoint and progression-free survival as the surrogate endpoint.

Global Landscape of Phase III Interventional Clinical Trials in Colorectal Cancer

Global Landscape of Phase III Interventional Clinical Trials in Colorectal Cancer

Recruitment strategies and consent rates in a national prospective colorectal cancer screening cohort: results from year 1 of the Voyage Study

ObjectiveTo identify the optimal incentive protocol for maximising participation while managing study costs during the Voyage trial.DesignProspective cohort (Voyage trial) of colorectal cancer (CRC) incidence and mortality outcomes in individuals...

TGFβ in Pancreas and Colorectal Cancer: Opportunities to Overcome Therapeutic Resistance.

TGFβ is a pleiotropic signaling pathway that plays a pivotal role in regulating a multitude of cellular functions. TGFβ has a dual role in cell regulation where it induces growth inhibition and cell death; however, it can switch to a growth-promoting state under cancerous conditions. TGFβ is upregulated in colorectal cancer and pancreatic cancer, altering the tumor microenvironment and immune system and promoting a mesenchymal state. The upregulation of TGFβ in certain cancers leads to resistance to immunotherapy, and attempts to inhibit TGFβ expression have led to reduced therapeutic resistance when combined with chemotherapy and immunotherapy. Here, we review the current TGFβ inhibitor drugs in clinical trials for pancreatic and colorectal cancer, with the goal of uncovering advances in improving clinical efficacy for TGFβ combinational treatments in patients. Furthermore, we discuss the relevance of alterations in TGFβ signaling and germline variants in the context of personalizing treatment for patients who show lack of response to current therapeutics.

Phase 1 clinical trials in refractory colorectal cancer: Do older patients benefit?

Phase 1 clinical trials in refractory colorectal cancer: Do older patients benefit?

Underrepresentation of Asian Americans, Native Hawaiians, and other Pacific Islanders (AA &amp; NHPI) in cancer clinical trials that led to FDA approvals in 2010-2022.

11026 Background: About 6% and 0.3% of the total United States (US) population identify as Asian or NHPI alone, respectively. The most commonly diagnosed cancers among AA &amp; NHPI in the US are breast, prostate, lung, thyroid, and colorectal. Liver, gastric, and head and neck cancers occur in higher rates in AA &amp; NHPI vs. non-Hispanic White. Enrollment of Asian &amp; NHPI patients in multiregional cancer clinical trials may provide additional data regarding intrinsic and extrinsic factors (e.g., diet, infections, environmental exposures) impacting the etiology of cancer. We investigated enrollment trends of NHPI and Asian (within and outside of US) patients in cancer clinical trials that led to an FDA approval from 2010-2022. Methods: We analyzed data from ~98,000 patients in 171 cancer therapeutic clinical trials that led to FDA approvals for breast, prostate, lung, thyroid, colorectal, liver, gastric, and head and neck cancer indications from 2010-2022. Separate race categories of Asian and Native Hawaiian and other Pacific Islander were used. Results: Descriptive statistics of NHPI and Asians within and outside of US enrollment in breast, prostate, lung, thyroid, colorectal, liver, gastric, and head and neck cancer trials that led to an FDA approval from 2010-2022 are summarized in the table. Enrollment of Asian patients in the US was &lt;1% (except for liver cancer) and NHPI patients was &lt;0.2%. Conclusions: Although cancer is the leading cause of death for AA &amp; NHPI, AA &amp; NHPI are under-represented in cancer clinical trials, especially when data are further disaggregated into enrollment of NHPI and Asians within and outside of the US. Cancer etiology may vary in Asians in the US vs. Asia due to different intrinsic/extrinsic risk factors, underscoring the importance of enrolling more AA &amp; NHPI into clinical trials to expand the evidence supporting drug approvals in the US and to advance health equity through clinical trial diversity. [Table: see text]

Updates on the Management of Colorectal Cancer in Older Adults.

Colorectal cancer (CRC) poses a significant global health challenge. Notably, the risk of CRC escalates with age, with the majority of cases occurring in those over the age of 65. Despite recent progress in tailoring treatments for early and advanced CRC, there is a lack of prospective data to guide the management of older patients, who are frequently underrepresented in clinical trials. This article reviews the contemporary landscape of managing older individuals with CRC, highlighting recent advancements and persisting challenges. The role of comprehensive geriatric assessment is explored. Opportunities for treatment escalation/de-escalation, with consideration of the older adult's fitness level. are reviewed in the neoadjuvant, surgical, adjuvant, and metastatic settings of colon and rectal cancers. Immunotherapy is shown to be an effective treatment option in older adults who have CRC with microsatellite instability. Promising new technologies such as circulating tumor DNA and recent phase III trials adding later-line systemic therapy options are discussed. Clinical recommendations based on the data available are summarized. We conclude that deliberate efforts to include older individuals in future colorectal cancer trials are essential to better guide the management of these patients in this rapidly evolving field.

Abstract 2386: Meta-analysis of efficacy and safety in early-phase clinical trials for refractory colorectal cancer

Abstract Introduction: Despite a decade of metastatic colorectal cancer (mCRC) therapeutic innovations, a comprehensive synthesis of patient outcome and risk-benefit assessment of phase 1/2 trials, extending beyond single-center studies, is missing. The aim of this meta-analysis is to assess efficacy, safety, and trends over time for phase 1 and 2 mCRC trials by examining clinical benefit rate (CBR), overall response rate (ORR), grade 3 or higher adverse events (AE), and discontinuation due to AE. Methods: The protocol and search were preregistered on PROSPERO. We searched PubMed and Embase for publications of phase 1/2 trials between 2010-2022. Reports were screened for inclusion criteria, followed by data-extraction by two researchers. Trials reporting on non-standard therapies for treatment-refractory mCRC or trials reporting specific mCRC efficacy data were included. CBR was defined as the proportion of patients with complete/partial response or stable disease ≥14 weeks. We used logit transformations for pooled effect analysis via a random-effects model, assigning study weights by the inverse variance method. Subgroup analyses were performed for publication year, preselection on molecular traits, and drug class: antiangiogenics, chemotherapy, immunomodulator, targeted therapy, or vaccine. Data are presented with 95% confidence intervals (CI); reported differences had non-overlapping CIs. Results: The search strategy yielded 4175 unique reports, from which we extracted data for 279 trials. Most trials were phase 1 (63%). ORR was limited to 6% [6-7] in both phase 1 and 2, CBR was higher in phase 2 than in phase 1 trials (36% vs 27%). Trials testing antiangiogenic drugs had the highest CBR (47%) and immunomodulators the highest ORR (8%). Trials with patients preselected on molecular traits had higher CBR compared to other trials (38% vs 28%). We observed an increase in efficacy, especially in phase 2 trials, with a CBR rising from 22% to 42% between trials published in 2010-2012 and 2019-2021. Compared with 2010-2012, trials in 2019-2021 were more often testing immunomodulators (23% vs 4%), performed on molecular preselected populations (38% vs 4%), and including younger patients (median age &amp;lt;60 in 66% vs 44%). The occurrence of grade 3+ AE was 33% [28-38] in both phase 1 and 2. AE led to discontinuation in 12% of phase 1 trial patients, and 7% of phase 2 patients. Grade 3+ AE occurred in 4% of vaccine trial patients, in contrast to 41% in trials on targeted therapies. Occurrence of grade 3+ AE did not change over time. Conclusion: We found limited ORR and CBR in early phase trials conducted in 2010-2021 for mCRC patients, while noting severe AEs in many patients. However, during this period, clinical benefit rate increased for phase 2 trials, possibly due to evolving study strategies that entail testing new treatment types in a younger, fitter, and stricter preselected study population based on molecular traits. Citation Format: Maarten A. Huismans, Lidwien P. Smabers, Niels N. van Nieuwenhuijzen, Monique C. Minnema, Miriam Koopman, Hugo J. Snippert, Anne M. May, Jeanine M. Roodhart. Meta-analysis of efficacy and safety in early-phase clinical trials for refractory colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2386.

Abstract 6357: Establishing a reverse translational platform to dissect mode of action and mechanisms of resistance to GUCY2C-CD3 T cell engager

Abstract PF-07062119 (GUCY2C x CD3), a bispecific T cell engager (TCE) targeting Guanylyl Cyclase C (GUCY2C), a GI tumor associated antigen, is currently being evaluated in a Phase 1 clinical trial in colorectal cancer (CRC) and other GI malignancies. Improved pre-clinical understanding of the correlates of PF-07062119 resistance mechanisms and PD in a human disease relevant context is critical to better inform drug combination and patient selection strategy. Due to limited translatability of mouse syngeneic tumor models, establishing a more human disease-relevant platform leveraging tumor patient material to better inform PF-07062119 clinical strategy is needed. Here, we will discuss our efforts to perform immune profiling of T cell and myeloid tumor infiltrates, and to evaluate tumor cell depletion and cytokine production of colorectal carcinoma (CRC) samples treated ex vivo with PF-07062119. This platform may be leveraged to 1) provide clinically relevant disease insights to the effect of TCEs across a range of tumor indications; 2) determine impact of different combinatorial partners on tumor cell killing to inform clinical decisions; 3) address questions related to the minimal efficacy of TCEs in the solid tumor space; and 4) provide potential solutions for future combination partners to overcome immunosuppression in the tumor microenvironment. Citation Format: Joana Borlido, Jade Lolarga, Rachael Whaley, Michael A. Damore, Cen Guo, Keith Abayasiriwardana, Xiaojun Xu, Maggie Liu, Gosia Nocula-Lugowska, Sam Stoner, Christopher Kraser, Ioanna Cheronis, Maria Delioukina, Lee Clark, Raj Bhadra, Murali Gururajan. Establishing a reverse translational platform to dissect mode of action and mechanisms of resistance to GUCY2C-CD3 T cell engager [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6357.