tbuckley/cabot-search huggingface dataset:
Phase 2 trial of defactinib in combination with avutometinib in patients with advanced diffuse-type gastric cancer.
Authors: Ryan H. Moy, Lawrence Wen Wu, Hope Cho, Shikun Wang, Sarah Sta Ana, Matthew Strickland, Naomi Sender, Samuel J. Klempner
Journal: Journal of Clinical Oncology (2025)

TPS505 Background: Diffuse-type gastric cancer (DGC) accounts for approximately one third of gastric cancer diagnoses. DGC is characterized by poor differentiation, discohesive growth, frequent peritoneal spread, chemoresistance, and inferior survival compared to intestinal-type gastric cancer. Moreover, DGC is commonly genomically stable and often lacks clinically actionable targets such as ERBB2 amplification. Alterations enriched in DGC including loss-of-function CDH1 mutations and gain-of-function RHOA mutations can facilitate increased focal adhesion kinase (FAK) signaling that drives tumor proliferation, invasiveness, and metastasis. Recent preclinical studies demonstrated that the FAK inhibitor defactinib can inhibitor DGC growth in vitro and in vivo . FAK inhibitor monotherapy leads to compensatory mitogen-activated protein kinase (MAPK) pathway upregulation, which can be overcome with combined FAK and MEK inhibition. In preclinical DGC xenograft models, defactinib plus the RAF/MEK clamp avutometinib led to deep tumor regressions, suggesting synergistic activity of the combination. The goal of this study is to investigate the efficacy and tolerability of avutometinib plus defactinib in patients with advanced DGC refractory to standard therapy. Methods: This investigator-initiated, multicenter phase 2 trial will enroll 27 patients with metastatic/unresectable gastric or gastroesophageal junction carcinoma classified as diffuse, poorly cohesive, signet ring cell, or mixed type with progression on at least one line of therapy including platinum/fluorouracil chemotherapy. Patients with known pathogenic CDH1 and/or RHOA alterations regardless of histology are also eligible. Patients must have ECOG PS 0/1 and can have either measurable or evaluable non-measurable disease per RECIST 1.1 criteria. Avutometinib is given 3.2 mg orally twice weekly and defactinib is given 200 mg orally twice a day, both for 3 weeks on/1 week off for each 28-day cycle. The primary endpoint is 6-month PFS rate, with secondary endpoints including ORR, OS, DOR, and tolerability. Exploratory studies will interrogate FAK/MAPK pathway activation, ctDNA dynamics, and the impact of the combination of avutometinib/defactinib on the tumor microenvironment from pre- and on-treatment biopsies. The trial was opened for enrollment in August 2024. Clinical trial information: NCT06487221 .
Genomic analysis of paired primary and metastatic pancreatic ductal adenocarcinoma tumors.
Authors: Caitlin A McIntyre, Vasilisa Rudneva, Allison L. Richards, Wungki Park, William R. Jarnagin, Mark Donoghue, Eileen M. O'Reilly
Journal: Journal of Clinical Oncology (2025)

758 Background: The genomics of pancreatic ductal adenocarcinoma (PDAC) have been increasingly understood allowing for improvements in treatment, yet the clinical relevance of PDAC evolution is less well studied. The aim of this study is to evaluate genomic differences and clinical correlations between primary pancreatic tumors and paired metastases using a targeted sequencing panel. Methods: Patients who underwent surgical resection for PDAC with recurrent disease who had targeted genomic sequencing of both the primary tumor and a metastasis were included. Genomic alterations were determined using a panel of cancer-related genes (MSK-IMPACT). OncoKB was used to annotate driver alterations. MATH scores were used to quantify intratumoral heterogeneity. Comparison between paired samples was performed and association with clinical variables was assessed. Results: There were 55 patients included; 20% (n=11) received neoadjuvant therapy, 91% (n=50) had adjuvant therapy and 36% (n=20) had adjuvant radiation. The most common sites of metastasis sequenced were lung (36%, n=20), liver (35%, n=19) and local (13%, n=7). There was concordance between the first site of recurrence and site sequenced in 93% (n=51) of cases with a median time between resection and biopsy of recurrence of 25 months. The most commonly altered genes are KRAS (96%), TP53 (83%), CDKN2A (40%), SMAD4 (25%) and RNF43 (13%). The majority of alterations are shared between the primary tumor and metastasis. Clonal mutations were defined as cancer cell fraction (CCF) &gt;0.8. The majority of shared mutations are clonal; 52% of mutations are clonal in both the primary and metastasis, and clonality is preserved in 76% of shared mutations in metastases. The most commonly shared alterations are in driver genes and the majority are clonal- TP53 (80%), KRAS (78%), CDKN2A (77%) and SMAD4 (64%). The proportion of clonal mutations among drivers is higher than variants of unknown significance (p=0.005). There are 31 mutations private to the metastasis in 19 patients, 12 of which are clonal (39%). Mutations private to the metastasis are more common in patients who received adjuvant systemic therapy (p=0.035); however this was not seen when comparing patients who received adjuvant radiation to those who did not (p=0.38). MATH scores are higher in the metastasis as compared to the primary in all patients (p=0.0096), including those who received adjuvant treatment (p=0.002), indicating increased intratumoral heterogeneity in metastases. Conclusions: A targeted sequencing panel demonstrates that the majority of driver mutations are clonal and preserved between the primary tumor and metastasis. Additional private mutations and increased intratumoral heterogeneity are noted in metastasis, and our data suggests that this may be associated with exposure to systemic therapy.
Comprehensive analysis of Native Hawaiians and other Pacific Islanders with early-onset colorectal cancer.
Authors: Manasawee Tanariyakul, Jared David Acoba
Journal: Journal of Clinical Oncology (2025)

31 Background: Rates of early-onset colorectal cancers (EOCRC) are increasing in Hawaii across all racial groups. Although previous studies have shown that Native Hawaiians have a higher mortality rate compared to other racial groups, the adjustment for sociodemographic factors have been limited. Our objective is to perform a comprehensive analysis of outcomes among patients with EOCRC in a racially diverse population accounting for tumor factors and patient sociodemographics. Methods: Patients diagnosed with EOCRC between 2000 and 2022 in Hawaii. Overall survival of Asians, Whites, and Native Hawaiian or Other Pacific Islanders (NHOPI) were calculated using the Kaplan-Meier method. Cox proportional hazard regression models assessed survival predictors adjusting for clinical and sociodemographic factors. Results: We included 379 patients in the final analysis. NHOPI had higher prevalence of underinsured status and higher histopathology grade compared to Whites and Asians. In unadjusted Cox regression, NHOPI race, underinsured status, grade, and stage were prognostic for survival. After adjusting for confounders, underinsured status, grade, and stage remained prognostic, but race was not significantly associated with survival. Conclusions: This study concludes that while NHOPI patients with EOCRC demonstrated poorer survival outcomes compared to other racial groups, this disparity was largely explained by the large percentage of underinsured NHOPI patients. Addressing treatment disparities in underinsured or uninsured is essential to improve survival outcomes. Univariate and multivariate analysis of survival. Univariate Multivariate HR (95% CI) p-value HR (95% CI) p-value Insurance Private Insurance - - - - Underinsured &amp; Uninsured 1.865 (1.331-2.612) &lt;0.001 1.843 (1.285-2.643) &lt;0.001 Race White - - - - Asian 1.179 (0.746-1.865) 0.48 0.936 (0.585-1.496) 0.781 NHOPI 2.005 (1.231-3.265) 0.005 1.051 (0.714-1.547) 0.8 Age at diagnosis 0.996 (0.967-1.025) 0.771 1.002 (0.971-1.034) 0.901 Histopathology grade Grade 1&amp;2 - - - - Grade 3&amp;4 2.785 (1.958-3.963) &lt;0.001 2.278 (1.571-3.303) &lt;0.001 Stage Stage 1 - - - - Stage 2 1.104 (0.49-2.487) 0.81 1.028 (0.451-2.342) 0.948 Stage 3 3.255 (1.666-6.359) &lt;0.001 2.873 (1.447-5.706) 0.003 Stage 4 14.851 (7.499-29.41) &lt;0.001 12.778 (6.283-25.987) &lt;0.001 Unknown 3.738 (1.506-9.275) 0.004 3.008 (1.189-7.608) 0.02 Sex Male - - - - Female 0.812 (0.587-1.123) 0.22 0.852 (0.609-1.194) 0.352 Microsatellite status Stable - - Unstable 0.481 (0.148-1.562) 0.204 Not done/Unknown 1.08 (0.737-1.582) 0.739 Time to Treatment Less than 1 month - - - - More than 1 month 1.221 (0.863-1.727) 0.26 1.123 (0.784-1.609) 0.527 Location of Tumors Right - - - - Left 1.239 (0.76-2.02) 0.391 1.466 (0.886-2.425) 0.137 Rectal 1.391 (0.86-2.249) 0.178 1.211 (0.738-1.986) 0.449 NHOPI: Native Hawaiians and Other Pacific Islanders; HR: Hazard Ratio; CI: Confidence Interval.
Pattern and predictors of D3 lymph node station positivity in patients undergoing curative surgery for adenocarcinoma of colon.
Authors: Anjaly Mohan, Madhu Muralee, Chandramohan Krishnana Nair, Mira Wagh
Journal: Journal of Clinical Oncology (2025)

137 Background: The prognosis and surgical management of colon cancer is intricately related to its lymphatic drainage. The oncological outcome of apical node positivity has been evaluated in different studies with varying results. There is no published regional data on the rate of apical node positivity in colon cancer. An insight into the probability of apical node metastases and the risk factors for the same may help us in prognosticating colon cancer patients better. Methods: This was a prospective observational study conducted at the Regional Cancer Centre Thiruvananthapuram from September 2022 to June 2024. Our primary objective was to determine the prevalence of apical lymph node positivity in patients undergoing surgery for colon cancer with D3 lymphadenectomy. The secondary objectives were to find out the factors associated with the risk of apical node metastasis, the incidence of skip metastases to apical nodes, the adequacy of lymph node harvest and the postoperative complications. Patients undergoing primary surgery for adenocarcinoma of the colon were included. Patients with metastatic disease, synchronous colon or rectal cancers, past history of colonic surgery were excluded. All patients underwent D3 lymphadenectomy along with colectomy depending upon the tumour location. Lymphatic tissue corresponding to the D3 station was retrieved and sent separately after grossing the fresh specimen on the side table in the operating room. Results: A total of 139 patients were included in the study. Fifty two (37.4%) patients had stage III disease, 38.9% had stage II disease and the rest had stage I colon cancer. The mean nodal harvest was 17.86 and mean apical node harvest was 2.04. Node harvest was adequate in 89.21% patients. The apical node positivity rate was 7.19% (10 patients). Skip metastasis to the apical nodes was found in 2 patients. Lymphovascular invasion, number of positive lymph nodes and young age (≤45 years) had a significant correlation with apical node positivity on multivariate analysis. Clavien Dindo grade 3 and above complications were seen in 5.03%. Conclusions: Our study showed an apical node positivity rate of 7.19%, with a skip metastasis rate of 1.4%. This is the first Indian data on apical node positivity rate in colon cancer and its predictors. The prognostic value of apical nodes and the occurrence of skip metastasis to the apical nodes are compelling reasons to advocate D3 dissection, even with relatively low prevalence of apical node positivity.
Randomized study to assess colonic microbiome changes in response to energy drink consumption (ROSANNA Trial).
Authors: Tim Jang, Doga Kahramangil, Ji-Hyun Lee, George P. Kim, Krista P. Terracina, Johan Nordenstam, Thomas Read, Ryan M. Thomas, Ye Yang, Sarah M Tatum, Christian Jobin, Thomas J. George
Journal: Journal of Clinical Oncology (2025)

TPS325 Background: Colorectal cancer (CRC), the second leading cause of cancer deaths in the US, is increasingly diagnosed in individuals under 50. This rise in early-onset CRC (eoCRC) led the U.S. Preventative Services Task Force to recommend a reduction in the age to begin colorectal cancer screening in average-risk persons, from 50 to 45. The etiology of eoCRC is multifaceted, with one postulated theory pointing to alterations in the young adult colonic microbiome. Hydrogen sulfide (H 2 S) producing bacteria, like Bilophila wadsworthia , Fusobacterium nucleatum and Atopobium parvulum , are typically minor gut microbiota components but are overrepresented in CRC cases, linked to inflammation, and may promote a pro-carcinogenic environment. These bacteria preferentially use taurine, an essential amino acid, as a primary energy source. Energy drinks represent one of the largest dietary sources (6-16x normal daily intake) of taurine in contemporary diets. Our hypothesis is that high taurine levels in energy drinks could exacerbate CRC risk by promoting preferential growth and metabolic activities of already present H 2 S-producing bacteria, contributing to the rise of eoCRC. Methods: This randomized open-label trial is actively enrolling up to 60 young adults (18-40 years) without personal or family history of CRC, other major GI disease/distress, and baseline infrequent energy drink consumption. Group 1 (Arm A; n=30), will consist of subjects consuming at least one of two protocol-specified energy drinks daily for 4 weeks. Group 2 (Arm B; n=30), will consist of usual dietary intake. Enrollments are randomized 1:1 and stratified, by gender, age (18-25 vs. 26-40), and baseline energy drink consumption (rare/none vs. 1-2 per week). Every subject will complete: 1) a daily dietary and fitness log, 2) a weekly wellness log, 3) collection of stool/saliva/skin/urine at 3 sequential time points (baseline, after 2 weeks, after 4 weeks), and 4) blood collection at the same time points. The primary endpoint is the change in H 2 S-metabolizing bacterial communities between baseline and 1 month of energy drink exposure within Arm A and also compared to those in Arm B using microbiome analysis (diversity, taxonomy, sulfur-enriched gene pathways). Several secondary and exploratory assessments include changes related to subject demographic and dietary differences, concordance of microbiome changes with dietary logs and in other biospecimens beyond stool, H 2 S-production measurements, and analyses of subject metabolic and immune function. Trial opened in February 2024 with active enrollment ongoing. Updated data on trial status and any amendment modifications will be presented at the meeting. Clinical trial information: NCT06137248 .
Cetuximab and vemurafenib plus liposomal irinotecan (II), leucovorin and fluorouracil for BRAF <sup>V600E</sup> -mutated advanced colorectal cancer (IMPROVEMENT2): A multicenter, open-label, randomized controlled trial.
Authors: Zhan Wang, Chen-Yang Ye, Xiao-Dong Jiao, Ke Liu, Bao-Dong Qin, Wen-Xin Zhai, Biao-Long Yang, Li Sun, Wei-Ping Dai, Yan Ling, Ying Wu, Shi-Qi Chen, Ying-Fu Zhang, Dong-Min Shi, Xiao-Peng Duan, Xue Zhong, Xi He, Cheng-Hao Jia, Yuan-Sheng Zang
Journal: Journal of Clinical Oncology (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 .
Adagrasib (Ada) + cetuximab (Cetux) for <i>KRAS</i> <sup>G12C</sup> -mutated metastatic colorectal cancer (mCRC): Longer follow-up analysis from KRYSTAL-1.
Authors: Rona Yaeger, Nataliya V. Uboha, Samuel J. Klempner, Tanios S. Bekaii-Saab, Joshua K. Sabari, Minal A. Barve, Joel N. Saltzman, Julio Antonio Peguero, Andrew Scott Paulson, Pasi A. Jänne, Meredith Pelster, Marcia Cruz-Correa, Amy Min Kyung Kim, Nan Hu, Harris A. Ahmad, Scott Kopetz
Journal: Journal of Clinical Oncology (2025)

131 Background: KRAS G12C mutations occur in 3%–4% of CRC cases and are associated with poor prognosis. In the phase 1/2 KRYSTAL-1 study (NCT03785249), at a median follow-up of 11.9 months (mo), Ada (irreversible inhibitor of KRAS G12C ) in combination with Cetux (anti-EGFR antibody) demonstrated promising clinical activity (objective response rate [ORR] of 34% per blinded independent central review [BICR] and 43% per investigator [INV]) and was well tolerated in patients (pts) with previously treated KRAS G12C -mutated mCRC. Based on these findings, Ada + Cetux was granted accelerated approval in the United States for these pts. Here, we present longer-term follow-up analyses from this study. Methods: Adults with previously treated KRAS G12C -mutated mCRC and ECOG performance status of 0 or 1 were treated with Ada (600 mg BID) in combination with Cetux (400 mg/m 2 followed by 250 mg/m 2 QW or 500 mg/m 2 Q2W) until disease progression, unacceptable toxicity, withdrawal of consent, or death, in separate phase 1 and phase 2 cohorts. Primary endpoints were safety (phase 1) and ORR per BICR (phase 2). Secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety (phase 2). Results: A total of 94 pts received Ada + Cetux. The median number of prior lines of systemic therapy was 3 (range, 1–9); 23 pts (24%) had received ≥ 4 prior lines of systemic therapy. The most frequent sites of metastases at baseline were the lung (71%) and liver (64%). At a median follow-up of 20.4 mo, ORR per INV was 43% (95% CI 32–53) and all were partial responses; median DOR was 5.9 (95% CI 5.5–7.6) mo. Disease control rate per INV was 86% (95% CI 78–92). Median PFS per INV was 6.9 (95% CI 5.9–7.4) mo; 6- and 12-mo PFS rates were 61% and 19%, respectively. Median OS was 16.0 (95% CI 13.3–18.8) mo; 6- and 12-mo OS rates were 88% and 66%, respectively. Any-grade treatment-related adverse events (TRAEs) were reported in 100% of pts, 28% of which were grade 3/4. TRAEs led to discontinuation in 10% of pts. Efficacy analyses by BICR, subgroup analyses, and additional safety results will be presented. Conclusions: In heavily pretreated pts with KRAS G12C -mutated mCRC, Ada + Cetux continued to demonstrate clinically meaningful activity and tolerable safety with longer follow-up. These updated results are consistent with those from the primary analysis and constitute the longest duration of follow-up for dual KRAS G12C /EGFR blockade in this setting. Efficacy of second-line Ada + Cetux vs chemotherapy in KRAS G12C -mutated mCRC is being investigated in the phase 3 KRYSTAL-10 study (NCT04793958). Clinical trial information: NCT03785249 .
The role of sequential PET/CT imaging to predict complete response after definitive chemoradiotherapy for locally advanced squamous cell carcinoma of the anal canal.
Authors: Marianna Valzano, Michele Aquilano, Mauro Loi, Ilaria Morelli, Giulio Frosini, Pierluigi Bonomo, Alessandra Galardi, Giulio Francolini, Vanessa Di Cataldo, Monica Mangoni, Icro Meattini, Lorenzo Livi
Journal: Journal of Clinical Oncology (2025)

12 Background: The standard treatment for locally advanced squamous cell carcinoma of the anal canal (SCCAC) is definitive radiotherapy (RT) with concurrent chemotherapy (CRT), with excellent outcomes. Nevertheless, rates of locoregional failure of 10% to 30% have been reported. Due to the narrow therapeutic window between time-dependent response to RT and prompt salvage surgery, the definition of a surveillance strategy after radical CRT is challenging. In particular the contribution of 18-FDG PET/CT is not clearly established. The purpose of this study was to evaluate the effectiveness of follow-up MR and 18-FDG PET/CT to predict response to CRT in patients with SCCAC. Methods: We analyzed a cohort of consecutive patients who received definitive RT/CRT from January 2019 to February 2024. After completion of therapy, radiologic (rCR) and metabolic complete response (mCR) was assessed with pelvic MR (RECIST v.1.0) and 18-FDG PET/CT at 3 ad 6 months respectively. Local Control (LC) was defined as time from the end of CRT to local failure or last follow-up. Univariate analysis (UVA) was performed to identify variables associated with outcome using the log rank test. Sensitivity and Specificity analysis was performed to assess the correlation between rCR/mCR and LC. Results: A total of 67 patients (median age 67 years, range 44-83) were included. All patients completed RT, and 52 received concurrent CRT. Baseline and surveillance MR and 18-FDG PET/CT were available for 49 patients. After a median follow-up of 28 months, 12 patients experienced disease progression (PD) (10 local; 2 distant), resulting to salvage surgery in 10 cases after biopsy. At 3 years, LC rate was 78%. At UVA, only mCR was correlated with LC (3-year LC 90% versus 59%, p=0,0137; HR 0,01660, IC 95% 0,03-0,84). For prediction of LC, accuracy of mCR at 6 months was 83.7% versus 62.5% for rCR. Specificity/Sensitivity analysis is summarized in the table. Conclusions: 18FDG PET/CT at 6 months may identify patients with a higher likelihood of developing complete tumor regression following CRT. Further data is needed to confirm the appropriate surveillance strategy for patient undergoing CRT in clinical practice. Specificity and sensitivity analysis. Sensitivity Specificity Positive Predictive Value Negative Predictive Value mCR 83.3% 84.0% 92.6% 68.7% rCR 25.0% 70.0% 14.0% 82%