Pub Date : 2026-01-06DOI: 10.1016/s2468-1253(25)00379-6
Holly Baker
<h2>Section snippets</h2><section><section><h2>Perioperative immunotherapy for hepatocellular carcinoma</h2>Perioperative camrelizumab plus rivoceranib shows benefit in patients with hepatocellular carcinoma at intermediate or high risk of relapse, according to the <span><span>CARES-009 phase 2/3 trial</span><svg aria-label="Opens in new window" focusable="false" height="20" viewbox="0 0 8 8"><path d="M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z"></path></svg></span>. Zheng Wang and colleagues randomly assigned patients to receive either perioperative therapy comprising two cycles of neoadjuvant camrelizumab plus rivoceranib, followed by surgery and adjuvant camrelizumab plus rivoceranib (n=148), or surgery alone (n=146). At a prespecified interim analysis, with a median</section></section><section><section><h2>Pemvidutide for MASH</h2>Pemvidutide, a GLP-1–glucagon dual receptor agonist, shows promise in treating metabolic dysfunction-associated steatohepatitis (MASH), according to the 24-week results from the ongoing <span><span>IMPACT phase 2b trial</span><svg aria-label="Opens in new window" focusable="false" height="20" viewbox="0 0 8 8"><path d="M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z"></path></svg></span>. Mazen Noureddin and colleagues randomly assigned patients to receive once-weekly subcutaneous pemvidutide 1·2 mg (n=41) or 1·8 mg (n=85), administered without dose titration, or placebo (n=86). The primary endpoint of MASH resolution without fibrosis worsening was achieved by a greater</section></section><section><section><h2>Tobevibart plus elebsiran for hepatitis D</h2>Tobevibart plus elebsiran shows promise in patients with chronic hepatitis D virus (HDV) infection, according to the 48-week results of the <span><span>SOLSTICE phase 2 trial</span><svg aria-label="Opens in new window" focusable="false" height="20" viewbox="0 0 8 8"><path d="M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z"></path></svg></span>. Tarik Asselah and colleagues randomly assigned patients to receive tobevibart plus elebsiran every 4 weeks (n=32) or tobevibart monotherapy every 2 weeks (n=33).At week 24, a combined response—defined as an HDV RNA level below the limit of detection or a decrease in the HDV RNA level of at least 2 log<sub>10</sub> IU per mL from baseline</section></section><section><section><h2>Combination therapy for metastatic colorectal cancer</h2>Zanzalintinib plus atezolizumab improves overall survival in patients with relapsed or refractory metastatic colorectal cancer, according to results from the <span><span>STELLAR-303 phase 3 trial</span><svg aria-label="Opens in new window" focusable="false" height="20" viewbox="0 0 8 8"><path d="M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z"></path></svg></span>. J Randolph Hecht and colleagues randomly assigned patients to rece
{"title":"Research in Brief","authors":"Holly Baker","doi":"10.1016/s2468-1253(25)00379-6","DOIUrl":"https://doi.org/10.1016/s2468-1253(25)00379-6","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Perioperative immunotherapy for hepatocellular carcinoma</h2>Perioperative camrelizumab plus rivoceranib shows benefit in patients with hepatocellular carcinoma at intermediate or high risk of relapse, according to the <span><span>CARES-009 phase 2/3 trial</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"20\" viewbox=\"0 0 8 8\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg></span>. Zheng Wang and colleagues randomly assigned patients to receive either perioperative therapy comprising two cycles of neoadjuvant camrelizumab plus rivoceranib, followed by surgery and adjuvant camrelizumab plus rivoceranib (n=148), or surgery alone (n=146). At a prespecified interim analysis, with a median</section></section><section><section><h2>Pemvidutide for MASH</h2>Pemvidutide, a GLP-1–glucagon dual receptor agonist, shows promise in treating metabolic dysfunction-associated steatohepatitis (MASH), according to the 24-week results from the ongoing <span><span>IMPACT phase 2b trial</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"20\" viewbox=\"0 0 8 8\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg></span>. Mazen Noureddin and colleagues randomly assigned patients to receive once-weekly subcutaneous pemvidutide 1·2 mg (n=41) or 1·8 mg (n=85), administered without dose titration, or placebo (n=86). The primary endpoint of MASH resolution without fibrosis worsening was achieved by a greater</section></section><section><section><h2>Tobevibart plus elebsiran for hepatitis D</h2>Tobevibart plus elebsiran shows promise in patients with chronic hepatitis D virus (HDV) infection, according to the 48-week results of the <span><span>SOLSTICE phase 2 trial</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"20\" viewbox=\"0 0 8 8\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg></span>. Tarik Asselah and colleagues randomly assigned patients to receive tobevibart plus elebsiran every 4 weeks (n=32) or tobevibart monotherapy every 2 weeks (n=33).At week 24, a combined response—defined as an HDV RNA level below the limit of detection or a decrease in the HDV RNA level of at least 2 log<sub>10</sub> IU per mL from baseline</section></section><section><section><h2>Combination therapy for metastatic colorectal cancer</h2>Zanzalintinib plus atezolizumab improves overall survival in patients with relapsed or refractory metastatic colorectal cancer, according to results from the <span><span>STELLAR-303 phase 3 trial</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"20\" viewbox=\"0 0 8 8\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg></span>. J Randolph Hecht and colleagues randomly assigned patients to rece","PeriodicalId":56028,"journal":{"name":"Lancet Gastroenterology & Hepatology","volume":"29 1","pages":""},"PeriodicalIF":35.7,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145947506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-06DOI: 10.1016/s2468-1253(25)00291-2
Eva Visser,Maud A Reijntjes,Lianne Heuthorst,Merle E Stellingwerf,Rachel West,Koen van Dongen,Rogier M P H Crolla,Susan van Dieren,Jarmila D W van der Bilt,Willem A Bemelman,Geert R D'Haens,Christianne J Buskens,
BACKGROUNDAlthough retrospective and limited prospective observational studies have suggested a potential benefit of appendicectomy in therapy-refractory ulcerative colitis, its effectiveness compared with advanced medical therapy in active, biologic-exposed patients has not been evaluated prospectively. We evaluated the efficacy of laparoscopic appendicectomy in inducing remission, compared with JAK inhibitor therapy, in patients with active ulcerative colitis who had persistent disease activity despite previous advanced therapy exposure (a small molecule or a biologic).METHODSIn this multicentre, patient-preference, interventional cohort study, conducted in five hospitals in the Netherlands, patients with a total Mayo score (TMS) of 5-12 and an endoscopic subscore of 2 or higher despite treatment with an advanced therapy were offered one of three treatments: laparoscopic appendicectomy while continuing their existing advanced therapy at a stable dose; switching their advanced therapy to a JAK inhibitor; or colectomy. This analysis focuses on patients who chose appendicectomy or to switch their advanced therapy; patients who chose colectomy were included in a non-comparative registry cohort, and outcomes in this group were recorded but not included in the comparative analyses. The primary outcome was the proportion of patients in clinical remission (TMS ≤2, no subscore >1) at 12 months without therapy failure (defined as start or restart of oral corticosteroids; switch to other advanced therapies; initiation of experimental treatment in a clinical trial; or colectomy), assessed in the modified intention-to-treat population (all patients who underwent appendicectomy or received at least one dose of the JAK inhibitor, excluding patients who had a change in disease diagnosis from ulcerative colitis to Crohn's disease). The primary endpoint was analysed by χ2 test, with an additional analysis using logistic regression adjusting for baseline confounding variables. Safety outcomes were assessed in all patients who underwent appendicectomy or received at least one dose of the JAK inhibitor. This study was registered with ClinicalTrials.gov, NCT03912714.FINDINGSBetween Aug 24, 2018, and Dec 15, 2023, 211 patients were screened for eligibility, of whom 125 (59%) patients were enrolled in the study; 116 patients were included in the modified intention-to-treat-analysis (67 received appendicectomy and 49 received JAK inhibitor). 22 (32·8%) of 67 patients in the appendicectomy group were in clinical remission without therapy failure at 12 months compared with six (12·2%) of 49 patients in the JAK inhibitor group (unadjusted difference of 20·6 percentage points [95% CI 6·1-35·1]; p=0·010; adjusted difference of 22·9 percentage points [95% CI 6·1-39·8]; p=0·016). At 12 months, corticosteroid-free clinical remission without therapy failure was attained in 22 (32·8%) of 67 patients in the appendicectomy group compared with six (12·2%) of 49 patients in the JAK
虽然回顾性和有限的前瞻性观察性研究表明阑尾切除术对治疗难治性溃疡性结肠炎有潜在的益处，但与先进的药物治疗相比，其在活性、生物暴露患者中的有效性尚未得到前瞻性评价。我们评估了腹腔镜阑尾切除术在诱导缓解方面的疗效，与JAK抑制剂治疗相比，这些患者尽管先前接受过先进的治疗（小分子或生物药物），但仍有持续的疾病活动。方法：在荷兰的5家医院进行的这项多中心、患者偏好、介入性队列研究中，梅奥总评分（TMS）为5-12，内镜亚评分为2或更高的患者，尽管接受了先进的治疗，但仍接受三种治疗中的一种：腹腔镜阑尾切除术，同时继续现有的稳定剂量的先进治疗；将他们的先进疗法转换为JAK抑制剂；或结肠切除术。本分析的重点是选择阑尾切除术或转换高级治疗的患者；选择结肠切除术的患者被纳入非比较登记队列，该组的结果被记录，但不包括在比较分析中。主要结局是12个月内临床缓解（TMS≤2，无亚评分>1）的患者比例，无治疗失败(定义为口服皮质类固醇开始或重新开始；切换到其他先进疗法；在临床试验中开始实验性治疗；或结肠切除术)，在修改意向治疗人群（所有接受阑尾切除术或至少接受一剂JAK抑制剂的患者，不包括疾病诊断从溃疡性结肠炎转变为克罗恩病的患者）中进行评估。主要终点采用χ2检验进行分析，并对基线混杂变量进行logistic回归校正。对所有接受阑尾切除术或至少接受一剂JAK抑制剂的患者的安全性结果进行了评估。本研究已在ClinicalTrials.gov注册，编号NCT03912714。在2018年8月24日至2023年12月15日期间，211例患者进行了资格筛选，其中125例（59%）患者入组研究；116例患者纳入改良意向治疗分析（67例接受阑尾切除术，49例接受JAK抑制剂治疗）。阑尾切除术组67例患者中22例（32.8%）12个月临床缓解，无治疗失败，而JAK抑制剂组49例患者中6例（12.2%）（未调整差异为20.6个百分点[95% CI 6.1 ~ 35.1]; p= 0.010；调整差异为22.9个百分点[95% CI 6.1 ~ 39.8]; p= 0.016）。12个月时，阑尾切除术组67例患者中有22例（32.8%）达到无糖皮质激素临床缓解，而JAK抑制剂组49例患者中有6例（12.2%）达到无治疗失败（差异为20.6个百分点[95% CI 6.1 - 35.1]; p= 0.010）， 67例患者中有49例（73.1%）达到临床缓解，49例患者中有26例（53.1%）达到临床缓解(20.1个百分点[2.5 - 37.6]；P = 0.025)， 64例患者中31例（48.4%）有内镜反应，43例患者中11例（25.6%；22.9个百分点[5.0 - 40.7];P = 0.018）有内镜反应。到症状缓解的时间（风险比1.06 [95% CI 0.62 ~ 1.82]; p= 0.82）、治疗失败（67例患者中39例[58.2%]vs 49例患者中28例[57.1%]；差异1.1个百分点[95% CI - 17.1 ~ 19.3]; p= 0.91）和结肠切除术率（67例患者中6例[9.0%]vs 49例患者中4例[8.2%]；差异0.8个百分点[95% CI - 9.5 ~ 11.1]; p= 1.0）在阑尾切除术和JAK抑制剂组之间相似。阑尾切除术组69例患者中有39例（56.5%）报告不良事件，JAK抑制剂组50例患者中有30例（60%）报告不良事件（差异为3.5个百分点[95% CI - 21.4 ~ 14.4]; p= 0.70]）。69例患者中有3例（4.3%）发生阑尾切除术相关并发症，均为Clavien-Dindo II级或以下。与改用JAK抑制剂相比，阑尾切除术作为生物暴露的活动性溃疡性结肠炎患者高级治疗的辅助治疗与12个月时更高的临床缓解率相关，表明潜在的有效性，并且该手术可以安全地在该患者组中进行。
{"title":"Appendicectomy versus switching to a JAK inhibitor in inducing remission in patients with active ulcerative colitis after biologic therapy failure (COSTA): 1-year results of a multicentre, prospective, cohort study.","authors":"Eva Visser,Maud A Reijntjes,Lianne Heuthorst,Merle E Stellingwerf,Rachel West,Koen van Dongen,Rogier M P H Crolla,Susan van Dieren,Jarmila D W van der Bilt,Willem A Bemelman,Geert R D'Haens,Christianne J Buskens, ","doi":"10.1016/s2468-1253(25)00291-2","DOIUrl":"https://doi.org/10.1016/s2468-1253(25)00291-2","url":null,"abstract":"BACKGROUNDAlthough retrospective and limited prospective observational studies have suggested a potential benefit of appendicectomy in therapy-refractory ulcerative colitis, its effectiveness compared with advanced medical therapy in active, biologic-exposed patients has not been evaluated prospectively. We evaluated the efficacy of laparoscopic appendicectomy in inducing remission, compared with JAK inhibitor therapy, in patients with active ulcerative colitis who had persistent disease activity despite previous advanced therapy exposure (a small molecule or a biologic).METHODSIn this multicentre, patient-preference, interventional cohort study, conducted in five hospitals in the Netherlands, patients with a total Mayo score (TMS) of 5-12 and an endoscopic subscore of 2 or higher despite treatment with an advanced therapy were offered one of three treatments: laparoscopic appendicectomy while continuing their existing advanced therapy at a stable dose; switching their advanced therapy to a JAK inhibitor; or colectomy. This analysis focuses on patients who chose appendicectomy or to switch their advanced therapy; patients who chose colectomy were included in a non-comparative registry cohort, and outcomes in this group were recorded but not included in the comparative analyses. The primary outcome was the proportion of patients in clinical remission (TMS ≤2, no subscore >1) at 12 months without therapy failure (defined as start or restart of oral corticosteroids; switch to other advanced therapies; initiation of experimental treatment in a clinical trial; or colectomy), assessed in the modified intention-to-treat population (all patients who underwent appendicectomy or received at least one dose of the JAK inhibitor, excluding patients who had a change in disease diagnosis from ulcerative colitis to Crohn's disease). The primary endpoint was analysed by χ2 test, with an additional analysis using logistic regression adjusting for baseline confounding variables. Safety outcomes were assessed in all patients who underwent appendicectomy or received at least one dose of the JAK inhibitor. This study was registered with ClinicalTrials.gov, NCT03912714.FINDINGSBetween Aug 24, 2018, and Dec 15, 2023, 211 patients were screened for eligibility, of whom 125 (59%) patients were enrolled in the study; 116 patients were included in the modified intention-to-treat-analysis (67 received appendicectomy and 49 received JAK inhibitor). 22 (32·8%) of 67 patients in the appendicectomy group were in clinical remission without therapy failure at 12 months compared with six (12·2%) of 49 patients in the JAK inhibitor group (unadjusted difference of 20·6 percentage points [95% CI 6·1-35·1]; p=0·010; adjusted difference of 22·9 percentage points [95% CI 6·1-39·8]; p=0·016). At 12 months, corticosteroid-free clinical remission without therapy failure was attained in 22 (32·8%) of 67 patients in the appendicectomy group compared with six (12·2%) of 49 patients in the JAK ","PeriodicalId":56028,"journal":{"name":"Lancet Gastroenterology & Hepatology","volume":"20 1","pages":""},"PeriodicalIF":35.7,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/s2468-1253(25)00350-4
Eirini Dimidi,Kevin Whelan
{"title":"Dietary management of constipation: time for clinical guidelines to catch up with evidence.","authors":"Eirini Dimidi,Kevin Whelan","doi":"10.1016/s2468-1253(25)00350-4","DOIUrl":"https://doi.org/10.1016/s2468-1253(25)00350-4","url":null,"abstract":"","PeriodicalId":56028,"journal":{"name":"Lancet Gastroenterology & Hepatology","volume":"1 1","pages":"11"},"PeriodicalIF":35.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145689003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-13DOI: 10.1016/s2468-1253(25)00300-0
Jeffrey V Lazarus, Leire Agirre-Garrido, Trenton M White, Anish K Arora, Melina I Manolas, Luis Antonio Diaz, Juan Pablo Arab, Shira Zelber-Sagi, Naim Alkhouri, C Wendy Spearman, Jörn M Schattenberg, Loreta A Kondili, Patrizia Carrieri, Holly F Lofton, Priya Jaisinghani, Sonal Kumar, Ajay Duseja, Mohamed El-Kassas, Hirokazu Takahasi, Debbie L Shawcross, Jonathan G Stine, Marcela Villota-Rivas, Juan Emilio Miralles-Sanchez, Silvana Pannain, Paul N Brennan
{"title":"Best buys for metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis: a global Delphi study","authors":"Jeffrey V Lazarus, Leire Agirre-Garrido, Trenton M White, Anish K Arora, Melina I Manolas, Luis Antonio Diaz, Juan Pablo Arab, Shira Zelber-Sagi, Naim Alkhouri, C Wendy Spearman, Jörn M Schattenberg, Loreta A Kondili, Patrizia Carrieri, Holly F Lofton, Priya Jaisinghani, Sonal Kumar, Ajay Duseja, Mohamed El-Kassas, Hirokazu Takahasi, Debbie L Shawcross, Jonathan G Stine, Marcela Villota-Rivas, Juan Emilio Miralles-Sanchez, Silvana Pannain, Paul N Brennan","doi":"10.1016/s2468-1253(25)00300-0","DOIUrl":"https://doi.org/10.1016/s2468-1253(25)00300-0","url":null,"abstract":"","PeriodicalId":56028,"journal":{"name":"Lancet Gastroenterology & Hepatology","volume":"143 1","pages":""},"PeriodicalIF":35.7,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145731063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<h3>Background</h3><em>KRAS</em><sup>G12C</sup> mutations are present in around 4% of patients with colorectal cancer and are associated with lower treatment response rates and overall survival. EGFR signalling has been identified as a primary mechanism of resistance to KRAS<sup>G12C</sup> inhibitors. We aimed to evaluate the efficacy and safety of a novel, covalent, small molecule KRAS<sup>G12C</sup> inhibitor, glecirasib (JAB-21822), as monotherapy or in combination with the anti-EGFR cetuximab, in patients with <em>KRAS</em><sup>G12C</sup>-mutated colorectal cancer.<h3>Methods</h3>JAB-21822-1002 was an open-label, non-randomised, dose escalation (phase 1) and expansion (phase 2a) trial evaluating glecirasib monotherapy in <em>KRAS</em><sup>G12C</sup>-mutated solid tumours. JAB-21822-1007 was an open-label, non-randomised, dose escalation (phase 1b) and expansion (phase 2) study evaluating glecirasib plus cetuximab in <em>KRAS</em><sup>G12C</sup>-mutated colorectal, small intestine, and appendiceal cancer. Adult participants (aged ≥18 years) were recruited in China from 17 hospitals for the monotherapy trial and 16 hospitals for the combination trial. Here, we report only on patients with colorectal cancer treated with oral glecirasib at the recommended phase 2 dose (800 mg once daily in 21-day treatment cycles [until disease progression, intolerable toxicity, investigator's discretion, or withdrawal of consent]), pooling phase 1 and 2 data together. In the combination trial, cetuximab was administered intravenously with an initial loading dose of 400 mg/m<sup>2</sup> in the first week, followed by 250 mg/m<sup>2</sup> every week or 500 mg/m<sup>2</sup> every 2 weeks. For this analysis, key eligibility criteria were histologically or cytologically confirmed locally advanced or metastatic colorectal cancer with <em>KRAS</em><sup>G12C</sup> mutation; Eastern Cooperative Oncology Group performance status of 0 or 1; and at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST). For phase 1 of both trials, patients must not have responded to, were not suitable for, or refused standard of care. For phase 2 of both trials, patients must have received at least first-line standard of care and had disease progression or intolerance. Primary endpoints for the monotherapy trial were safety (treatment-emergent adverse events, serious adverse events, treatment-related adverse events, dose-limiting toxicity, and clinically significant changes in vital signs, physical examination, and electrocardiography, and clinically significant unexpected laboratory values of grade ≥3) for phase 1 and objective response rate (complete and partial response) for phase 2a. Primary endpoints for the combination trial were dose-limiting toxicities, maximum tolerated dose, and recommended phase 2 dose for phase 1b and objective response rate for phase 2. The full analysis set was defined as patients with at least one measurable lesion at baseline w
{"title":"Glecirasib with or without cetuximab in previously treated locally advanced or metastatic colorectal cancer with KRASG12C mutation (JAB-21822-1002 and JAB-21822-1007): two open-label, non-randomised phase 1/2 trials","authors":"Jian Li, Zhenghang Wang, Jing Huang, Yi Ba, Baoshan Cao, Suxia Luo, Wenhua Li, Chunmei Bai, Zhengbo Song, Jianping Xiong, Liangjun Zhu, Guangyu An, Yanqiao Zhang, Zhihua Li, Yongsheng Li, Yanhong Gu, Changlu Hu, Xingya Li, Chenghui Huang, Qihan Fu, Lin Shen","doi":"10.1016/s2468-1253(25)00267-5","DOIUrl":"https://doi.org/10.1016/s2468-1253(25)00267-5","url":null,"abstract":"<h3>Background</h3><em>KRAS</em><sup>G12C</sup> mutations are present in around 4% of patients with colorectal cancer and are associated with lower treatment response rates and overall survival. EGFR signalling has been identified as a primary mechanism of resistance to KRAS<sup>G12C</sup> inhibitors. We aimed to evaluate the efficacy and safety of a novel, covalent, small molecule KRAS<sup>G12C</sup> inhibitor, glecirasib (JAB-21822), as monotherapy or in combination with the anti-EGFR cetuximab, in patients with <em>KRAS</em><sup>G12C</sup>-mutated colorectal cancer.<h3>Methods</h3>JAB-21822-1002 was an open-label, non-randomised, dose escalation (phase 1) and expansion (phase 2a) trial evaluating glecirasib monotherapy in <em>KRAS</em><sup>G12C</sup>-mutated solid tumours. JAB-21822-1007 was an open-label, non-randomised, dose escalation (phase 1b) and expansion (phase 2) study evaluating glecirasib plus cetuximab in <em>KRAS</em><sup>G12C</sup>-mutated colorectal, small intestine, and appendiceal cancer. Adult participants (aged ≥18 years) were recruited in China from 17 hospitals for the monotherapy trial and 16 hospitals for the combination trial. Here, we report only on patients with colorectal cancer treated with oral glecirasib at the recommended phase 2 dose (800 mg once daily in 21-day treatment cycles [until disease progression, intolerable toxicity, investigator's discretion, or withdrawal of consent]), pooling phase 1 and 2 data together. In the combination trial, cetuximab was administered intravenously with an initial loading dose of 400 mg/m<sup>2</sup> in the first week, followed by 250 mg/m<sup>2</sup> every week or 500 mg/m<sup>2</sup> every 2 weeks. For this analysis, key eligibility criteria were histologically or cytologically confirmed locally advanced or metastatic colorectal cancer with <em>KRAS</em><sup>G12C</sup> mutation; Eastern Cooperative Oncology Group performance status of 0 or 1; and at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST). For phase 1 of both trials, patients must not have responded to, were not suitable for, or refused standard of care. For phase 2 of both trials, patients must have received at least first-line standard of care and had disease progression or intolerance. Primary endpoints for the monotherapy trial were safety (treatment-emergent adverse events, serious adverse events, treatment-related adverse events, dose-limiting toxicity, and clinically significant changes in vital signs, physical examination, and electrocardiography, and clinically significant unexpected laboratory values of grade ≥3) for phase 1 and objective response rate (complete and partial response) for phase 2a. Primary endpoints for the combination trial were dose-limiting toxicities, maximum tolerated dose, and recommended phase 2 dose for phase 1b and objective response rate for phase 2. The full analysis set was defined as patients with at least one measurable lesion at baseline w","PeriodicalId":56028,"journal":{"name":"Lancet Gastroenterology & Hepatology","volume":"5 1","pages":""},"PeriodicalIF":35.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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