ESMO GI 2025微专辑扫描二维码可查看更多内容编者按2025年欧洲肿瘤内科学会胃肠道肿瘤大会（ESMO GI）于当地时间7月2日盛大启幕！作为全球肿瘤学界瞩目的学术盛会，本届大会Proffered Pape session与Mini Oral session再度汇胃肠肿瘤聚领域重磅前沿成果。其中，Mini Oral session专场特设"胃肠肿瘤创新专场"，从全球众多投稿中遴选出7项突破性研究。为及时传递学术价值，此前我们已优先完成胰腺癌与GI领域3项研究的梳理（ESMO GI 2025丨胃肠肿瘤创新专场：联合疗法突破耐药困境，精准诊疗开启新纪元），本文将剩余的胃食管癌、结直肠癌、肝癌领域的4项成果进行了整理，以飨读者。388MO - 新型Claudin 18.2/4-1BB双特异性抗体Givastomig联合纳武利尤单抗和mFOLFOX治疗转移性胃食管癌（mGEC）的初步安全性和有效性背景Givastomig/ABL111（Giva）是一种首创的Claudin 18.2（CLDN18.2）和4-1BB双特异性抗体。作为单药治疗，Giva在广泛CLDN18.2表达范围内耐受性良好且具有活性。方法一项正在进行的Ⅰb期研究（NCT04900818）评估了Giva联合纳武利尤单抗和mFOLFOX在CLDN18.2阳性（定义为≥1%肿瘤细胞中≥1+强度）胃、食管或胃食管腺癌（GEC）一线治疗中的安全性、有效性、药代动力学（PK）和药效学。主要终点是评估安全性。结果截至2025年2月28日，17例GEC患者（中位年龄57岁，71%为女性）接受了5 mg/kg（n=5）、8 mg/kg（n=6）或12 mg/kg（n=6）的Giva联合治疗。未观察到剂量限制性毒性，未达到最大耐受剂量。常见治疗相关不良事件（TRAE，≥10%患者）包括恶心（47%）、呕吐（29%）、输液相关反应（29%）、疲劳（24%）、食欲下降（18%）、腹泻（18%）、腹痛（12%）、寒战（12%）、消化不良（12%）和胃炎（12%）。归因于Giva的3级TRAE罕见，包括单例腹痛、ALT/AST升高、胃炎和输液相关反应。未报告4级或5级TRAE。观察到剂量依赖性PK，与单药治疗相似。可溶性4-1BB的诱导呈剂量/时间依赖性，并在第1周期第8天达到平台期。17例患者中有12例观察到部分缓解（PR，ORR 71%），其中5 mg/kg组2例，8 mg/kg组5例，12 mg/kg组4例+1例未确认PR。在选定剂量扩展组（8 mg/kg和12 mg/kg）中，ORR为83%。所有亚组均观察到PR（见表1）。疾病控制率为100%。8例患者仍在治疗中，最长治疗持续时间为11.3个月。表1. 扩展阶段入选队列（8 mg/kg、12 mg/kg）及全剂量递增阶段患者的ORR结论Giva联合纳武利尤单抗和mFOLFOX在12 mg/kg Q2W剂量下耐受性良好，并在1L转移性GEC中显示出令人鼓舞的初步活性。剂量扩展研究正在进行中。临床试验编号：NCT04900818。6MO - Amivantamab（EGFR-MET双特异性抗体）在左侧RAS/BRAF野生型转移性结直肠癌（mCRC）EGFR抑制剂进展后再挑战治疗的更新结果（OrigAMI-1研究）背景在EGFR抑制剂（EGFRi）停药后，耐药克隆的突变半衰期为4.4个月（Parseghian Ann Onc 2019）。本研究分析了Amivantamab（一种具有免疫细胞导向活性的EGFR-MET双特异性抗体）在左侧RAS/BRAF野生型mCRC患者EGFRi进展后的再挑战治疗。方法OrigAMI-1研究的B队列（NCT05379595）评估了Amivantamab单药治疗在左侧mCRC患者中的疗效，这些患者既往接受过2~3线治疗且对EGFRi进展。所有患者通过中央ctDNA检测为KRAS、NRAS、BRAF和EGFR胞外域野生型，且无ERBB2/HER2扩增。疗效评估依据RECIST v1.1标准。根据既往EGFRi治疗与Amivantamab治疗启动的时间间隔，将患者分为≤2个半衰期（8.8个月）的“较短间隔组”和＞2个半衰期的“较长间隔组”。结果截至2024年10月31日，54例左侧mCRC患者接受了Amivantamab治疗（中位随访13.7个月）。其中29例在8.8个月内（“较短间隔组”），25例在8.8个月后（“较长间隔组”）接受再挑战治疗。较长间隔组的ORR显著高于较短间隔组（32% vs. 7%，见表2）。较长间隔组的中位无进展生存期（PFS）为7.0个月，显著优于较短间隔组的2.8个月（P=0.008）。较长间隔组的中位总生存期（OS）呈数值优势（16.1个月 vs. 10.4个月，P=0.088）。基线ctDNA的突变分析未能预测疗效，但对既往EGFRi有反应的患者更可能对Amivantamab产生反应。表2. 各组疗效数据结论Amivantamab再挑战治疗在既往EGFRi治疗间隔≥9个月的患者中显示出更有前景的抗肿瘤活性、更长的PFS和OS。临床试验编号：NCT05379595。149MO - Irpagratinib（ABSK-011）联合阿替利珠单抗治疗FGF19过表达（+）晚期肝细胞癌（HCC）的Ⅱ期ABSK-011-201研究更新结果背景对于免疫检查点抑制剂（ICI）治疗后进展的HCC，亟需有效治疗方法。FGF19+在约30%的HCC中表达，并与预后不良相关。Irpagratinib是一种口服高选择性FGFR4抑制剂，已在HCC中显示出抗肿瘤活性。本研究报告了Ⅱ期研究（NCT05441475）在推荐扩展剂量下的更新结果。方法FGF19+ HCC患者（ECOG PS≤1，BCLC B或C期，Child-Pugh评分5~7分，无论是否接受过系统治疗）接受220 mg BID Irpagratinib联合1200 mg Q3W阿替利珠单抗治疗。每6周根据RECIST v1.1标准进行肿瘤评估。结果截至2024年11月19日，15例一线治疗患者和18例既往治疗患者入组，其中16例接受过ICI治疗。患者中位年龄54.8岁，84.8%为男性，72.7% ECOG PS 1分，84.8% HBV阳性，93.9% BCLC C期。中位随访7.1个月时，所有可评估疗效患者（n=29）的ORR为51.7%。一线治疗和既往治疗亚组的ORR分别为50.0%和52.9%；ICI初治和ICI经治亚组的ORR分别为57.1%和46.7%。中位缓解持续时间（DOR）尚未达到，多数缓解仍在持续，包括1例DOR超过13.9个月。中位PFS为7.0个月（一线治疗7.0个月，既往治疗8.3个月），9个月PFS率为40.6%。总生存期因仅报告6例死亡事件而无法评估。最常见（≥20%）治疗相关不良事件（TRAE，任何级别/3级）包括ALT升高（75.8%/12.1%）、AST升高（69.7%/3.0%）、腹泻（51.5%/3.0%）、血胆红素升高（45.5%/0）、高磷血症（36.4%/0）和血小板计数减少（27.3%/3.0%）。未报告4/5级TRAE，无患者因TRAE停药。结论Irpagratinib联合阿替利珠单抗在FGF19+ HCC的一线治疗和既往ICI治疗中均表现出良好的安全性和抗肿瘤活性。显著的缓解率及明确的PFS获益凸显了FGFR4抑制剂联合方案在ICI治疗和未治疗患者中的进一步开发潜力。临床试验编号：NCT05441475。150MO-Ⅲb期SIERRA研究：度伐利尤单抗（D）和曲美木单抗（T）作为预后不良的HCC患者一线治疗的安全性结果背景对于不可切除的HCC，预后不良的患者常被排除在临床试验之外。Ⅲb期SIERRA研究（NCT05883644）评估了STRIDE方案（单次T常规间隔D）作为一线治疗在预后较HIMALAYA研究（NCT03298451）更差的人群中的安全性和有效性，包括Child-Pugh（CP）评分B7/B8且ECOG PS 0~1分、CP A类且ECOG PS 2分，或伴有慢性主干门静脉血栓（Vp4）的患者。本研究报告安全性数据。方法患者接受D 1500 mg + T 300 mg单次给药（第1天），随后每4周接受D 1500 mg单药治疗。共同主要终点为治疗开始后6个月内可能与研究治疗相关的3/4级不良事件（PRAE）发生率和客观缓解率。本次安全性分析在约60例患者随访≥6个月时进行（数据截止日期：2024年9月27日）。结果截至数据截止日，98例患者接受了研究治疗，包括35例CP B7/B8患者、44例ECOG PS 2分患者和19例Vp4患者。患者中位年龄70岁，87%为男性。CP B7/B8患者的D治疗中位周期数为2.0，ECOG PS 2分患者为7.0，Vp4患者为3.0，总体为4.0。治疗开始后6个月内，19.4%的患者报告了3/4级PRAE。任何级别的AE和PRAE分别发生于90.8%和65.3%的患者；严重不良事件（SAE）和严重PRAE分别发生于32.7%和14.3%的患者。26.5%的患者报告了3/4级SAE。25.5%的患者报告了免疫相关不良事件。10.2%的患者因不良事件停止任何治疗。2.0%的患者报告了导致死亡的PRAE。各亚组的安全性结果详见表3。表3. 各亚组安全性结果结论尽管SIERRA研究纳入了肝功能更差、ECOG PS更差或血管侵犯更严重的患者，但STRIDE方案的安全性可控，与HIMALAYA研究一致。临床试验编号：NCT05883644。摘要原文388MO - Preliminary safety and efficacy of givastomig, a novel claudin 18.2/4-1BB bispecific antibody, in combination with nivolumab and mFOLFOX in metastatic gastroesophageal carcinoma (mGEC)BackgroundGivastomig/ABL111 (giva) is a first-in-class, bispecific antibody targeting Claudin 18.2 (CLDN18.2) and 4-1BB. Giva was well tolerated as monotherapy with activity across a wide range of CLDN18.2 expression.MethodsAn ongoing phase 1b study (NCT04900818) is evaluating the safety, efficacy, pharmacokinetics (PK), and pharmacodynamics of giva with nivolumab and mFOLFOX in 1L CLDN18.2+ gastric, esophageal, or gastroesophageal adenocarcinomas (GEC). CLDN18.2+ is defined as ≥1+ intensity in ≥1% of tumor cells. The primary endpoint is to evaluate safety.ResultsAs of February 28, 2025, 17 GEC patients (pts) (median age 57 [35-79], 71% female) received giva at 5 mg/kg (n=5), 8 mg/kg (n=6), or 12 mg/kg (n=6) in combination. No dose limiting toxicities were observed; a maximum tolerated dose was not reached. Common treatment related adverse events (TRAEs, ≥10% of pts) included nausea (47%), vomiting (29%), infusion related reaction (29%), fatigue (24%), decreased appetite (18%), diarrhea (18%), abdominal pain (12%), chills (12%), dyspepsia (12%), and gastritis (12%). Grade 3 TRAEs attributed to giva were rare, with single cases of abdominal pain, ALT/AST increase, gastritis, and infusion related reaction. No grade 4 or 5 TRAE were reported. Dose-dependent PK was observed, similar to monotherapy. Induction of soluble 4-1BB was dose/time-dependent and plateaued at Cycle 1 Day 8. Partial responses (PR) were observed in 12 of 17 pts (ORR 71%), including 2 at 5 mg/kg, 5 at 8, mg/kg, and 4 + 1 uPR at 12 mg/kg. In doses selected for expansion (8 & 12 mg/kg), ORR was 83%. PRs were observed in all subgroups (see table). Disease control rate was 100%. 8 pts are ongoing; the longest treatment duration is 11.3 months.?Table: 388MOORR % (n) in cohorts selected for expansion (8, 12 mg/kg) and in all dose escalation patientsConclusionsGiva with nivolumab and mFOLFOX was well tolerated up to 12 mg/kg Q2W and shows encouraging preliminary activity in 1L metastatic GEC. Dose expansion is ongoing.Clinical trial identificationNCT04900818.6MO - Rechallenge with amivantamab, an EGFR-MET bispecific antibody, after disease progression on prior EGFR inhibitor in left-sided RAS/BRAF wild-type metastatic colorectal cancer: Updated results from OrigAMI-1BackgroundAfter EGFR inhibitor (EGFRi) withdrawal, resistant clones decay at a mutational half-life of 4.4 months (Parseghian?Ann Onc?2019). Rechallenge with amivantamab, an EGFR-MET bispecific antibody with immune cell-directing activity, was analyzed in participants (pts) with left (L)-sided?RAS/BRAF?wild-type metastatic colorectal cancer (mCRC) after prior EGFRi.MethodsCohort B of OrigAMI-1 (NCT05379595) assessed amivantamab monotherapy in pts with L-sided mCRC and prior disease progression on EGFRi, with 2-3 prior lines. All pts were wild-type for?KRAS,?NRAS,?BRAF, and?EGFR?ectodomain by central ctDNA testing, without?ERBB2/HER2?amplification. Response was assessed by investigator per RECIST v1.1. To assess the effect of time between prior EGFRi and initiation of amivantamab monotherapy, subgroups were categorized by 2 half-lives (or 8.8 months).ResultsAs of 31-Oct-2024, 54 pts with L-sided mCRC received amivantamab (median follow-up of 13.7 months [mo]). There were 29 pts who were rechallenged with amivantamab within 8.8 mo (“shorter interval group”) and 25 pts after 8.8 mo (“longer interval group”). Objective response rate (ORR) was higher for pts in the longer compared to the shorter interval group (32% vs 7%; Table). Median progression-free survival (PFS) was 7.0 mo in the longer interval group vs 2.8 mo in the shorter interval group (nominal?P=0.008). Median overall survival (OS) had a numerical trend in favor of the longer interval (16.1 mo) vs the shorter interval group (10.4 mo; nominal?P=0.088). Mutational analyses using baseline ctDNA was not predictive of response; however, having a response to prior EGFRi was correlated with responding to amivantamab.?Table: 6MOConclusionsRechallenge with amivantamab showed promising antitumor activity and longer PFS and OS for pts who had at least an ～9-mo interval between prior EGFRi therapy compared to those with a shorter interval.Clinical trial identificationNCT05379595.149MO - Irpagratinib (ABSK-011) plus atezolizumab in first-line (1L) and immune checkpoint inhibitors (ICIs) treated advanced hepatocellular carcinoma (HCC) with FGF19 overexpression (+): Updated results of the phase II ABSK-011-201 studyBackgroundEffective treatments are urgently needed for HCC after progression on ICI-based therapies. FGF19+ is in ～ 30% HCC and associated with poor prognosis. Irpagratinib, an oral and highly selective FGFR4 inhibitor, has demonstrated promising anti-tumor activity in HCC. Here, we report the updated results of phase 2 study (NCT05441475) with more patients (pts) at recommended dose of expansion.MethodsFGF19+ HCC pts with ECOG PS≤1, BCLC stage B or C, Child-Pugh score 5 to 7, with or without prior systemic treatments, were given 220 mg BID Irpagratinib plus 1200 mg Q3W Atezolizumab. Tumor assessments were every 6 weeks based on RECIST v1.1 by investigators.ResultsAs of 19 Nov 2024, 15 1L pts and 18 pre-treated pts were enrolled, including 16 pts who had prior ICI therapies. Mean age 54.8y, 84.8% male, 72.7% ECOG PS 1, 84.8% HBV, 93.9% BCLC C. With a median follow-up of 7.1m, an overall response rate (ORR) of 51.7% (15/29) was observed in all efficacy-evaluable pts. The ORR in 1L and pre-treated subgroups was 50.0% and 52.9%, respectively; and 57.1% and 46.7% in ICI-na?ve and ICI-treated subgroups, respectively. Median duration of response (DOR) was not achieved yet as majority of the responders were still ongoing including one DOR over 13.9m. Estimated median progression-free survival (PFS) was 7.0m (1L 7.0m, pre-treated 8.3m) and the 9m PFS rate was 40.6%, whereas overall survival was not evaluable as only 6 death events were reported. The most common (≥20%) treatment-related adverse events (TRAEs, any grade/Grade 3) included ALT increased (75.8%/12.1%), AST increased (69.7%/3.0%), diarrhoea (51.5%/3.0%), blood bilirubin increased (45.5%/0), hyperphosphataemia (36.4%/0), and platelet count decreased (27.3%/3.0%). No Grade 4/5 TRAE was reported and no pts discontinued due to TRAE.ConclusionsIrpagratinib combined with Atezolizumab was safe and demonstrated promising anti-tumor activity in both 1L and ICI-treated FGF19+ HCC. The remarkable response rate along with an evident PFS benefit underscores the potential of FGFR4i-based combinations for further development in both ICI-treated and treatment-na?ve settings.Clinical trial identificationNCT05441475.150MO - Safety results from the phase IIIb SIERRA study of durvalumab (D) and tremelimumab (T) as first-line (1L) treatment (tx) for hepatocellular carcinoma (HCC) participants (pts) with a poor prognosisBackgroundFor unresectable HCC, pts with a poor prognosis are often excluded from clinical trials. The phase 3b SIERRA study (NCT05883644) assesses the safety and efficacy of STRIDE (Single T Regular Interval D) as 1L tx in a broader population with poorer prognoses than the HIMALAYA study (NCT03298451), including pts with Child-Pugh (CP) score B7 or B8 with ECOG PS 0–1, or CP class A with ECOG PS 2, or with chronic main trunk portal vein thrombosis (Vp4). Safety data are reported.MethodsPts received D 1500 mg + T 300 mg x 1 dose on Day 1 followed by D 1500 mg monotherapy every 4 weeks. Co-primary endpoints are incidence of Grade 3 or 4 adverse events (AEs) possibly related to study tx (PRAEs) within 6 months (mo) of tx initiation and objective response rate. This safety review occurred once ～60 pts were followed for ≥6 mo (data cut-off [DCO]: 27 September 2024).ResultsBy DCO, 98 pts received any study tx including 35 pts with CP B7 / B8, 44 pts with ECOG PS 2, and 19 pts with Vp4. The median age was 70 years and 87% of pts were male. The median (Q1–Q3) number of D cycles was 2.0 (1.0–5.0) for pts with CP B7 / B8, 7.0 (4.0–8.5) for pts with ECOG PS 2, 3.0 (1.0–6.0) for pts with Vp4, and 4.0 (2.0–8.0) overall. Grade 3 or 4 PRAEs occurring within 6 mo of tx initiation were reported in 19.4% (95% CI, 12.1–28.6) of pts. AEs and PRAEs of any Grade were reported in 90.8% and 65.3% of pts, respectively; serious AEs (SAEs) and serious PRAEs occurred in 32.7% and 14.3% of pts, respectively. Grade 3 or 4 SAEs were reported in 26.5% of pts. Immune-mediated AEs were reported in 25.5% of pts. AEs leading to discontinuation of any tx were reported in 10.2% of pts. PRAEs leading to death were reported in 2.0% of pts. Safety outcomes by subgroup are reported in the table.Table: 150MOConclusionsThe safety profile of STRIDE was manageable and consistent with the HIMALAYA study despite enrolling pts with worse hepatic function, poorer ECOG PS or more advanced vascular invasion than in HIMALAYA.Clinical trial identificationNCT05883644.（来源：肿瘤瞭望消化时讯）声 明凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。
