编者按：2024年美国临床肿瘤学会胃肠道肿瘤研讨会（2024 ASCO Gastrointestinal Cancers Symposium，ASCO GI 2024）于美国当地时间2024年1月18～20日在旧金山召开。昨日ASCO GI官网披露了除LBA之外的所有研究，肝胆胰口头报告专场研究由已经整理发表的2篇中国讲者研究，和两篇尚未公布的LBA，后续将整理LBA研究，故不再整理口头报告专场肝胆胰研究。现整理已经公开的快速口头报告专场的肝胆胰研究，以飨读者。

NABNEC: A randomised phase II study of nab-paclitaxel in combination with carboplatin as first line treatment of gastrointestinal neuroendocrine carcinomas (GI-NECs)

NABNEC: 白蛋白紫杉醇联合卡铂作为胃肠道神经内分泌癌（GI-NECs）一线治疗的随机II期研究

背景

方法

结果

结论

卡铂联合白蛋白紫杉醇是治疗G3 GI-NENs的有效方案。需要在III期研究中进行进一步评估。

临床试验信息

Alternating application of gemcitabine/nab-paclitaxel (Gem/nab-Pac) and Gem monotherapy or continuous application of Gem/nab-Pac after induction treatment for first-line treatment of metastatic pancreatic cancer (mPC): First results from the randomized phase 2 ALPACA study from the German AIO study group (AIO-PAK-0114)

交替应用吉西他滨/白蛋白紫杉醇（Gem/nab-Pac）和Gem单药治疗或在诱导治疗后继续应用Gem/nab-Pac用于转移性胰腺癌（mPC）的一线治疗：来自德国AIO研究组（AIO-PAK-0114）的随机2期ALPACA研究的初步结果

摘要号：605

背景

方法

结果

结论

ALPACA试验表明，在标准Gem/nab-Pac诱导3个周期后，Gem/nab-Pac和Gem单药交替治疗的减剂量方案是可行的，其OS与标准治疗相当，同时耐受性提高。

Hepatic arterial infusion pump chemotherapy in patients with advanced intrahepatic cholangiocarcinoma confined to the liver: A multicenter phase II trial

肝动脉灌注泵化疗治疗局限于肝脏的晚期肝内胆管癌：一项多中心II期试验

摘要号：433

背景

方法

结果

结论

HAIP联合全身化疗治疗晚期iCCA患者的3年OS为28.6%，而在ABC试验中单独全身化疗患者的3年OS为2.8%。

临床试验信息NL8234

Efficacy and safety results of FGFR1-3 inhibitor, tinengotinib, as monotherapy in patients with advanced, metastatic cholangiocarcinoma: Results from phase II clinical trial

FGFR1-3抑制剂tinengotinib单药治疗晚期转移性胆管癌的疗效和安全性：来自II期临床试验的结果

摘要号：434

背景

方法

结果

结论

Tinengotinib对于既往FGFRi经治的FGFR2融合CCA和非融合FGFR改变后CCA具有良好的临床益处。Tinengotinib相关的毒性是可控的。一项正在进行的随机对照III期研究将评估Tinengotinib对比医生选择的方案治疗既往化疗和FGFRi治疗后的FGFR2改变的难治性/复发性CCA患者的临床疗效、安全性和药效学效应。

临床试验信息NCT04919642

Atezolizumab plus chemotherapy with or without bevacizumab in advanced biliary tract cancer: Results from a randomized proof-of-concept phase II trial (IMbrave151).

阿替利珠单抗联合化疗加或不加贝伐珠单抗治疗晚期胆道癌：一项随机概念验证II期试验的结果（IMbrave151）

摘要号：435

背景

方法

结果

结论

IMbrave151研究的最终分析表明，在意向治疗患者中，atezo联合bev和化疗有适度的PFS获益。该试验受限于样本数量少和非比较性设计。相关生物标志物的探索性分析表明，高VEGF-A基因表达和肝细胞高基因标记可能是atezo/bev获益的预测标志物，值得进一步研究。

摘要原文

（一）

NABNEC: A randomised phase II study of nab-paclitaxel in combination with carboplatin as first line treatment of gastrointestinal neuroendocrine carcinomas (GI-NECs)

Presenter:Lorraine A. Chantrill, PhD, MBBS, BS, FRACP | Wollongong Hospital, NSW

Abstract:589

Background:Neuroendocrine carcinomas (NEC) are rare and aggressive cancers. There are no randomised trials to date to establish standard therapy for advanced G3 gastrointestinal (GI) NENs. Extrapolating from small cell lung cancer data, standard practice is to treat G3 GI-NENs with etoposide and carboplatin. Paclitaxel is also active in NECs however there is no data on the role of nab-paclitaxel. NABNEC (ANZCTR # 12616000958482) aimed to determine the activity, safety and tolerability of carboplatin and nab-paclitaxel in advanced G3 GI-NENs and to enhance our understanding of the biology and imaging characteristics of such NENs.

Methods:NABNEC was designed as a randomised non-comparative phase II study, evaluating the activity of nab-paclitaxel in patients with advanced and/or metastatic non-resectable G3 GI-NENs. The statistical plan was that 46 evaluable patients in the experimental arm would give 80% power and 95% confidence to rule out a 30% RR in favour of a more interesting RR of 50% at 6 months. Protocol version 3.0 was amended and randomisation to the control arm was suspended after 12 patients. Primary endpoint was objective response rate (RR) by RECIST 1.1. Secondary endpoints were progression free survival, overall survival, adverse events by NCI-CTCAE V4.03 and quality of life (EORTC QLQC30, QLQ-GINET21 questionnaires). Translational research endpoints include blood and tissue biomarkers including circulating tumour cells profiling, mutation profile (whole exome sequencing) and DNA methylation profile correlated with clinical endpoints. Correlation of 18-fluoro-deoxyglucose positron emission tomography (FDG-PET) to early response has also been evaluated.

Results:60 patients were accrued between Sep 2016 and Dec 2021 from 16 centres, resulting in 58 evaluable patients, 12 (control arm), 46 (experimental arm). 43 patients (75%) had tumours with Ki-67>55%; the remainder had Ki-67 between 20 and 55%. About 20% had pancreatic primaries; more than half had liver metastases. The NABNEC trial met its primary endpoint. RR was 53% (38-69%) in the experimental treatment arm compared to 42% (16-71%) in the control group. Progression free survival was not different between the 2 treatments. 24m overall survival was 25% in the experimental group compared to 17% in the control. Grade 3 toxicity was worse in the nab-paclitaxel arms (52% v 42%). Quality of life and tertiary outcomes are being analysed.

Conclusions:The combination of carboplatin and nab-paclitaxel is an active regimen for G3 GI-NENs. Further evaluation in a Phase III study is warranted. Clinical trial information: ACTRN12616000958482.

（二）

Alternating application of gemcitabine/nab-paclitaxel (Gem/nab-Pac) and Gem monotherapy or continuous application of Gem/nab-Pac after induction treatment for first-line treatment of metastatic pancreatic cancer (mPC): First results from the randomized phase 2 ALPACA study from the German AIO study group (AIO-PAK-0114)

Presenter:Frank Kullmann, MD | Department of Medicine I, Klinikum Weiden

Abstract:605

Background:The aim of the ALPACA study was to investigate whether improved overall tolerability accompanied by prolonged treatment duration and increased efficacy can be achieved by alternating treatment cycles of Gem/nab-Pac and Gem monotherapy compared to standard continuous Gem/nab-Pac after a 3-month induction phase in patients with mPC.

Methods:The randomized, multicenter phase 2 ALPACA trial of the German AIO study group enrolled patients with confirmed mPC in the first-line setting. After an induction phase with 3 cycles of standard dose Gem/nab-Pac (Gem 1000 mg/m2 and nab-Pac 125 mg/m2 on d1, 8, 15 of each 28-day cycle), patients were randomized (1:1) either to continue treatment with standard Gem/nab-Pac, or to receive alternating cycles of standard dose Gem/nab-Pac combination therapy and Gem monotherapy (Gem 1000 mg/m2 on d1, 8, 15 of each 28-day cycle). Primary study endpoint was overall survival (OS) after randomization. The trial was registered with ClinicalTrials.gov, NCT02564146.

Results:Between May 2016 and May 2021, 325 patients were enrolled from 29 German centers. 6 of the enrolled patients did not start treatment within the study. Following 3 cycles of induction treatment, 174 patients (53.5%) could be randomized. Main reasons for premature dropout were death (24.8%), progression of disease (22.8%), and adverse events (15.9%). Median OS after randomization in the alternating treatment arm was comparable to the standard treatment arm (10.5 vs. 10.4 months; HR 0.903, 80% CI 0.723-1.128, p=0.5551). Likewise, median progression-free survival was comparable in both arms (5.5 vs. 5.3 months; HR 0.767, 95% CI 0.556-1.056, p=0.1017). Tolerability was improved for mPC patients treated with alternating cycles compared to standard therapy, especially regarding peripheral neuropathy (all grades, 44.7% vs. 52.5%), and occurrence of infections (all grades, 29.4% vs. 47.5%). Treatment duration after randomization was similar in both arms (3.25 vs. 3.02 months). Fewer patients receiving alternating treatment cycles dropped out of the study due to adverse events compared to patients treated with continuous Gem/nab-Pac (14.9% vs 27.5%). In return, these patients terminated the study slightly more often due to progression of disease (48.3% vs 42.5%).

Conclusions:The ALPACA trial suggests that a dose-reduced regimen with alternating cycles of Gem/nab-Pac and Gem monotherapy after 3 induction cycles of standard Gem/nab-Pac is feasible and associated with an OS comparable to standard treatment while resulting in improved tolerability. Clinical trial information: NCT02564146.

（三）

Hepatic arterial infusion pump chemotherapy in patients with advanced intrahepatic cholangiocarcinoma confined to the liver: A multicenter phase II trial

Presenter:Bas Groot Koerkamp, MD, PhD | Department of Surgery, Erasmus MC Cancer Institute

Abstract:433

Background:In the ABC-trials, the 3-year overall survival (OS) was only 2.8% for patients with advanced intrahepatic cholangiocarcinoma (iCCA) confined to the liver who received systemic gemcitabine with cisplatin. Hepatic arterial infusion pump (HAIP) combined with systemic chemotherapy had a pooled 3-year OS of 39.5% in a recent meta-analysis. HAIP chemotherapy involves continuous administration of floxuridine (FUDR) directly into the hepatic artery using a subcutaneous pump. The aim of this study was to prospectively assess the effectiveness of HAIP with systemic chemotherapy in patients with advanced iCCA confined to the liver in the Netherlands.

Methods:We performed a single arm phase II trial in 3 centers in the Netherlands. Six cycles of HAIP chemotherapy with floxuridine were scheduled with 8 cycles of concurrent systemic chemotherapy with gemcitabine and cisplatin, if not administered previously. The primary endpoint was OS, secondary endpoints were progression-free survival (PFS) and objective response.

Results:From January 2020 until September 2022, 50 patients with advanced iCCA were included. Combined HAIP and systemic chemotherapy was administered to 38 patients (76.0%). Eleven patients (22.0%) received HAIP chemotherapy alone, because they had received systemic treatment before enrollment. One patient (2.0%) didn’t start treatment, because he died 19 days after pump implantation due to COVID-19. The median follow-up was 26.4 months (95% CI: 21.7 – 39.0). The median OS was 22.1 months (95% CI: 19.7 – not reached). The 1-year OS rate was 80.0% (95% CI: 69.6% – 91.9%); the 3-year OS rate was 28.6% (95% CI: 16.0% – 51.2%). The median PFS was 10.0 months (95% CI: 8.7 – 12.2). An objective response on imaging (RECIST) was achieved in 27 patients (54.0%) and disease control at 6 months in 43 patients (86.0%). Four patients (8.0%) underwent a resection after HAIP chemotherapy of whom 2 patients had a complete pathologic response.

Conclusions:Combined HAIP with systemic chemotherapy for patients with advanced iCCA was associated with a favorable 3-year OS of 28.6% compared with 2.8% after systemic chemotherapy alone in the ABC trials. Clinical trial information: NL8234.

（四）

Efficacy and safety results of FGFR1-3 inhibitor, tinengotinib, as monotherapy in patients with advanced, metastatic cholangiocarcinoma: Results from phase II clinical trial

Presenter:Milind M. Javle, MD | Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center

Abstract:434

Background:Tinengotinib is a spectrum-selective multi-kinase inhibitor with unique binding properties to FGFR, potently inhibited FGFR2 fusion/rearrangement and acquired resistant mutations in pre-clinical models and in phase I trials that included cholangiocarcinoma (CCA) patients (pts). Here we present the efficacy and safety of tinengotinib in a phase II clinical trial.

Methods:Eligible pts with advanced/metastatic CCA who had received ≥ 1 prior systemic chemotherapy therapy and ECOG PS 0 or 1 were treated with tinengotinib 10 mg QD. Four cohorts included: Cohort A1:FGFR2 fusion(s) with primary progression on previous FGFR inhibitor (FGFRi), A2:FGFR2 fusion(s) with progression after prior response to FGFRi (acquired resistance); B: non-fusion FGFR alteration(s): C:FGFR wild-type (FGFRwt). Primary endpoint was objective response rate (ORR) per RECIST v1.1. CTCAE V5.0 was used for safety assessments.

Results:As of 7Aug2023, 48 pts with CCA were enrolled, 13 in Cohort A1, 10 in A2, 12 in B, 13 in C. Median age 61.5 [range 25-81] years old, 41.7% male, 58.3% had ≥ 3 lines of prior therapy. ECOG PS 0 in 47.9% pts. Among 35 pts with FGFR alterations, 80.0% had ≥ 1 prior FGFRi therapy, and 97.1% had prior chemotherapy. Forty (40) pts were efficacy evaluable. In A1, 1 out of 11 pts (9.1%) achieved PR with tumor reduction of 31.8%. In A2, 3 out of 8 pts (37.5%) achieved PR with tumor reduction of 40.7%, 47.0% and 54.6%. In B, 3 out of 9 pts (33.3%) achieved PR with tumor reduction of 36.5%, 48.6%, and 60.6%. No PR was observed in C. Overall DCR was 94.7% (18/19) in FGFR2 fusion/rearrangement pts (A1+A2), 88.9% (8/9) in other FGFR alterations pts (B), and 75% (9/12) in FGFRwt pts (C). Median progression-free survival (mPFS) was 5.26 months (95%CI, 2.86-9.10) in A1+A2, 5.98 months (95%CI, 1.87-NA) in B and 3.84 months (95% CI, 1.84-4.80) in C. Among 48 treated pts, treatment-related AEs (TRAEs) occurred in 45 (93.8%) pts, 14 (29.2%) in G1-2, 29 (60.4%) in G3 and 2 (4.2%) in G4. The most common G3 TRAEs were hypertension in 12 (25%), palmar-plantar erythrodysesthesia syndrome in 3 (6.3%), diarrhea in 3 (6.3%) and stomatitis in 3 (6.3%). One subject had G4 increased TSH and G4 increased lipase, and another subject had G4 posterior reversible encephalopathy syndrome. No G5 TRAE was observed.

Conclusions:Tinengotinib has promising clinical benefit for FGFR2 fusion CCA after prior FGFRi and for non-fusion FGFR alterations. Tinengotinib-related toxicities were manageable. An ongoing randomized, controlled phase III study will evaluate the clinical efficacy, safety, and pharmacodynamic effect of Tinengotinib vs Physicians’ choice in subjects with FGFR2-altered refractory/relapsed CCA after prior chemotherapy and FGFRi therapy. Clinical trial information: NCT04919642.

（五）

Atezolizumab plus chemotherapy with or without bevacizumab in advanced biliary tract cancer: Results from a randomized proof-of-concept phase II trial (IMbrave151).

Presenter:Anthony B. El-Khoueiry, MD | USC Norris Comprehensive Cancer Center

Abstract:435

Background:VEGF blockade coupled with cytotoxic chemotherapy can promote an immune-permissive tumor microenvironment that augments response to PD-L1 inhibition. IMbrave151 (NCT04677504) is a randomized, double-blinded, global proof-of-concept Phase II study evaluating atezolizumab (atezo), bevacizumab (bev) and cisplatin and gemcitabine (CisGem) as first-line treatment for advanced biliary tract cancer (aBTC). Here we report updated clinical data and molecular correlates of response and resistance.

Methods:Patients (pts) with previously untreated aBTC were randomized 1:1 to receive atezo (1200 mg every 3 weeks [q3w]) + bev (15 mg/kg q3w) or placebo (plb) + CisGem (Cis 25 mg/m2 and Gem 1000 mg/m2 on Days 1 and 8 q3w) for up to 8 cycles, followed by atezo (1200 mg q3w) + bev (15 mg/kg q3w) or plb until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DOR), and safety. The final OS analysis was done when ≈90 deaths occurred or when all pts had ≥2 years of follow-up. Transcriptome analysis (n=98) and mutation profiling (n=103) were done on baseline tumor samples. This was a signal-seeking trial to estimate the treatment effect in each arm with no formal hypothesis testing.

Results:In total, 162 pts were randomized to either atezo + bev + CisGem (atezo/bev; n=79) or atezo + plb + CisGem (atezo/plb; n=83). The updated PFS HR was 0.67 (95% CI: 0.46, 0.95) in favor of atezo/bev. Updated median PFS was 8.35 mo for atezo/bev and 7.9 mo for atezo/plb, with 6-mo rates of 78% and 63%, respectively. The updated OS HR was 0.97 (95% CI: 0.64, 1.47), with a median of 14.9 mo for atezo/bev and 14.6 mo for atezo/plb. Confirmed ORR was 26.6% for atezo/bev and 26.5% for atezo/plb, with median DORs of 10.28 (95% CI: 6.7, 16.7) and 6.18 mo (95% CI: 4.3, 6.7), respectively. The incidence of Grade 3/4 adverse events was 73% with atezo/bev and 74% with atezo/plb. High VEGFA gene expression was associated with an improved PFS (HR, 0.43; 95% CI: 0.22, 0.83) and OS (HR, 0.66; 95% CI: 0.31, 1.4) in favor of atezo/bev. Hepatocytes high gene signature also was associated with an improved PFS (HR, 0.47; 95% CI: 0.24, 0.92) and OS (HR, 0.66; 95% CI: 0.31, 1.4) in favor of atezo/bev. Pts with PI3k/AKT pathway mutations appeared to have worse OS than pts without mutations (HR, 3.7; 95% CI: 1.5, 9.1) with atezo/bev.

Conclusions:Final analysis of the IMbrave151 study indicates a modest PFS benefit in intent-to-treat pts combining atezo with bev and chemotherapy. The trial is limited by small numbers and a non-comparative design. Exploratory analysis of correlative biomarkers suggests that high VEGF-A gene expression and hepatocytes high gene signature may be predictive markers of benefit with atezo/bev, warranting further investigation. Clinical trial information: NCT04677504.