编者按：北京时间2024年1月17日美国临床肿瘤学会胃肠道肿瘤研讨会（ASCO GI ）官网披露了除LBA摘要外其他全部摘要内容，我们也对结直肠癌领域口头报告专场研究内容进行介绍，今天精彩继续！本文将对快速口头报告专场结直肠癌研究进行介绍，与大家共享前沿学术资讯！

循环肿瘤DNA（ctDNA）为II/III期结直肠癌辅助化疗（ACT）提供信息：BESPOKE CRC研究中期分析

背景

方法

结果

结论

基于ctDNA的MRD检测在BESPOKE CRC队列的早期代表性子集中具有很高的复发预后价值。扩大队列的数据将在会议上提出。ctDNA MRD结果也具有预测性：在MRD+中观察到ACT的显著益处，而在MRD-患者中则没有。此外，辅助治疗的早期ctDNA清除率和监测期间的ctDNA状态是患者结局的预后因素。我们的研究结果强调了ctDNA引导的辅助治疗在II/III期结直肠癌患者中的潜在效用。作为首批基于ctDNA的前瞻性研究之一，BESPOKE CRC的结果将通过正在进行的ctDNA导向的随机临床试验进一步验证。

临床试验信息

NCT04264702

在CodeBreaK 300中，接受索托拉西布和帕尼单抗治疗的转移性结直肠癌（mCRC）患者与三氟尿苷/替吡嘧啶（T/T）或瑞戈非尼治疗的健康相关生活质量（HRQoL）

摘要号：10

背景

方法

结果

结论

在CodeBreaK 300中，与对照组相比，两种剂量的索托拉西布均可改善HRQoL，并有降低恶化风险的趋势。除了改善临床结果外，这些发现还进一步证明了索托拉西布+帕尼单抗对化疗难治的mCRC患者的益处。

疲劳和疼痛值为阴性，而GHS/QoL和PF值为阳性表明soto+pmab与对照组相比有所改善。

腹膜灌洗细胞学在II期和III期结直肠癌根治性切除患者中的应用：一项多机构前瞻性研究

摘要号：11

背景

方法

结果

结论

与细胞学阳性患者相比，细胞学阴性的II期结直肠癌患者具有更好的RFS和OS。腹膜灌洗细胞学可用于预测II-III期结直肠癌根治性切除后腹膜复发。

循环肿瘤DNA分析提示局部晚期直肠癌的辅助化疗：随机AGITG动态直肠研究

摘要号：12

背景

方法

结果

结论

ctDNA引导下的LARC新辅助放化疗和手术后辅助治疗方法与CT给药率降低相关。小样本量排除了关于ctDNA引导与标准管理的非劣效性的任何结论。与未治疗的历史对照相比，接受治疗的ctDNA阳性患者的复发率较低。我们的数据证实，术后ctDNA检测不到的患者复发风险较低，其中肺部的比例显著。

结合临床生物标志物改善RAS野生型（RAS WT）转移性结直肠癌（mCRC）的一线治疗决策：随机III期试验FIRE-3（AIO KRK0306）的研究结果

摘要号：13

背景

方法

结果

结论

结合临床生物标志物PTS和LLD状态可能会改善RAS-WT mCRC患者一线靶向治疗的最佳选择，但是未来还有需要进一步进行数据集验证。

摘要原文

Abstrate 9

Circulating tumor DNA (ctDNA) for informing adjuvant chemotherapy (ACT) in stage II/III colorectal cancer (CRC): Interim analysis of BESPOKE CRC study.

Background:ctDNA-based post-surgical detection of molecular residual disease (MRD) is known to be predictive of a high risk of recurrence. Here, we report the first results of BESPOKE CRC, a multicenter, prospective, observational study evaluating the ability of a tumor-informed ctDNA assay to inform ACT treatment decisions in stage II/III CRC patients (pts).

Methods:Of the 1792 pts enrolled between 2020-07-02 and 2022-08-25, plasma samples from the first 350 pts with stage II-III CRC were analyzed. ctDNA was detected and quantified using a personalized, tumor-informed assay (Signatera, Natera, Inc.). Following curative resection, 232 pts received ACT and 118 underwent observation.

Results:The cohort included 154 stage II and 196 stage III CRC pts; the median follow-up was 24.8 months. ctDNA results at the post-op MRD time point (tp) were available for 295 pts; 15.6% (46/295; stage II: 9/130=6.9%; stage III: 37/165=22.4%) of pts were ctDNA positive (ctDNA+) at MRD tp (MRD+). MRD-positivity was significantly associated with inferior disease-free survival (DFS) in stages II-III combined (HR=20.8, 95% CI: 10.0-43.4, p<0.0001) and in stage-stratified subgroups (stage II: HR=25.7, 95% CI 6.8-96.7; stage III: HR=18.1, 95% CI 7.3-45.1). Within the MRD+ group, pts receiving ACT had longer DFS compared to those in the observation group (median DFS: 18.7 vs 6.7 months; HR=3.9, 95% CI: 1.3-11.5, p=0.01). In contrast, no benefit of ACT was observed in MRD- pts (HR=1.1, 95% CI: 0.3-3.9, p=0.89). Of the MRD+ pts, 39.1% (18/46) had ctDNA clearance at 12-weeks post-surgery tp. Pts with ctDNA clearance had longer DFS compared to those who remained positive (median DFS: 24.2 vs 13.8 months; HR=0.4, 95% CI 0.1-1.0, p=0.045), however, had worse DFS than pts who were ctDNA- at both 4- and 12-weeks (HR=22.5, 95% CI: 6.8-75.0, p<0.0001). Notably, 44.4% (8/18) pts with ctDNA clearance recurred; all 8 turned back ctDNA+ before radiological detection of relapse. ctDNA results during surveillance were available for 339 pts, of whom 8.3% (58/339) were ctDNA+ and had significantly worse DFS compared to serially ctDNA- pts (HR=124.3, 95% CI: 29.8-518.7, p<0.0001).

Conclusions:ctDNA-based MRD detection of MRD was highly prognostic of recurrence in an early representative subset of BESPOKE CRC cohort. Data from the expanded cohort will be presented at the meeting. ctDNA MRD results were also predictive: significant benefit from ACT was observed in MRD+ but not in MRD- pts. Additionally, early ctDNA clearance in response to adjuvant therapy and ctDNA status during surveillance were prognostic of pt outcomes. Our results highlight the potential utility of ctDNA-guided adjuvant therapy in pts with stage II/III CRC. The results of BESPOKE CRC herein, as one of the first ctDNA-based prospective studies, will be further validated by ongoing ctDNA-directed randomized clinical trials. Clinical trial information: NCT04264702.

Abstrate 10

Health-related quality of life (HRQoL) in patients with metastatic colorectal cancer (mCRC) treated with sotorasib and panitumumab (pmab) versus trifluridine/tipiracil (T/T) or regorafenib (rego) in CodeBreaK 300.

Background:CodeBreaK 300 (NCT05198934) is a phase 3, multicenter, randomized, open-label study, evaluating sotorasib 960 mg (soto960) + pmab, sotorasib 240 mg (soto240) + pmab against investigator’s choice T/T or rego in patients with chemorefractory KRAS G12C-mutated mCRC. The study met its primary endpoint and demonstrated statistically significant improvement in progression-free survival with both doses of sotorasib. This analysis evaluated patient-reported outcomes (PROs) as secondary and exploratory endpoints in CodeBreaK 300.

Methods:Change in PRO scores from study baseline through week 8 was compared for soto960+pmab and soto240+pmab vs the control group using a mixed effect model for repeated measures. PRO instruments included the Brief Fatigue Inventory, the Brief Pain Inventory, and the European Organisation for Research and Treatment of Cancer Core 30-item Quality of Life questionnaire. Time to deterioration (TTD) were assessed using Kaplan-Meier plots and Cox proportional hazard models. All analyses were conducted on patients with baseline and at least one post-baseline PRO score.

Results:160 pts were randomized 1:1:1 to soto960+pmab (n=53), soto240+pmab (n=53), or T/T or rego (n=54). Compliance rates for PRO assessments were high (>83%) and similar across the three treatment groups. Least square (LS) mean changes from baseline in fatigue at its worst, pain at its worst, physical functioning (PF), and global health status (GHS)/QoL favored the two sotorasib dose groups (Table). The 95% confidence intervals (CI) suggested improvement in pain at its worst and PF for both sotorasib dose groups, and improvement in GHS/QoL for the soto960+pmab group versus the control group. TTD hazard ratios < 1 indicated a trend in delayed deterioration for patients treated in both sotorasib dose groups. The 95% CIsuggested delays with respect to fatigue at its worst and PF for the soto240+pmab group.

Conclusions:In CodeBreaK 300, both doses of sotorasib resulted in better HRQoL and a trend to decreased risk of deterioration vs the control group. In addition to improved clinical outcomes, these findings provide further evidence on the benefit of soto+pmab in patients with chemorefractory mCRC. Clinical trial information: NCT05198934.

*Negative values for fatigue and pain whereas positive values for GHS/QoL and PF indicate improvement for soto+pmab vs control.

Abstrate 11

Peritoneal lavage cytology in patients with curative resection for stage II and III colorectal cancer: A multi-institutional prospective study.

Background:Although various prognostic factors in patients with colorectal cancer has been reported, the usefulness of intraoperative lavage cytology in patients with colorectal cancer is controversial. The aim of this study was to clarify the usefulness of intraoperative lavage cytology in patients with curative resection for pSage II-III colorectal cancer in a prospective multicenter study.

Methods:The 20 member hospitals of the Japanese Society for the Cancer of the Colon and Rectum prospectively registered the patients diagnosed as stage II or III colorectal cancer preoperatively between 2013 and 2017. Among these patients, pStage II-III patients went through analysis. Lavage cytology was performed twice during surgery. The first procedure was performed right after laparotomy, and the second was performed right after specimen retrieval. The primary endpoint of this study was an effect of lavage cytology on 5-year relapse-free survival (RFS) in patients with pStage II-III colorectal cancer. The secondary endpoint was an effect of lavage cytology on 5-year overall survival (OS) and peritoneal recurrence in patients with pStage II-III colorectal cancer.

Results:A total of 1378 patients were eligible and went through analysis. The number of patients with pStage II and III colorectal cancer were 670 and 708, respectively. Among 1378 patients, 54 (3.9%) had positive cytology. The median follow-up period of the entire cohort was 5.3 years. In pStage II patients, the 5-year RFS rate with positive and negative cytology was 61.1% and 81.6%, respectively (P = 0.023). The 5-year OS rate of pStage II patients with positive and negative cytology was 67.1% and 91.7%, respectively (P = 0.0083). However, there was no difference in RFS and OS between patients with positive and negative cytology in pStage III patients. Thirty-three patients had peritoneal recurrence. The peritoneal recurrence rate was 11.8% and 1.5% in pStage II patients with positive and negative lavage cytology, respectively (P = 0.032). That was 10.5% and 2.5% in pStage III patients with positive and negative lavage cytology, respectively (P = 0.022). In total, 11.1% of patients with positive lavage cytology had peritoneal recurrence in this cohort.

Conclusions:The pStage II colorectal cancer patients with negative cytology had better RFS and OS compared to those with positive cytology. Peritoneal lavage cytology was useful in predicting peritoneal recurrence after curative resection for pStage II-III colorectal cancer. Clinical trial information: UMIN000026070.

Abstrate 12

Circulating tumor DNA analysis informing adjuvant chemotherapy in locally advanced rectal cancer: The randomized AGITG DYNAMIC-Rectal study.

Background:Adjuvant chemotherapy (CT) following neoadjuvant chemoradiation and surgery for locally advanced rectal cancer (LARC) is widely adopted, despite uncertain survival benefit. Circulating tumor DNA (ctDNA) detection after surgery has been shown to be a strong prognostic marker in localized colorectal cancer and potentially could inform adjuvant treatment decision making.

Methods:AGITG DYNAMIC-Rectal is a multi-centre randomized controlled phase II trial. Eligible patients (pts) had LARC (cT3-4 and/or cN+) treated with neoadjuvant chemoradiation, total mesorectal excision, and were fit for adjuvant CT. Pts were randomly assigned 2:1 to ctDNA-guided management or standard management (clinician decision). A tumor-informed personalized ctDNA assay was used. For the ctDNA-guided group, a positive result at 4 and/or 7 weeks after surgery prompted 4 months of oxaliplatin-based or fluoropyrimidine CT; for ctDNA-negative patients, no chemotherapy if ypN0 or clinician’s choice if ypN+. The primary endpoint was adjuvant CT use. A key secondary endpoint was non-inferiority in RFS rate at 3 years. The target sample size of 408 would provide 80% power with 95% confidence to demonstrate non-inferiority between the two arms with a margin of at most 10%.

Results:The study ceased recruitment prematurely due to COVID-19 and increasing adoption of total neoadjuvant therapy. 230 eligible pts were enrolled from Jul 2018 to Nov 2021, median follow-up was 37 months. In the 155 ctDNA-guided patients, ctDNA analysis was successful in 150 (97%) pts and 42 (28%) were ctDNA-positive. Fewer pts in the ctDNA-guided arm received adjuvant CT (71/155, 46%) compared to 58/75 (77%) pts receiving standard management (p < 0.001). Overall, an oxaliplatin-based doublet was administered in 43 (28%) and 19 (25%) of ctDNA-guided compared to standard management pts (P = 0.82). 3-year recurrence-free survival for ctDNA-guided and standard management was 76% and 82% respectively (difference 6%, 95% CI: -6% to 17%). Cumulative probability of distant and locoregional recurrence at 3 years for ctDNA-positive pts treated with CT were 36% and 11% respectively; for ctDNA-negative pts without adjuvant CT were 12% and 1%. Of the 15 ctDNA-negative pts who recurred, 12 (80%) were lung only, 1 (7%) peritoneal and lung, and 2 (13%) nodal only relapse.

Conclusions:A ctDNA-guided approach to adjuvant therapy for LARC post neoadjuvant chemoradiation and surgery was associated with a reduced rate of CT administration. The small sample size precludes any conclusions to be drawn about the non-inferiority of ctDNA-guided vs standard management. The recurrence rate in treated ctDNA positive pts appears low when compared to untreated historical controls. Our data confirms a lower risk of recurrence in pts with undetectable post-op ctDNA, with a notable proportion of these being in the lung. Clinical trial information: ACTRN12617001560381.

Abstrate 13

Refining first-line treatment decision in RAS wildtype (RAS WT) metastatic colorectal cancer (mCRC) by combining clinical biomarkers: Results of the randomized phase 3 trial FIRE-3 (AIO KRK0306).

Background:Optimal patient selection for first-line treatment targeting epithelial growth factor receptor (EGFR) in RAS-WT mCRC is based on primary tumor sidedness (PTS) with anti-EGFR being the preferred option for patients with left-sided mCRC (LC). Right-sided mCRCs (RC) are preferentially treated in combination with bevacizumab targeting vascular endothelial growth factor (VEGF). Here, improvement in patient selection was evaluated by combining clinical biomarkers beyond PTS using the randomized phase III trial FIRE-3.

Methods:FIRE-3 evaluated first-line FOLFIRI (folinic acid, fluorouracil and irinotecan) plus cetuximab (FOLFIRI/Cet) versus FOLFIRI plus bevacizumab (FOLFIRI/Bev) in patients with RAS-WT mCRC. Besides PTS, further clinical biomarkers were evaluated in pairwise combinations using Cox regression models and model-based recursive partitioning with Weibull models to predict treatment benefit of either treatment arm regarding overall survival (OS): age, sex, liver-limited disease status (LLD) and baseline carcinoembryonic antigen serum level (CEA). The resulting P-values of second-order interactions were adjusted using Holm-Bonferroni correction. The model with the best test statistics and P-value was chosen for further evaluations.

Results:In 400 patients with RAS-WT mCRC, a model combining PTS and LLD status best predicted treatment outcome of either treatment arm (c-index = 0.603, p=0.005). Here, a significant survival benefit of FOLFIRI/Cet over FOLFIRI/Bev was evident in patients with LC/non-LLD (HR 0.62, p=0.02) compared to LC/LLD (HR 0.83, p=0.40). In patients with RC, FOLFIRI/Bev was significantly associated with increased OS compared to FOLFIRI/Cet when patients suffered from non-LLD (HR 2.09, p=0.010). However, patients with RC/LLD rather had a benefit from FOLFIRI/Cet compared to FOLFIRI/Bev (HR 0.59, p=0.218).

Conclusions:Combining clinical biomarkers PTS and LLD status might improve optimal patient selection for targeted first-line treatment in RAS-WT mCRC. Validation in further data sets is warranted. Clinical trial information: NCT00433927.