编者按：欧洲肿瘤内科学会胃肠肿瘤年会（ESMO GI）已于2024年6月26日在慕尼黑拉开帷幕。每年摘要内容都是大会的“重头戏”，按照重磅程度分为Proffered Paper、Mini Oral、Poster三种类型。今年入选Proffered Paper研究共5项，包括2项LBA和3项Oral，《肿瘤瞭望消化时讯》特将其中3项Oral研究内容进行了整理，LBA研究另做归类整理，以飨读者。

 

尽管化疗（CT）的疗效不断提高，但针对明确不可切除的结直肠癌肝转移（uCLM）患者的长期生存率仍然很低。TRANSMET研究旨在评估化疗联合肝移植（LT）对比单纯化疗用于uCLM患者的疗效。

 

 

研究入组非BRAF突变型结直肠癌、术后明确不可切除的肝转移、对化疗有反应（治疗时长≥3个月，≤3线治疗）且没有肝外疾病的患者，经独立专家委员会审查，将患者随机分配（1:1）接受化疗联合肝移植（CT+LT组）或单独化疗（CT组）。主要终点是5年总生存率（OS）。次要终点是无进展生存期（PFS）和生活质量（QoL）。该试验设计为CT组10%到CT+LT组50%之间40%的OS差异（双侧α水平5%，90%效力）。

 

 

从2016年2月至2021年7月，来自20个中心（3个国家）的157例患者经专家委员会评估后，94例（60%）患者被随机分配至化CT+LT组或CT组。在诊断时，uCLM的中位数数量和最大直径分别为20 mm和51.5 mm。随机分配后，经过中位数20个化疗周期后，在1（44%）、2（40%）或3（16%）线治疗中观察到客观缓解。两组中各有9例患者（19%）因肿瘤学原因（CT+LT组）或意外治愈性手术（CT组）而未接受分配治疗。在ITT分析中，CT+LT组的5年OS率为57%，而单独化疗组为13%（P=0.0003，HR 0.37；95%CI：0.21~0.65）。在符合方案集分析中，CT+LT组对比单独CT组，5年OS率分别为73%和9%（P<0.0001，HR 0.16；95%CI：0.07~0.33）。PFS分别为17.4个月和6.4个月（HR 0.34；95%CI：0.20~0.58）。在移植患者中，28例（74%）出现复发，可选择手术（36%）或局部消融（11%）治疗。15例（40%）患者最终实现无病生存。在生活质量方面，化疗组患者的身体功能维度和主要症状出现了下降趋势。

 

 

通过必要的选择过程，与单独化疗相比，肝移植联合化疗显著提高了部分uCLM患者的生存率。这些结果支持LT作为uCLM（单纯肝转移）患者一种新的标准选择。

 

 

 

在一线（1L）治疗中，对于经中心确认的MSI-H/dMMR mCRC，纳武利尤单抗（NIVO）联合伊匹木单抗（IPI）相较于化疗显示出了更长的无进展生存期，中位随访时间为31.5个月（HR 0.21；97.91%CI:0.13~0.35；P<0.0001）。我们首次报告了此次随访的健康相关生活质量（HRQoL）结果。

 

 

对于所有经中心确认MSI-H/dMMR状态并接受治疗的患者，使用EORTC QLQ-C30、QLQ-CR29和EQ-5D-3L评估其HRQoL。通过混合效应模型对重复测量数据进行处理，以提供从基线（BL）起变化的最小二乘（LS）均值和95%CI估计值；第21周被预先指定为主要关注的时间点。通过Kaplan-Meier乘积限方法估计确诊恶化时间（TTCD）。

 

 

在245例接受治疗的患者中，有170例接受了纳武利尤单抗（NIVO）联合伊匹木单抗（IPI）治疗，75例接受了化疗。其中，94%~96%的患者有基线HRQoL数据。从第13周开始，纳武利尤单抗联合伊匹木单抗组与化疗组之间的总体健康状况（GHS）差异超过了预先设定的最小重要差异（MID）5.0（最小二乘均值差[MD]，9.7；95%CI：3.6~15.9）。在第21周时，纳武利尤单抗联合伊匹木单抗组相较于化疗组，在具有临床意义的健康相关生活质量（GHS和功能量表）改善以及症状减少方面表现显著（如表所示），这表明纳武利尤单抗联合伊匹木单抗相较于化疗具有更好的健康相关生活质量效益。纳武利尤单抗联合伊匹木单抗相较于化疗降低了健康相关生活质量恶化的风险（GHS中的确诊恶化时间[TTCD]，HR 0.32；95%CI：0.18~0.57）。（表1）

 

表1.HRQoL结果

 

纳武利尤单抗联合伊匹木单抗一线治疗MSI-H/dMMR转移性结直肠癌，显著改善了健康相关生活质量，症状减少，健康相关生活质量恶化的风险也有所降低，与化疗相比具有优势。

 

【摘要号：30】PRODIGE 68-UCGI 38-SOREGATT：比较在标准治疗失败后使用瑞戈非尼和曲氟尿苷替匹嘧啶治疗转移性结直肠癌（mCRC）患者的不同用药顺序的随机Ⅱ期研究

 

 

mCRC经一线治疗进展后，患者就可以接受瑞戈非尼（reg）或曲氟尿苷替匹嘧啶（t/t）治疗。尽管这两种药物都已被批准用于治疗mCRC，但尚未有随机试验研究瑞戈非尼和曲氟尿苷替匹嘧啶的用药顺序。本研究旨在评估用药顺序是否会影响能够接受两药治疗的患者数量以及患者的生存期。

 

 

对于mCRC患者，年龄≥18岁，ECOG体能状况评分为0~1分，在氟尿嘧啶类化疗联合奥沙利铂和/或伊立替康加EGFR抑制剂（如果RAS为野生型）和/或VEGF抑制剂治疗失败后，按照1:1的比例随机分配至A组（先瑞戈非尼后曲氟尿苷替匹嘧啶）或B组（先曲氟尿苷替匹嘧啶后瑞戈非尼）。采用ReDOS方案。主要终点是治疗的可行性，评估为能够接受至少两个周期两药治疗的患者比例，这对应于每一线治疗的首次肿瘤评估。次要终点包括治疗持续时间、首次治疗序列的无进展生存期（PFS1）、策略失败时间（TFS）、总生存期（OS）和ECOG体能状况评分≥2分的恶化时间。

 

在30个欧洲中心，原计划纳入340例患者，实际随机分配了234例患者（A组/B组：114/119例）。由于SUNLIGHT试验（t/t+beva）结果导致的疾病管理变化，研究提前终止。在数据截止时，中位随访时间为19个月。患者主要特征为（A组/B组）：中位年龄68/67岁；男性占51/66%；PS0占34/35%；右侧、左侧、直肠：30%、46%、24%/35%、35%、30%。能够接受至少两个周期两药治疗的患者比例为40%/56%（P=0.018），中位治疗持续时间为95/111天。在第一阶段，主要终止治疗的原因是疾病进展（82/90%）和毒性（14/8%）；在第二阶段，主要原因是疾病进展（80/78%）和毒性（12/20%）。A组有39%的患者未接受后续治疗，而B组为27%，这主要是由于患者总体状况恶化或死亡。A组和B组的中位TFS分别为3.2个月和3.7个月。

 

 

SOREGATT研究结果显示，治疗的可行性，即能够接受至少两个周期两药治疗的患者比例，在曲氟尿苷替匹嘧啶后瑞戈非尼的用药顺序下更好。次要终点将确认是否对生存结果有影响。

 

 

1O-Chemotherapy and liver transplantation versus chemotherapy alone in patients with definitively unresectable colorectal liver metastases:Updated results from the randomized TRANSMET trial

 

Background

 

Definitively unresectable colorectal liver metastases(uCLM)are still associated with poor long-term survival despite the increasing efficacy of chemotherapy(CT).TRANSMET trial aimed to assess the efficacy of CT combined to LT vs CT alone for patients with uCLM.

 

Methods

 

Patients with definitively uCLM from resected BRAF non mutated colorectal cancer，responding to CT(≥3 months，≤3 lines)and with no extrahepatic disease，were submitted to an independent experts committee(EC)and randomly assigned(1:1)to receive CT and LT or CT alone.Primary endpoint was 5-year overall survival(OS).Secondary endpoints were progression free survival(PFS)and quality of life(QoL).The trial was designed to detect a 40%difference in OS from 10%(CT)to 50%(CT+LT)(2-sidedαlevel 5%-90%power).

 

Results

 

From February 2016 to July 2021，among 157 patients from 20 centers(3 countries)assessed by EC，94(60%)were randomly assigned to CT+LT or CT arm.Median number and maximal diameter of uCLM at diagnosis were 20(13-25)and 51.5(37-78)mm，respectively.At randomization，objective response was obtained after a median number of 20(14-27)CT cycles during 1(44%)，2(40%)or 3(16%)lines.9 patients(19%)in each arm did not receive the allocated treatment for oncological reasons(CT+LT arm)or unexpected curative procedures(CT arm).In ITT analysis，5-year OS was 57%in CT+LT arm and 13%in CT alone arm(p 0.0003-HR 0.37;95%CI 0.21-0.65).In per protocol analysis，5-year OS rate was 73%and 9%，respectively(p<0.0001，HR 0.16;95%CI 0.07-0.33).Median PFS was 17.4 and 6.4 months(HR 0.34;95%CI 0.20-0.58)，respectively.Among transplanted patients，28(74%)had recurrence，optionally treated by surgery(36%)or local ablation(11%).Fifteen(40%)patients were ultimately disease-free.In term of QoL，a trend towards a degradation in the physical functioning dimension and main symptoms were observed in arm C.

 

Conclusions

 

Through a selection process which is essential，LT combined with CT significantly improves survival compared to CT alone and may become a new standard option in the treatment strategy of liver-only uCLM patients.

 

Clinical trial identification

 

NCT02597348.

 

2O-Health-related quality of life(HRQoL)with first-line(1L)nivolumab(NIVO)plus ipilimumab(IPI)vs chemotherapy(chemo)in patients(pts)with microsatellite instability-high(MSI-H)/mismatch repair-deficient(dMMR)metastatic colorectal cancer(mCRC):CheckMate 8HW

 

Background

 

NIVO+IPI showed superior progression-free survival vs chemo in pts with centrally confirmed MSI-H/dMMR mCRC in the 1L setting at 31.5-mo median follow-up(HR 0.21;97.91%CI:0.13，0.35;P<0.0001).We present the first HRQoL results from this follow-up.

 

Methods

 

HRQoL was assessed in all treated pts with centrally confirmed MSI-H/dMMR status using the EORTC QLQ-C30，QLQ-CR29，and EQ-5D-3L.Mixed-effects model for repeated measures provided least squares(LS)means and 95%CI estimates of change from baseline(BL);week(wk)21 was prespecified as the primary timepoint of interest.Time to confirmed deterioration(TTCD)was estimated using Kaplan-Meier product limit methods.

 

Results

 

Of 245 pts treated with NIVO+IPI(n=170)or chemo(n=75)，94–96%had BL HRQoL data.Global Health Status(GHS)differences between the NIVO+IPI and chemo groups exceeded the prespecified minimally important difference(MID)of 5.0 starting at wk 13(LS mean difference[MD]，9.7;95%CI:3.6，15.9).At wk 21，clinically meaningful HRQoL improvement(GHS and functional scales)and decrease in symptoms with NIVO+IPI vs chemo was noted(Table)，indicating HRQoL benefits with NIVO+IPI vs chemo.There was a decreased risk of HRQoL deterioration with NIVO+IPI vs chemo(TTCD in GHS，HR 0.32;95%CI:0.18，0.57).Additional data will be shared.Table:2O

 

 

aPositive change=improvement

 

bNegative change=improvement

 

cPrespecified MID was reached

 

Conclusions

 

In pts with centrally confirmed MSI-H/dMMR mCRC，1L NIVO+IPI improved HRQoL and reduced symptoms，with a decreased risk of HRQoL deterioration vs chemo.

 

Clinical trial identification

 

NCT04008030.

 

3O-PRODIGE 68-UCGI 38-SOREGATT:A randomized phase II study comparing the sequences of regorafenib(reg)and trifluridine/tipiracil(t/t)after failure of standard therapies in patients(pts)with metastatic colorectal cancer(mCRC)

 

Background

 

Once first-line treatments(trt)for mCRC have been used，or are no longer appropriate，pts are eligible for either reg or t/t.Although both trt are approved in mCRC，no randomised trial has investigated the sequence of reg and t/t.We have designed this trial to evaluate if trt sequence has an impact on the number of pts who can received both trt and on survival.

 

Methods

 

Pts with mCRC，≥18 yo，ECOG PS 0-1，after failure of fluoropyrimidine-based chemotherapy combined with oxaliplatin and/or irinotecan plus EGFR(if RAS wild-type)and/or VEGF inhibitors were assigned in a 1:1 ratio in arm A(reg then t/t)or arm B(t/t then reg).ReDOS scheme was used.The primary endpoint is trt feasibility，assessed as the rate of pts able to receive at least 2 cycles of both trt，corresponding to the 1st tumor evaluation at each line.Secondary endpoints include duration of trt，progression-free survival in 1st sequence of trt(PFS1)，time to failure of strategy(TFS)，overall survival(OS)and time to deterioration of ECOG PS≥2.

 

Results

 

A total of 234 pts out of 340 planned were randomized(arm A/B:114/119)in 30 European centers.Study was prematurely stopped following disease management changes induced by SUNLIGHT trial results(t/t+beva).At time of data cut-off，the median follow-up was 19 mo.Main characteristics were(arm A/B):median age 68/67 yo;male 51/66%;PS0 34/35%;right，left side，rectum:30，46，24%/35，35，30%.The rate of pts able to receive at least 2 cycles of both trt is 40%/56%(p=0.018)with a median trt duration of 95/111 d.Main reason for end of trt were progression 82/90%and toxicity 14/8%in first phase;progression 80/78%and toxicity 12/20%in second phase.39%of arm A pts do not switch to subsequent trt vs 27%in arm B，mainly due to deterioration of general condition or death.Median TFS is 3.2 mo[2.4;3.5]vs 3.7[3.5;4.0]in arm A vs B.Secondary endpoints will be presented at the congress.

 

Conclusions

 

SOREGATT trial results show that the trt feasibility，i.e.rate of pts able to receive at least 2 cycles of both trt，is better with the sequence t/t then reg.Secondary endpoints will allow to confirm if there is an impact on survival outcomes.

 

Clinical trial identification

 

EudraCT 2019-004196-39.