基于cirDNA的RAS/BRAF状态的抗EGFR单抗联合化疗治疗mCRC是否有效

编者按：欧洲肿瘤内科学会（ESMO）年会是欧洲乃至世界最负盛名和最具影响力的肿瘤学会议之一。2023年ESMO年会已于当地时间10月20～24日在西班牙马德里召开。结直肠肿瘤的多项优秀研究成果被选为大会的口头报告，肿瘤瞭望消化时讯特此整理了相关研究，以飨读者！

01

LBA30 -帕尼单抗（P） FOLFIRINOX或mFOLFOX6治疗循环DNA (cirDNA) RAS/BRAF野生型（WT）不可切除转移性结直肠癌（mCRC）患者（pts）：随机化II期PANIRINOX-UCGI28研究的首次结果分析

▌背景

对于RAS/BRAF WT肿瘤的缩小，抗EGFR抗体联合三联化疗（CT）方案在I、II期试验中显示出有希望的结果。使用IntPlex®技术的超灵敏cirDNA分析可能会更好地选择基于抗EGFR治疗的敏感患者。因此，PANIRINOX研究的目的是探索帕尼单抗 三联化疗(FOLFIRINOX=A组)或标准两联化疗(mFOLFOX6 = B组)治疗cirDNA RAS/BRAF V600E WT不可切除mCRC患者的完全缓解(CR)率。

▌方法

在这项随机非比较多中心II期试验中，患者按2:1的比例分到A/B组（最多12个周期），根据疾病程度分为2个不同的分层（str1：仅肝脏受转移，str2：非仅肝脏转移）。主要终点是根据RECIST 1.1（中心评价）的CR率和CEA正常化。次要终点包括无进展生存期（PFS）和总生存期（OS）。

▌结果

从2017年10月到2022年7月，78/33例患者被分配到str2的A/B组。主要特征为（A/B组）：中位年龄64/62岁；男性67%/45%;PS 0分63%/42%；左半81%/79%；同时性转移85%/87%;>1个转移部位82%/72%。下列表格列出了可评估患者的CR、PFS和OS。主要≥3级治疗相关不良事件为（A/B组）：腹泻39%/9%，周围神经病变22%/24%，皮肤反应18%/24%。

▌结论

在A组中有5例患者达到CR，在B组中95%CI区间包含预先设定的假设值，该研究在str2中达到了主要目标。我们证实，在一线进行抗EGFR治疗之前，通过cirDNA分析对肿瘤进行基因分型是一种相关的组织学检测的替代方法。（试验信息：NCT02980510）

02

553O - KRAS和BRAF突变在微卫星稳定（MSS）和微卫星不稳定（MSI） III期结肠癌中的预后价值：7项试验的ACCENT/IDEA汇总分析

▌背景

KRAS和BRAFV600E突变是否影响III期CC的预后仍然存在争议，由于样本量的限制，从未在MSI-H患者亚组中进行过明确的分析。患者个体的KRAS突变的预后价值也没有得到广泛的研究。

▌方法

我们研究了KRAS外显子2和BRAF V600E突变对手术切除的III期CC患者的预后影响，这些患者参加了来自ACCENT/IDEA数据库的7项临床试验。通过Cox模型评估突变与复发时间（TTR）、总生存期（OS）和复发后生存期（SAR）之间的关系，根据研究进行分层，并根据性别、年龄、体能状态、T和N分期、肿瘤分级和原发肿瘤位置进行调整。分析KRAS外显子2亚突变个体（G12A、G12C、G12D、G12R、G12S、G12V、G13D等）的预后价值。

▌结果

纳入8286例患者，其中11.6%为MSI-H (N=967)，MSI-H亚组5年复发率为24.1%，MSS亚组为30.3%。BRAF V600E、KRAS外显子2突变或双野生型分别占MSI-H组的40.6%、18.1%和41.3%，占MSS组的7.8%、38.6%和53.7%。在MSS组中，BRAF V600E、KRAS外显子2突变和双野生型患者的5y TTR率分别为61.7%、66.4%和73.2% (adj HR: 1.34和1.32,P<0.001)，而在MSI组中，突变亚组的5y TTR率未见缩短，分别为76.1%、75.8%和75.6% (adj HR: 1.01和0.98,P>0.05)。在OS中也发现了类似的结果。然而，在MSS组和MSI组中存在KRAS外显子2突变或BRAF V600E突变的肿瘤患者的SAR显著缩短（adj HR: 1.16和2.05;P<0.0001）、(adj HR: 1.76和2.00;P<0.05)。KRAS外显子2亚突变的预后价值没有明显差异。

▌结论

在对KRAS外显子2突变和BRAF V600E突变与切除的III期CC的疾病结局的相关性最大规模分析中，任何一种突变都与MSS肿瘤中较短的DFS、OS和SAR相关，但仅与MSI-H肿瘤中较短的SAR相关。此外，所有KRAS密码子12和13突变具有相似的预后价值。

摘要原文

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For shrinkage of RAS/BRAF WT tumors, anti-EGFR antibodies combinated with triplet chemotherapy (CT) regimen have shown promising results in phase I-II trials. Ultrasensitive cirDNA analysis as those with IntPlex® technology might result in better selection of super-responders to anti-EGFR-based therapies. Thus, the aim of PANIRINOX was studying the complete response (CR) rate obtained with P plus a tri-CT regimen (FOLFIRINOX = Arm A) or a standard bi-CT (mFOLFOX6 = Arm B) in pts with cirDNA-based RAS/BRAF V600E WT unresectable mCRC tumors.

In this randomised non-comparative multicentric phase II trial, pts were assigned in a 2:1 ratio in arm A/B (12 cycles max) in 2 different strata (str) according to disease extent (str 1: liver limited /str2: non-liver-limited). Primary endpoint was the CR rate according to RECIST 1.1 (central review) and CEA normalization (Fleming’s one-step design, one-sided a=5%, b=10%, H0: 3%; H1: 12%; 60 pts in Arm A needed with at least 4 successes; Arm B as internal control). Secondary endpoints included progression-free and overall survival (PFS and OS).

From 10/2017 to 07/2022, 78/33 pts were assigned in arm A/B in str2. Main characteristics were (arm A/B): median age 64/62 yo; males 67/45%; PS0 63/42%; left-sided 81/79%; synchronous metastases 85/87%; >1 metastatic site 82/72%. The table lists CR, PFS and OS in evaluable pts. Main grade≥3 treatment-related adverse events were (arm A/B): diarrhea 39/9%, peripheral neuropathy 22/24%, skin 18/24%. Table: LBA30

With 5 pts achieving CR in arm A and 95%CI including predetermined hypothesis in arm B, the study met its primary objective in str2. We confirm that genotyping tumors from cirDNA analysis is a relevant alternative to tissue before administrating anti-EGFR-based therapies in first line.

EudraCT 2016-001490-33, NCT02980510.

Whether KRAS and BRAFV600E mutations are prognostic in stage III CC remains controversial and has never been clearly analyzed in the subgroup of MSI-H patients (pts) due to sample size limitations. The prognostic value of individual KRAS mutations has also not been widely studied.

We studied the prognostic impact of individual KRAS exon 2 and BRAFV600E mutations in pts with surgically resected stage III CC who participated in 7 clinical trials from the ACCENT/IDEA databases. Associations between mutations and time to recurrence (TTR), overall survival (OS) and survival after recurrence (SAR) were assessed by Cox model, stratified by study and adjusted for sex, age, performance status, T and N stage, disease grade, and primary tumor location. The prognostic value of individual KRAS exon 2 submutations (G12A, G12C, G12D, G12R, G12S, G12V, G13D and others) was also analyzed.

8286 pts were included, 11.6% were MSI-H (N=967) with 5 yr recurrence rates of 24.1% for MSI-H and 30.3% for MSS subgroups. BRAFV600E, KRAS exon 2 mutants or double wild type represented 40.6%, 18.1% and 41.3% of the MSI-H group and 7.8%, 38.6% and 53.7% of the MSS group, respectively. In the MSS group, 5y TTR rates of 61.7%, 66.4% and 73.2% emerged in pts with BRAFV600E , KRAS exon 2 mutants and in double wild-type pts, respectively, (adjHR: 1.34 and 1.32, both p<0.001), while in the MSI group shorter TTR in mutated subgroups was not seen with 5y TTR rates of 76.1%, 75.8% and 75.6%, respectively (adjHR: 1.01 and 0.98, both p>0.05).

Similar results were found for OS. However, SAR was significantly shorter for pts with tumors harboring a KRAS exon 2 or BRAFV600E mutation in both MSS (adjHR: 1.16 and 2.05; both p<0.0001) and MSI (adjHR: 1.76 and 2.00; both p<0.05) pts. No major differences were noted in the prognostic value of KRAS exon 2 submutations.

In the largest analysis of the association of KRAS exon 2 and BRAFV600E mutations and disease outcome in resected stage III CC, either mutation was associated with significantly shorter DFS, OS and SAR in MSS tumors, but only with shorter SAR in MSI-H tumors. In addition, all KRAS codon 12 and 13 mutations had similar prognostic value.

IDEA France: NCT00958737 PMID: 29620995 C07: NCT00004931 PMID: 17470851 C89803: PMID: 17687149 PETACC3: PMID: 19451425 C08: PMID: 20940184 PETACC8: EudraCT 2005-003463-23 PMID: 24928083 N0147: NCT00079274 PMID: 22474202