编者按：欧洲肿瘤内科学会（ESMO）年会在西班牙马德里已如期举行。《肿瘤瞭望》选取ESMO 2023报道的重要研究，邀请国内大咖专家予以点评。复旦大学附属肿瘤医院李心翔教授针对EGFR抑制剂在ctDNA RAS/BRAF野生型难治性转移性结直肠癌中的再挑战的数据分享了见解和思考。
▌背景
▌方法
▌结果
▌结论
李心翔教授点评
该研究主要聚焦于EGFR抑制剂用于治疗循环肿瘤DNA (ctDNA) RAS/BRAF野生型转移性结直肠癌（mCRC）患者的疗效，其整合了既往CAVE[1]、VELO[2]、CRICKET[3]、和CHRONOS[4]四项临床研究中EGFR抑制剂用于治疗ctDNA RAS/BRAF 野生型转移性结直肠癌患者的生存数据，并进行了一系列个体化分析。
从研究结果上来看，114/194例血浆ctDNA阳性 RAS/BRAF 野生型患者接受了EGFR抑制剂的治疗。分别有83/114（72.8%）和31/114（27.2%）的患者接受了EGFR抑制剂作为三线或前期治疗失败的尝试性治疗。患者中位PFS和中位OS分别为4.0个月（95% CI：3.2~4.7）和13.1个月（95%CI：9.5~16.7）。1例患者评估达到完全缓解（CR），19例达到部分缓解（PR），65例和29例分别评估为疾病稳定（SD）和疾病进展为最佳缓解。约三分之一的患者可以从EGFR抑制剂治疗中显著获益（6个月PFS率为32.5%；18个月生存率为31.6%），并且治疗毒副反应可控。
这一数据为转移性结直肠癌患者治疗提供了新的思路，已知血浆ctDNA检测与组织检测具有良好的一致性[5]，那么未来ctDNA检测是否有希望可以代替组织基因检测用于指导治疗。并且对于既往接受EGFR抑制剂治疗的结直肠癌患者，基于ctDNA检测结果是否可以再次使用EGFR抑制剂治疗并从中获益，这是抗EGFR治疗针对转移性结直肠癌患者的再挑战，也是部分难治性结直肠癌患者的新希望。
但值得注意的是，该数据是选取自多个小样本的回顾或前瞻性临床试验，该结果仍亟需大样本的前瞻性临床试验加以验证。
摘要原文
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559MO - Rechallenge with EGFR inhibitors in ctDNA RAS/BRAF wild type refractory metastatic colorectal cancer: Individual patients’ data pooled analysis from 4 phase II trials
Background
Rechallenge with anti-EGFR inhibitors demonstrated clinical activity in patients (pts) with refractory circulating tumor DNA (ctDNA) RAS/BRAF wild type (wt) metastatic colorectal cancer (mCRC) and it is included as an option in clinical guidelines. However, the available evidence (III C) is derived from small retrospective/prospective studies.
Methods
We conducted an individualized patients’ data pooled analysis of pts enrolled in the CAVE, VELO, CRICKET and CHRONOS trials treated with anti-EGFR rechallenge with RAS/BRAF wt ctDNA. Overall survival (OS), progression free survival (PFS), overall response rate (ORR) and disease control rate (DCR) were calculated. Safety was reported.
Results
Overall, 114/194 pts that received anti-EGFR rechallenge as experimental therapy (48 cetuximab plus avelumab, 26 trifluridine/tipiracil plus panitumumab, 13 irinotecan plus cetuximab and 27 panitumumab) had RAS/BRAF wt baseline plasma ctDNA and were included in the current analysis. The study population included heavily pre-treated pts: 83/114 (72.8%) and 31/114 (27.2%) pts received rechallenge with EGFR inhibitors as third- or later lines of treatment, respectively. Median PFS (mPFS) and median OS (mOS) were 4.0 months (95% CI, 3.2-4.7) and 13.1 months (95% CI, 9.5-16.7). One patient achieved complete response (CR), 19 pts displayed partial response (PR), while 65 and 29 had stable disease (SD) and progressive disease as best response, respectively. The ORR (CR+PR) was 17.5% (20/114); DCR (CR+PR+SD) was 74.6% (85/114). Almost one of three pts significantly benefited from anti-EGFR rechallenge therapy (6-months PFS rate, 32.5%; 18-months OS rate, 31.6%). Treatments showed manageable toxicity, in lines with previous findings.
Conclusions
Results of this individual patients’ pooled analysis demonstrate promising clinical activity of rechallenge with EGFR inhibitors with nearly one-third of the pts experiencing long PFS that lead to prolonged survival. Thus, rechallenge with anti-EGFR-based strategies might be considered as a therapeutic option in the continuum of care of pts with refractory ctDNA RAS/BRAF wt mCRC.
Clinical trial identification
NCT05291156; NCT05468892; NCT02296203; NCT03227926.
[1] S. Napolitano et al., “CAVE-2 (Cetuximab-AVElumab) mCRC: A Phase II Randomized Clinical Study of the Combination of Avelumab Plus Cetuximab as a Rechallenge Strategy in Pre-Treated RAS/BRAF Wild-Type mCRC Patients.,” Front. Oncol., vol. 12, p. 940523, 2022, doi: 10.3389/fonc.2022.940523.
[2] S. Napolitano et al., “Panitumumab Plus Trifluridine-Tipiracil as Anti-Epidermal Growth Factor Receptor Rechallenge Therapy for Refractory RAS Wild-Type Metastatic Colorectal Cancer: A Phase 2 Randomized Clinical Trial.,” JAMA Oncol., vol. 9, no. 7, pp. 966–970, Jul. 2023, doi: 10.1001/jamaoncol.2023.0655.
[3] C. Cremolini et al., “Rechallenge for Patients With RAS and BRAF Wild-Type Metastatic Colorectal Cancer With Acquired Resistance to First-line Cetuximab and Irinotecan: A Phase 2 Single-Arm Clinical Trial.,” JAMA Oncol., vol. 5, no. 3, pp. 343–350, Mar. 2019, doi: 10.1001/jamaoncol.2018.5080.
[4] A. Sartore-Bianchi et al., “Circulating tumor DNA to guide rechallenge with panitumumab in metastatic colorectal cancer: the phase 2 CHRONOS trial.,” Nat. Med., vol. 28, no. 8, pp. 1612–1618, Aug. 2022, doi: 10.1038/s41591-022-01886-0.
[5] M. Loft, Y. H. To, P. Gibbs, and J. Tie, “Clinical application of circulating tumour DNA in colorectal cancer.,” lancet. Gastroenterol. Hepatol., vol. 8, no. 9, pp. 837–852, Sep. 2023, doi: 10.1016/S2468-1253(23)00146-2.
李心翔 教授
中国临床肿瘤学会（CSCO）理事
CSCO肿瘤微创外科专委会 副主任委员
CSCO结直肠癌诊疗指南执笔人
中国初级卫生保健基金会结直肠癌专业委员会 主任委员
中国研究型医院学会结直肠肛门外科专委会 副主任委员
中国医师协会肛肠医师分会 常委
中国医师协会肛肠医师分会大肠癌综合治疗专委会 主任委员
中西医结合学会普外专委会直肠癌防治专家委员会 主任委员
中国医师协会结直肠肿瘤专委会腹腔镜专委会 副主任委员
上海市抗癌协会胃肠肿瘤腹腔镜专业委员会 主任委员
上海市抗癌协会肿瘤微创专委会腔镜外科学组 组长
国际结直肠癌协会（ICRCC)中国分会 副主席
