江苏省肿瘤医院 肿瘤内科
江苏省肿瘤防治联盟第二届大肠癌专家委员会委员
主要从事肠癌的侵袭转移基础研究及临床转化研究。至今已发表SCI论文10余篇,10分以上1篇,5分以上6篇,累计总影响因子50+,总被引次数50+,其中第一/通讯作者4篇,包括:CANCER RESEARCH (IF 12.5), CELL DEATH AND DESEASE (IF 9.7)等杂志。
0.序言
结直肠癌(Colorectal Cancer, CRC)是世界上发病率和致死率排名靠前的恶性肿瘤,我国的结直肠癌发病率目前不断上升,但患者整体预后不佳,尤其是进展期结肠癌治疗效果较差[1, 2]。由于部分患者症状隐匿,确诊常常需要有创检查,因此有相当数量的患者初诊时是肿瘤晚期阶段,同时部分根治性切除患者也会出现远处转移;这些晚期病例中,80-90%是转移灶不可切除的患者[3]。近年来免疫检查点抑制剂(Immune Checkpoint Inhibitors,ICIs)在肿瘤治疗领域蓬勃发展,特别在MSI-H/dMMR型肿瘤中战果丰硕。循证医学证据证实各类ICIs的疗效一路高歌猛进,从后线逐渐进军一线,并拓展至新辅助治疗领域,已改变了MSI-H/dMMR型CRC患者的临床治疗格局。高度微卫星不稳定(Microsatellite Instability-High,MSI-H)/错配修复缺陷(Deficient Mismatch Repair, dMMR)的转移性CRC(mCRC)的肿瘤微环境通常有T细胞浸润,与对ICIs的治疗敏感相关。但MSI-H/dMMR在CRC中发生率较低,绝大多数(≥95%)mCRC属于微卫星稳定(microsatellite stable,MSS)或错配修复稳定(mismatch repair proficient,pMMR),这些患者并不能从目前可用的单免疫治疗方式中获益,效果并不明显,且尚无生物标志物有效预测ICIs治疗MSS/pMMR的mCRC潜在反应和副作用;这种对免疫治疗不耐受的肿瘤称为免疫治疗“冷肿瘤”[4],如何将“冷肿瘤”变成对免疫治疗敏感的“热肿瘤”一直是热门研究方向,目前临床对难治性mCRC尝试多种联合治疗模式,本文主要对MSS型mCRC的免疫联合治疗研究进展进行综述。
1.MSI-H/dMMR人群免疫治疗研究取得突飞猛进的进展,新的科学证据不断地证实该亚组人群免疫治疗的敏感性。
经过部分MSI-H/dMMR mCRC的II或III期临床研究证实,仅MSI-H/dMMR mCRC患者(比例<5%)可从ICIs治疗中明显获益[5]。在Checkmate-142 II期临床研究中,纳武单抗单药治疗MSI-H/dMMR难治性mCRC的ORR率为31%,1年PFS率为50%[6];而纳武单抗联合伊匹木单抗治疗类似mCRCs的ORR率升高达54.6%,1年PFS率则高达71%[7]。Keynote-164是一项全球多中心II期临床研究,分析帕博利珠单抗治疗MSI-H/dMMR的mCRC患者的疗效和安全性,所有患者入组前均接受了二线(n=63)或三线(n=61)治疗方案:两组患者的ORR率均为33%,中位PFS分别为4.1和2.3个月,1年OS率分别为76%和72%[8]。Keynote-177是首个专门招募MSI-H/dMMR mCRC的III期随机试验:与标准联合化疗(n=154)相比,一线帕博利珠单抗(n=153)治疗患者的中位PFS明显更长(16.5个月 vs.8.2个月,P<0.001);两组患者的12个月和24个月的PFS分别为55.3% vs. 37.3%和48.3% vs.18.6%,该研究的数据奠定了FDA在2020年06月29日批准了帕博利珠单抗一线治疗MSI-H/dMMR mCRC患者的理论依据[9]。
ICIs单药治疗MSI-H/dMMR的CRC的临床研究
2.非MSI-H/dMMR人群疗效相关研究
2.1非MSI-H/dMMR亚组人群免疫单药治疗疗效欠佳,尚待进一步发掘新的治疗策略。
对未经选择的CRC患者进行单用ICIs治疗,效果并不明显。一项探索不同剂量纳武利尤单抗的I期临床研究提示,19例mCRC患者均未能从纳武利尤单抗中显著获益[12]。Keynote-028是一项Ib期临床研究,分析了帕博利珠单抗一线治疗23例PD-L1阳性的晚期CRC患者,其中22(96.0%)例为MSS。中位随访5.3个月后,ORR仅4.0%,中位PFS仅1.8个月[13]。一项全球多中心III期临床研究(IMblaze370)探索了阿特珠单抗(PD-L1抑制剂)单药或联合帕博西尼对比瑞戈非尼三线治疗mCRC的疗效,结果发现3组患者在OS、PFS和ORR方面均无显著差异,且基于年龄、人种、PD-L1表达、RAS基因突变等亚组分析均未提示组间的显著差异[14]。度伐利尤单抗(durvalumab,PD-L1抑制剂)联合曲美木单抗(tremelimumab,CTLA-4抑制剂)对比最佳支持治疗晚期难治性CRC的II期临床研究提示,联合治疗组有OS的获益趋势(P=0.07);亚组分析显示,MSS的CRC患者OS显著获益(P=0.02);MSS且肿瘤突变负荷显著的患者(占MSS患者的21%)OS获益最大(P=0.004)[15]。此外,在MSS/pMMR mCRC患者接受PD-1单药治疗或双重ICIs治疗时,亦未发现明显的临床或生存获益[16]。对于未经选择的CRC患者,ICI治疗的ORR低于4%,中位PFS则短于2.2个月。因此,对于未能从ICIs治疗中获益的患者,期待未来的研究探索新的联合治疗方案,如ICIs联合靶向药物、化疗或放疗等进一步更新相关治疗方案选择。
MSS/pMMR人群单免治疗研究
2.2免疫联合治疗临床研究
单用免疫检查点抑制剂治疗MSS mCRC患者常常没有临床获益,PD-1/PD-L1抑制剂联合其他抗肿瘤治疗可能发挥协同作用从而增强抗肿瘤效应[4, 13],免疫联合系统化疗和靶向药物治疗mCRC的安全性和疗效已被初步证实,相关结果有待大样本临床研究进一步证实。
2.2.1联合血管生成抑制剂综合治疗
贝伐珠单抗是一种用于mCRC的抗血管生成药物,与化疗联合使用,抑制VEGF/VEGFR途径,从而使血管正常化,增加T细胞的浸润,并通过刺激树突状细胞的成熟和减少调节性T细胞和髓源性抑制细胞的扩增来激活效应免疫细胞[17-19]。然而,有临床试验评估了化疗和贝伐珠单抗联合atezolizumab与化疗和贝伐珠单抗一线治疗mCRC的比较,其中199例MSS mCRC患者,联合治疗组的PFS为12.9个月,对照组为11.4个月(P=0.07)[20]。另外,还有一些临床试验也正在开展以评估一线化疗和贝伐珠单抗联合免疫治疗的组合,结果尚未见报道。
2.2.2联合酪氨酸激酶抑制剂
多靶点酪氨酸激酶抑制剂瑞戈非尼是三线治疗mCRC的主要药物之一。有研究表明瑞戈非尼可以通过抑制肿瘤相关巨噬细胞、降低PD-L1和IDO1表达[21],从而增强抗肿瘤免疫作用。2019年REGONIVO研究纳入24例标准治疗失败后的pMMR/MSS肠癌患者,予瑞戈非尼80 mg联合纳武利尤单抗治疗,ORR达33.3%,可显著改善PFS和OS,且耐受性较好[22],且肺转移比肝转移患者、高TMB比低TMB患者更能获益。REGOMUNE试验评估了瑞戈非尼160 mg联合PD-L1抑制剂avelumab治疗48例MSS mCRC患者的疗效和安全性,54%患者病情稳定,中位PFS为3.6个月,中位OS为10.8个月。该研究发现与患者基线状况相比,第2周期第1天CD8+T细胞的肿瘤浸润增加的患者PFS显著延长[23]。我国一项Ⅰb/Ⅱ期临床试验显示瑞戈非尼联合特瑞普利单抗治疗难治性pMMR mCRC患者,ORR为15.2%,其中不伴肝转移的ORR达30%,中位PFS为2.1个月, 中位OS达15.5个月[24]。同时发现基线肠道微生物菌群中梭杆菌属可作为预测标志物。另外,呋喹替尼联合免疫治疗等临床试验也正在开展。有临床前研究显示,帕博利珠单抗联合仑伐替尼可通过减少肿瘤相关巨噬细胞和激活干扰素途径来激活CD8+T细胞,从而产生协同效应,增强抗肿瘤作用[25]。一项Ⅱ期临床试验显示帕博利珠单抗联合仑伐替尼治疗(“可乐组合”)曾接受过治疗的非dMMR/MSI-H mCRC,结果显示具有很好的抗肿瘤活性,共纳入32例患者,ORR为22%,中位PFS为2.3个月,安全性可控。这些研究显示部分pMMR/MSS mCRC患者可以从PD-1抑制剂联合酪氨酸激酶抑制剂这种模式中获益。
免疫联合瑞戈非尼治疗在肠癌临床前模型中的抗肿瘤活性[26]。
2.2.3联合抗EGFR药物综合治疗
抗EGFR药物是治疗RAS野生型mCRC的靶向药物之一,临床前研究显示抗EGFR治疗能激活肿瘤特异性免疫反应和免疫原性细胞凋亡,免疫治疗联合抗EGFR治疗可能增强抗肿瘤效应[27]。2021年ASCO-GI报道了LCCC1632Ⅱ期临床试验,结果显示了伊匹木单抗联合纳武利尤单抗联合帕尼单抗治疗pMMR/MSS mCRC的潜力。另外,Ⅱ期单臂CAVE试验探讨了三线治疗方案中用avelumab联合西妥昔单抗“再挑战”治疗RAS野生型mCRC曾一线经抗EGFR单抗治疗有效的患者[28]。在纳入的77名患者中,92%为MSS型mCRC,中位OS时间为11.6个月,将血浆循环肿瘤DNA(circulating tumor DNA, ctDNA)进行基线分析,ctDNA RAS/BRAF野生型患者较突变型患者的中位OS和PFS更长,前景值得我们期待,但还需要Ⅲ期研究进一步探索。ctDNA RAS/BRAF野生型可能是其潜在预测性生物标志物,综上研究表明,免疫+抗EGFR治疗MSS转移性结直肠癌患者值得进一步探索。
伊匹木单抗、纳武利尤单抗和帕尼单抗在 KRAS/NRAS/BRAF 野生型 (WT) MSS、转移性结直肠癌 (mCRC) 患者中的II期研究结果[29]。
2.2.4联合MAPK信号转导抑制剂
在mCRC中常检测到RAS/BRAF/MEK/ERK通路的过表达和激活[30]。有研究报道MAPK信号转导对T细胞的发育、活化、增殖和存活至关重要,并且MAPK信号转导可能控制PD-L1和CTLA-4的表达[30-32],这为探索免疫治疗药物和RAS/BRAF/MEK/ERK途径选择性抑制剂在pMMR/MSS mCRC中的协同作用提供了依据。临床前研究表明MEK抑制剂可上调主要组织相容性复合物I类分子表达,增加肿瘤内T细胞浸润,免疫检查点抑制剂联合MEK抑制剂可能提高疗效[5]。但有研究提示atezolizumab联合MEK抑制剂考比替尼对比瑞戈非尼并未提高晚期结直肠癌患者的疗效。2020年ASCO会议报道了MEK抑制剂比美替尼联合贝伐珠单抗联合帕博利珠单抗治疗经多线治疗失败的mCRC患者的临床试验结果,共入组了21例pMMR/MSS mCRC患者,ORR为12%,DCR为94%,中位PFS为6.4个月,不良反应可耐受,这个方案初见疗效,但仍需Ⅲ期临床试验来确认[33]。
抗EGFR药物和BRAF抑制剂及MEK抑制剂联用是BRAF V600E突变mCRC的治疗方案之一,但疗效仍有限。研究发现BRAF抑制剂和MEK抑制剂及PD-1/PD-L1抑制剂联合治疗BRAF V600E突变mCRC,其反应率和耐受性均良好[34]。此外,KRAS G12C抑制剂联合PD-1/PD-L1抑制剂的临床试验正在开展。
BRAF突变促进该通路的激活和肿瘤发生。迄今为止针对 BRAF 突变 CRC 开发的分子靶向药物与级联反应[35]。
2.2.5联合系统化疗或放疗治疗CRC的疗效
放疗可以通过多种机制增强免疫反应。一方面,放疗通过破坏DNA诱导肿瘤细胞死亡,促进抗原呈递、T细胞募集和活化,上调炎性细胞因子,从而增强抗肿瘤免疫作用。另一方面,放疗可诱导远隔效应,为联合治疗提供了依据[36-38]。一项Ⅱ期试验显示伊匹木单抗联合纳武利尤单抗联合放疗治疗MSS mCRC患者,非放疗区域的远处肿瘤缩小,ORR为12.5%,显示了免疫治疗联合放疗用于MSS mCRC患者的潜在可行性,但需要进一步探索免疫治疗和放疗的方案[39]。
ICIs联合其他治疗方案治疗CRC的临床研究
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