RAS基因突变型转移性结直肠癌的治疗研究进展

结直肠癌是常见的消化道肿瘤之一,部分结直肠癌患者确诊时已发生转移,以化疗为主的综合治疗是转移性结直肠癌(mCRC)患者的主要治疗策略。近10余年来,靶向治疗的出现改善了mCRC患者的预后。目前临床用于m CRC的靶向治疗药物主要包括以表皮生长因子受体(EGFR)和血管内皮生长因子(VEGF)为靶点的药物。而前期诸多研究已经证实了有大鼠肉瘤病毒(RAS)基因突变的mCRC患者对抗EGFR治疗无效。因此,RAS基因突变型mCRC的治疗存在局限性。本文针对RAS基因突变型mCRC的治疗进展进行综述。     

150例转移性结直肠癌预后因素分析

摘 要：［目的］ 回顾性分析转移性结直肠癌（mCRC）的临床特征和治疗方法对mCRC患者预后的影响，为临床治疗决策提供循证依据。［方法］ 对黄山市人民医院肿瘤科2014年9月至2019年12月期间收治的150例mCRC患者的临床特征、治疗方法与患者总生存之间的关系进行单因素和多因素回归分析。［结果］ 150例mCRC患者中位总生存期(MST)为24.8个月。单因素分析显示，M分期、CA199、局部治疗、西妥昔单抗或贝伐珠单抗、免疫治疗为mCRC生存影响因素(P<0.05)。根治性局部治疗组（24例）、姑息性局部治疗组（66例）、无局部治疗组（60例）的MST分别为未达到、24.4个月和14.5个月（P=0.00）；西妥昔单抗或贝伐珠单抗使用组（83例）、未使用组（67例）的MST分别为34.8个月和23.3个月（P=0.03）。多因素分析显示，M分期、CA199、局部治疗、西妥昔单抗或贝伐珠单抗是影响mCRC生存的独立影响因素。［结论］ 影响mCRC生存的主要治疗因素是局部治疗和大分子靶向药物，多学科综合诊治和优化的全程管理是改善预后的关键。     

EGFR单克隆抗体治疗转移性结直肠癌的耐药分子机制

靶向表皮生长因子受体（EGFR）的单克隆抗体是转移性结直肠癌（mCRC）的重要治疗药物,但有效率并不理想,主要原因是存在严重的原发性和继发性耐药。本文从分子改变的方面就靶向EGFR单克隆抗体（anti EGFR mAb）治疗mCRC的耐药分子机制作一综述,旨在为进一步研究anti EGFR mAb耐药机制提供参考,为mCRC患者实现临床个体化治疗提供理论依据。     

转移性结直肠癌维持治疗的研究现状与治疗策略

结直肠癌是常见的恶性肿瘤之一,其发病率和死亡率分别位于第三位和第四位。大约60%的患者确诊时已处于晚期,其5年生存率在13%左右。近20年来,由于转移性结直肠癌(mCRC)晚期一线化疗方案及靶向药物的规范化应用,mCRC的治疗获得了重大突破。奥沙利铂、卡培他滨、贝伐珠单抗、西妥昔单抗等药物的应用使患者的中位生存期提高了一倍,5年生存率提高了20%。mCRC晚期一线治疗的常规模式是持续用药,直至病情进展或出现不可耐受的毒性。但是由于化疗药物的毒性累积,只有三分之一的患者能够坚持接受治疗直至病情进展。而患者在完成既定的初始化疗周期数,达到CR/PR/SD后,继续采用低剂量、低毒性的药物进行维持治疗,既可以延缓肿瘤的进展和转移,又可以减轻药物的毒副作用。目前,维持治疗已经成为mCRC晚期一线化疗后的主要治疗模式。但是,mCRC的最佳维持治疗方案仍无定论,现有的维持治疗方案仍不能找到最佳疗效与最大生活质量之间的平衡点。本文将回顾mCRC现有的维持治疗方案的临床研究,总结mCRC维持治疗现状,并对个体化的治疗策略进行讨论。     

PTEN表达水平与转移性结直肠癌患者西妥昔单抗临床获益关系的Meta分析

[目的]评价PTEN表达水平与转移性结直肠癌（mCRC）患者西妥昔单抗临床获益之间的关系,为临床用药和个性化治疗提供参考。[方法]计算机检索PubMed、CNKI、CBM和万方中文数据库,采用Meta分析的方法,评价PETN表达与mCRC患者西妥昔单抗疗效的关系。[结果]共纳入文献14篇,病人总人数1 227人。未经K-ras基因筛选mCRC患者PTEN表达阳性与西妥昔单抗治疗敏感性及无进展生存（PFS）均相关。K-ras野生型mCRC患者PTEN表达阳性与西妥昔单抗治疗PFS、总生存（OS）获益有关。[结论]PTEN表达水平可以作为mCRC患者西妥昔单抗临床获益的预测因素。     

RAS突变型转移性结直肠癌的精准治疗

转移性结直肠癌（mCRC）是一种异质性疾病，临床表现和分子分型差异大。目前，mCRC在治疗前需要常规行大鼠肉瘤病毒（RAS）基因检测。RAS突变状态与患者预后显著相关并能预测抗表皮生长因子受体（EGFR）治疗的疗效，然而仍缺乏针对RAS靶点的特异性治疗手段。既往研究表明直接抑制RAS蛋白带来的临床获益非常有限，最近报道了一种能够直接抑制KRAS G12C的有前景的药物—AMG-510，但还需要大样本研究进一步证实。近年来，通过抑制RAS基因相关效应器间接抑制RAS的表达、多靶点联合治疗及免疫治疗等均取得重要进展，有望成为针对RAS靶点的有效治疗手段。本文针对RAS突变型mCRC的精准治疗进行总结。     

生物标记物在转移性结直肠癌的抗EGFR治疗中的预测作用

目前,在肿瘤的治疗中EGFR信号通路成为重要的靶点,尤其在转移性结直肠癌(mCRC)的治疗中.EGFR单克隆抗体(mAbs)包括西妥昔单抗和帕尼单抗,抗EGFR mAbs联合传统的化疗在很大程度上改善了mCRC患者的无进展生存期(PFS)和总生存期(OS).然而,抗EGFR mAbs仅仅对KRAS野生型的mCRC患者有效,说明还有其他方面的因素影响着抗EGFR mAbs的疗效.研究表明,在结直肠癌中KRAS野生型(WT)的患者常伴有BRAF、PIK3A、NRAS突变和PTEN缺失,这些分子基因状态的改变可能与抗EGFR单克隆抗体靶向治疗抵抗性相关.因此检测患者对抗EGFR mAbs靶向治疗的相关生物标记物,可以对mCRC患者个体化治疗提供依据.     

三药化疗联合靶向治疗在转移性结直肠癌的临床研究进展

转移性结直肠癌（metastatic colorectal cancer,mCRC）的治疗多年来一直是困扰临床医生的一大难题,近年来国内外开展了一系列对mCRC一线治疗的相关临床试验。TRIBE 研究结果表明三药化疗联合靶向治疗较双药化疗联合靶向治疗在有效率、无进展生存期、总生存期都有显著提高,并推动国内外各指南将三药化疗联合靶向治疗作为mCRC的一线治疗方案。2019年中国临床肿瘤协会（Chinese Society of Clinical Oncology,CSCO）结直肠癌诊疗指南将三药化疗联合靶向治疗在 mCRC 转化治疗中的推荐意见提升至I级。本文就三药化疗联合靶向治疗在 mCRC的临床研究进展来探讨个体化、精准化医学理念指导下该治疗模式在 mCRC 的应用范围及不良反应。     

替吉奥单药治疗老年或体弱转移性结直肠癌患者疗效分析

目的 观察分析替吉奥单药作为老年或体弱转移性结直肠癌(mCRC)患者治疗方案的疗效和毒副反应.方法 24例老年或体弱mCRC患者接受口服替吉奥治疗,即替吉奥35 mg·m-2,每天2次,连用2周,停药1周.观察其近期疗效、疾病无进展生存期、总生存期、毒副反应等.结果 全组24例患者的总有效率为16.7％,疾病控制率为75.0％;中位无进展生存期为4.1(95％CI为2.8 ～5.4)个月,中位总生存期:12.3(95％CI为9.9 ～14.7)个月;主要毒副反应为胃肠道反应、骨髓抑制,多为轻度,无患者因毒副反应终止治疗.结论 替吉奥单药治疗老年或体弱mCRC患者安全性高、疗效好.     

治疗前胆碱酯酶联合纤维蛋白原/前白蛋白比值对转移性结直肠癌患者预后价值研究

摘 要：［目的］ 探讨治疗前血清胆碱酯酶（cholinesterase,CHE）联合纤维蛋白原/前白蛋白比值（fibrinogen-to-prealbumin ratio,FPR）对转移性结直肠癌（metastatic colorectal cancer,mCRC）患者的预后价值,建立mCRC患者的预后列线图预测模型并进行验证。［方法］ 回顾性分析161例mCRC患者的临床病理学资料。应用Cox回归模型分析临床基线特征和实验室检测指标在全体、左侧和右侧mCRC患者预后中的作用,确定独立预后因素;建立列线图预测模型。［结果］ 161例mCRC患者中,CHE、FPR的最佳截断值分别为4 140 U/L和23.6。生存分析显示,CHE≥4 140 U/L组和CHE＜4 140 U/L组中位生存期分别为23.0个月和10.1个月（χ2=40.429,P＜0.001）;FPR＜23.6组和FPR≥23.6组中位生存期分别为27.0个月和12.0个月（χ2=59.338,P＜0.001）;CHE-FPR评分为0、1和2分组中位生存期为别为29.6个月、14.6个月和7.2个月(1 vs 0：χ2=80.984,2 vs 0：χ2=161.671,P均＜0.001）。单因素和多因素Cox回归分析显示,ECOG 评分（HR=1.923,95%CI：0.989~3.739,P=0.05)、临床治疗方案（HR=0.663,95%CI：0.403~1.092,P=0.01）、CHE（HR=0.187,95%CI：0.041~0.850,P=0.03）、FPR（HR=1.956,95%CI：1.014~3.775,P=0.04）和CHE-FPR（HR=7.906,95%CI：4.636~13.481,P＜0.001）是mCRC的独立预后因素,构建列线图预测模型,包含CHE-FPR评分指标的预后列线图预测模型的一致性指数（C-index）为0.754;而不包含CHE-FPR评分指标的预后列线图预测模型的C-index则为0.606。［结论］ 治疗前CHE-FPR评分是mCRC患者有效的独立预后指标,可较准确个体化地预测不同治疗方式、不同原发肿瘤部位mCRC患者的预后,并可以辅助临床医生进行治疗决策。     

Role of targeted therapy in metastatic colorectal cancer

Colorectal cancer (CRC) is a significant cause of cancer-related morbidity and mortality all over the world. Improvements of cytotoxic and biologic agents have prolonged the survival in metastatic CRC (mCRC), with a median overall survival of approximately 2 years and more in the past two decades. The biologic agents that have proven clinical benefits in mCRC mainly target vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR). In particular, bevacizumab targeting VEGF and cetuximab and panitumumab targeting EGFR have demonstrated significant survival benefits in combination with cytotoxic chemotherapy in the first-line, second-line, or salvage setting. Aflibercept, ramucirumab, and regorafenib are also used in second-line or salvage therapy. Recent retrospective analyses have shown that KRAS or NRAS mutations were negative predictive markers for anti-EGFR therapy. Based on the evidence from large randomized clinical trials, personalized therapy is necessary for patients with mCRC according to their tumor biology and characteristics. The aim of this paper was to summarize the results of the major randomized clinical trials and highlight the benefits of the molecular targeted agents in patients with mCRC.     

Molecular therapies of colorectal cancer: where will we go from here?

Until the late 1990’s colorectal cancer had a poor prognosis with a median survival of 12 months for metastatic disease. The discovery of molecular mechanisms for malignant transformation, tumor growth, angiogenesis, and metastasis formation have opened an abundance of biologic insights and subsequent therapeutic approaches, which have led to improved prognosis in many cancers, among them colorectal cancer. While inhibition of vascular endothelial growth factor (VEGF) either by blocking antibodies or synthetic soluble receptor fragments—the so-called VEGF-traps—have been shown to be beneficial when combined with chemotherapy, blocking antibodies against the epidermal growth factor receptor (EGFR) have revealed cytotoxic activity as monotherapy or in combination with chemical agents. Recently, the tyrosine kinase inhibitor regorafenib has been shown to be beneficial as a monotherapy in the salvage treatment setting for metastatic colorectal cancer (mCRC) patients. However, as major driver mechanisms for malignant transformation in colorectal cancer have so far not been accounted, we may expect an abundance of novel therapeutic options in CRC. In this review, novel promising therapeutic approaches will be outlined.     

Current Options for Third-line and Beyond Treatment of Metastatic Colorectal Cancer. Spanish TTD Group Expert Opinion

Colorectal cancer (CRC) is a public health problem: it is the third most common cancer in men (746,000 new cases/year) and the second in women (614,000 new cases/year), representing the second leading cause of death by cancer worldwide. The survival of patients with metastatic CRC (mCRC) has increased prominently in recent years, reaching a median of 25 to 30 months. A growing number of patients with mCRC are candidates to receive a treatment in third line or beyond, although the optimal drug regimen and sequence are still unknown. In this situation of refractoriness, there are several alternatives: (1) To administer sequentially the 2 oral drugs approved in this indication: trifluridine/tipiracil and regorafenib, which have shown a statistically significant benefit in progression-free survival and overall survival with a different toxicity profile. (2) To administer cetuximab or panitumumab in treatment-naive patients with RAS wild type, which is increasingly rare because these drugs are usually indicated in first- or second-line. (3) To reuse drugs already administered that were discontinued owing to toxicity or progression (oxaliplatin, irinotecan, fluoropyrimidine, antiangiogenics, anti-epidermal growth factor receptor [if RAS wild-type]). High-quality evidence is limited, but this strategy is often used in routine clinical practice in the absence of alternative therapies especially in patients with good performance status. (4) To use specific treatments for very selected populations, such as trastuzumab/lapatinib in mCRC human epidermal growth factor receptor 2-positive, immunotherapy in microsatellite instability, intrahepatic therapies in limited disease or primarily located in the liver, although the main recommendation is to include patients in clinical trials.     

Retrospective Study of Regorafenib Versus TAS-102 Efficacy and Safety in Chemorefractory Metastatic Colorectal Cancer (mCRC) Patients: A Multi-institution Real Life Clinical Data

IntroductionThere have been significant developments in colorectal cancer (CRC) research over the last few years, with the introduction of new agents that have been prolonged median overall survival of metastatic colorectal cancer (mCRC). These therapies have improved patient outcomes; however, despite significant progress in strategies for cancer treatment, their use is limited by development of resistant mechanism. Almost 30% of patients with refractory mCRC will remain good candidates for further treatment. Regorafenib and TAS-102 are novel antitumor agents for patients with refractory mCRC. However, it is unclear which patients may derive a survival benefit from these drugs in real-life clinical practice.MethodsWe performed a retrospective analysis evaluating safety and efficacy of TAS-102 and regorafenib in a cohort of refractory mCRC patients, in 3 different centers between January 1 2018 and May 31 2020, with the aim of assessing the optimal sequence treatment for these 2 drugs.ResultsOne hundred and forty mCRC patients were included in the analysis. Of these patients, 64 received regorafenib and 76 received TAS-102 as first treatment. After progression, in the regorafenib 24 (37%) patients switched to secondary treatment with TAS-102, instead, in the TAS-102 group, among 76 patients, 29 (45%) patients switched to secondary treatment with regorafenib. Disease control was achieved in 8 (12.5%) of 64 patients in the regorafenib group and 17 (22.4%) of 76 patients in the TAS-102 group. In terms of efficacy, the PFS and OS were similar in both treatment groups for primary and secondary treatments. AEs reported in this analysis were mostly consistent with the known safety profiles of regorafenib and TAS-102 in previous clinical trials.ConclusionThe present study is the first one to compare the activity of the two agents in a large cohort of chemo-refractory mCRC patients providing more details about the best sequence, to be incorporated in clinical practice.     

Targeted Therapies in Metastatic Colorectal Cancer: A Systematic Review and Assessment of Currently Available Data

Background.

Survival of patients with metastatic colorectal cancer (mCRC) has been significantly improved with the introduction of the monoclonal antibodies targeting the vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR). Novel molecular-targeted agents such as aflibercept and regorafenib have recently been approved. The aim of this review is to summarize and assess the effects of molecular agents in mCRC based on the available phase II and III trials, pooled analyses, and meta-analyses/systematic reviews.

Methods.

A systematic literature search was conducted using the meta-database of the German Institute of Medical Documentation and Information. Criteria of the Scottish Intercollegiate Guidelines Network were used to assess the quality of the controlled trials and systematic reviews/meta-analyses.

Results.

Of the 806 retrieved records, 40 publications were included. For bevacizumab, efficacy in combination with fluoropyrimidine-based chemotherapy in first- and subsequent-line settings has been shown. The benefit of continued VEGF targeting has also been demonstrated with aflibercept and regorafenib. Cetuximab is effective with fluoropyrimidine, leucovorin, and irinotecan (FOLFIRI) in first-line settings and as a single agent in last-line settings. Efficacy for panitumumab has been shown with oxaliplatin with fluoropyrimidine in first-line settings, with FOLFIRI in second-line settings, and as monotherapy in last-line settings. Treatment of anti-EGFR antibodies is restricted to patients with tumors that do not harbor mutations in Kirsten rat sarcoma and in neuroblastoma RAS.

Conclusion.

Among various therapeutic options, the future challenge will be a better selection of the population that will benefit the most from specific anti-VEGF or anti- EGFR treatment and a careful consideration of therapy sequence.     

Evolving role of regorafenib for the treatment of advanced cancers

Regorafenib is an oral tyrosine kinase inhibitor (TKI) approved for the treatment of refractory metastatic colorectal cancer (mCRC), advanced gastrointestinal stromal tumors (GIST) previously treated with imatinib and sunitinib, and unresectable hepatocellular carcinoma (HCC) following progression on sorafenib. Regorafenib was initially approved for mCRC based on improved overall survival (OS) in the randomized, placebo-controlled, phase 3 CORRECT trial, which was confirmed in an expanded population of Asian patients in the randomized, placebo-controlled phase 3 CONCUR trial. Approvals in GIST, and more recently in HCC, were based on the results from the randomized, placebo-controlled, phase 3 GRID and RESORCE trials, respectively. In this review, we provide a comprehensive summary of the clinical evidence for approval of regorafenib in mCRC, GIST, and HCC, present emerging evidence of regorafenib activity in other tumor types (namely, gastroesophageal cancer, sarcomas, biliary tract cancer, and glioblastoma), and discuss trials in progress within the context of regorafenib’s mechanism of action. We describe recent advances and key lessons learned with regorafenib, including the importance of managing common drug-related toxicities using dose-optimization strategies, the search for biomarkers to predict response to treatment, and highlight some of the unaddressed questions and future directions for regorafenib across tumors.     

Regorafenib (BAY 73‐4506): Antitumor and antimetastatic activities in preclinical models of colorectal cancer

Regorafenib, a novel multikinase inhibitor, has recently demonstrated overall survival benefits in metastatic colorectal cancer (CRC) patients. Our study aimed to gain further insight into the molecular mechanisms of regorafenib and to assess its potential in combination therapy. Regorafenib was tested alone and in combination with irinotecan in patient‐derived (PD) CRC models and a murine CRC liver metastasis model. Mechanism of action was investigated using in vitro functional assays, immunohistochemistry and correlation with CRC‐related oncogenes. Regorafenib demonstrated significant inhibition of growth‐factor‐mediated vascular endothelial growth factor receptor (VEGFR) 2 and VEGFR3 autophosphorylation, and intracellular VEGFR3 signaling in human umbilical vascular endothelial cells (HuVECs) and lymphatic endothelial cells (LECs), and also blocked migration of LECs. Furthermore, regorafenib inhibited proliferation in 19 of 25 human CRC cell lines and markedly slowed tumor growth in five of seven PD xenograft models. Combination of regorafenib with irinotecan significantly delayed tumor growth after extended treatment in four xenograft models. Reduced CD31 staining indicates that the antiangiogenic effects of regorafenib contribute to its antitumor activity. Finally, regorafenib significantly delayed disease progression in a murine CRC liver metastasis model by inhibiting the growth of established liver metastases and preventing the formation of new metastases in other organs. In addition, our results suggest that regorafenib displays antimetastatic activity, which may contribute to its efficacy in patients with metastatic CRC. Combination of regorafenib and irinotecan demonstrated an increased antitumor effect and could provide a future treatment option for CRC patients.     

Does the efficacy of regorafenib differ in chemotherapy refractory metastatic colorectal cancer patients who had mucinous pathology compared to those who had non-mucinous pathology?

Purpose: To investigate the importance of mucinous histopathology on the assessment of tumor response in patients with metastatic colorectal cancer (mCRC) receiving regorafenib. Materials and method: All patients diagnosed with histologically confirmed mCRC in 2 oncology centers between 2013 and 2018 were retrospectively analyzed. Among 678 patients diagnosed with mCRC, 103 patients were treated with regorafenib. Ninety-four of these patients who had used at least 2 cycles of regorafenib and evaluable for treatment response were included in the analysis. Histopathologically, 18 patients with mucinous adenocarcinoma and 76 patients with nonmucinous adenocarcinoma were compared in terms of response rate and survival durations. Results: Median follow-up duration of 6 months, median age of the patients was 61 (34-77) years. While 19.1% of the patients had mucinous histology, 80.9% had nonmucinous histology. The overall response rate was significantly lower in the mucinous subgroup than the nonmucinous subgroup (5.6% vs 43.4%, respectively, P = 0.003). Similarly, both progression-free survival (3.0 vs 4.0 months, respectively, P = 0.011) and overall survival duration were shorter in the mucinous subgroup (3.0 vs 7.0 months, P = 0.016, respectively) compared with the nonmucinous subgroup. Conclusion: The histological subgroup may predict tumor response in mCRC patients receiving regorafenib. Its efficacy on nonmucinous histology had significantly more favorable than mucinous subtype.     

Sequencing of Antiangiogenic Agents in the Treatment of Metastatic Colorectal Cancer

Significant advances have been made with respect to our understanding of the critical role of agents targeting angiogenic pathways in the treatment of metastatic colorectal cancer (mCRC). The approval of 3 agents that target angiogenic signaling, bevacizumab, ziv-aflibercept, and regorafenib, provides strong evidence that angiogenesis is an important process in mCRC. The addition of bevacizumab to combination chemotherapy in the first- and second-line treatment of mCRC has resulted in meaningful improvement in overall and progression-free survival. The standard of care for mCRC has evolved to incorporate cytotoxic chemotherapy as the backbone regimens (eg, FOLFOX [folinic acid, 5-fluorouracil, and oxaliplatin], FOLFIRI [folinic acid, 5-fluorouracil, and irinotecan]) with or without bevacizumab, and epidermal growth factor receptor–targeted therapies (eg, cetuximab, panitumumab) in the setting of wild-type KRAS. The development of ziv-aflibercept in combination with FOLFIRI has improved clinical efficacy in the second-line treatment of mCRC. Regorafenib, a small-molecule multikinase inhibitor, has recently been approved by the US Food and Drug Administration as single-agent therapy in the treatment of refractory and progressive mCRC. Each of these agents has been integrated into an evidence-based—albeit, still evolving—treatment continuum for initial treatment, treatment after first progression, and treatment after second progression. However, the most effective strategy for the use of these agents, and others in development remains unclear. This review provides an overview of the current clinical evidence for the use of antiangiogenic agents targeting in the treatment of mCRC.     

Recent Advances in the Clinical Development of Immune Checkpoint Blockade Therapy for Mismatch Repair Proficient (pMMR)/non-MSI-H Metastatic Colorectal Cancer

Metastatic colorectal cancer (mCRC) continues to be associated with a poor prognosis, and there remains a significant unmet need for novel agents and treatment regimens. Major breakthroughs have been made with immune checkpoint blockade therapy in several disease types, including DNA mismatch repair deficient/microsatellite instability-high (MSI-H) tumors. To date, however, immune checkpoint monotherapy has not shown significant clinical activity in the treatment of patients with mismatch repair proficient (pMMR)/non-MSI-H mCRC. The immune resistance mechanisms in pMMR/non-MSI-H mCRC have not yet been clearly elucidated. Significant efforts are currently focused on identifying effective combination immunotherapy regimens for the treatment of patients with pMMR/non-MSI-H mCRC. The combination of atezolizumab with cobimetinib had shown promising clinical activity in an early-phase clinical trial. Unfortunately, the IMblaze 370 (COTEZO) phase III trial of atezolizumab/cobimetinib combination in patients with mCRC failed to show significant improvement in overall survival in patients treated with the atezolizumab/combimetinib combination in comparison with regorafenib alone. This review summarizes the recent major advances in the clinical development of immunotherapy regimens for patients with pMMR/non-MSI-H mCRC.