Encorafenib

For many people, the end of the year is a mad rush to wrap things up before the holidays, and so it was for the FDA. Notable regulatory decisions include the first drug approval for a prevalent chronic condition and a novel regenerative medicine approach to help trauma patients. In one case, a new drug approval comes as its developer takes on a new identity in the new year. Here’s a look back at some highlights from a busy regulatory month: presented by Health IT Transforming Patient Care: The Role of AI-Powered Assistants The progress in artificial intelligence (AI) is reshaping patient care, across various dimensions, from facilitating faster discharge to curating treatment plans and suggesting lifestyle changes. By IT Medical Notable Firsts —The prevalent sleeping disorder obstructive sleep apnea has historically been managed with a medical device that helps breathing. Eli Lilly’s Zepbound is now the first FDA-approved drug treatment for the chronic condition. Obesity is a risk factor for sleep apnea and clinical trial results showed that weight reductions from treatment with Zepbound were accompanied by breathing improvement. Approval in obstructive sleep apnea adds another potential blockbuster indication for a metabolic medication that has fast become one of Lilly’s top-selling products. —Patients who have the rare inherited metabolic disorder familial chylomicronemia syndrome lack the ability to break down triglycerides, a type of fat from food. The only way to avoid potentially fatal complications to the pancreas is by maintaining an extremely restrictive diet. Approval of Ionis Pharmaceuticals’ olezarsen gives patients a therapeutic option. The once-monthly injected genetic medicine, which is designed to block the body’s production of a liver protein that regulates triglyceride metabolism, will be marketed under the brand name Tryngolza. Ionis previously brought drugs through late-stage development and commercialization under partnerships with larger companies. Tryngolza will be the first product Ionis commercializes on its own. —When trauma to an arm or leg requires replacement of a blood vessel, the standard treatment is grafting a vein from the patient or implanting a synthetic vein. Now there’s a new regenerative medicine option. Humacyte won FDA approval for Symvess, a bioengineered blood vessel for restoring blood flow to avoid the loss of a limb when grafting a vein from the patient is not feasible. Here’s more about the biotech’s regenerative technology. Sponsored Post The Funding Model for Cancer Innovation is Broken — We Can Fix It Closing cancer health equity gaps require medical breakthroughs made possible by new funding approaches. By Eve McDavid - CEO of Mission-Driven Tech —Mesoblast’s regulatory approval was a long time coming. In 2020 and 2023, the FDA turned down the Australian company’s application for remestemcel, an allogeneic cell therapy for graft versus host disease, an immune response that develops when donor T cells attack the recipient’s cells following a transplant procedure. Remestemcel, brand name Ryoncil, is a made from mesenchymal stromal cells sourced from the bone marrow of healthy donors. The product’s approval covers acute graft versus host disease that is refractory to treatment with steroids in patients age 2 months and older. It’s the first affirmative regulatory decision for a cell therapy made from mesenchymal stromal cells. Approvals in Immunology —Vtama, an Organon drug acquired from Roivant Sciences earlier this year, received FDA approval as a treatment for atopic dermatitis in adults and children age 2 and older. The drug is topical cream that was initially approved in 2022 as a treatment for plaque psoriasis. Approval in atopic dermatitis brings the product to a much larger dermatologic indication, albeit one served my many branded and generic medications. —In other atopic dermatitis news, Galderma landed FDA approval for nemolizumab, brand name Nemluvio. The drug is an antibody designed to block IL-31, a signaling protein associated with the itch and inflammation of the chronic skin disorder. FDA approval of Nemluvio covers use of the drug in patients age 12 and older who have moderate-to-severe atopic dermatitis. It’s the second approval in the past year for Nemluvio, which was first approved over the summer as a treatment for prurigo nodularis. Rare Disease Regulatory Decisions —Neurocrine Biosciences received approval for Crenessity, a treatment for the rare inherited hormone disorder congenital adrenal hyperplasia. The small molecule helps bring the hormone imbalance back to more normal levels. The FDA approved a pill formulation for adults and an oral solution for pediatric patients. Analysts project Crenessity could achieve blockbuster sales, pending regulatory approvals in other countries. —Novo Nordisk is best known for metabolic medicines, but its rare disease portfolio is getting a boost with FDA approval of Alhemo, a drug that reduces bleeding episodes in patients with either hemophilia A or B. Alhemo, known in development as concizumab, is an antibody designed to bind to TFPI, preventing that protein from blocking factor Xa, a different protein that plays a role in blood clotting. That’s the same mechanism of action as Pfizer’s Hympavzi, which won its FDA approval in October. Both drugs are subcutaneous injections that provide alternatives to intravenously infused hemophilia therapies. But Pfizer’s once-weekly Hmypavzi has a dosing edge over Alhemo, which must be injected once daily. —Vertex Pharmaceuticals is adding a new cystic fibrosis (CF) drug to its portfolio with FDA approval of Alyftrek, which combines three compounds in a single therapy. Like Vertex’s other CF therapies, Alyftrek is a modulator of the CFTR a protein that regulates the movement of chloride ions into and out of cells. Alyftrek’s approval is based on clinical data comparing the once-daily therapy to Trikafta, a Vertex triple combination drug initially approved in 2019 as a twice-daily CF treatment. Results showed Alyftrek was non-inferior to Trikafta on a key measure of lung function and was superior in reducing sweat chloride levels, which is a surrogate indicator of the function of CFTR proteins. Besides the dosing advantage, Alyftrek addresses 31 additional mutations that are not addressable by other CFTR modulators. The Dec. 20 approval of Alyftrek came nearly two weeks ahead of the Jan. 2 target date for a regulatory decision. Developments in Cancer Drugs —The FDA awarded accelerated approval to Merus Therapeutics drug zenacutuzumab as a treatment for advanced cases of two types of cancer: non-small cell lung cancer and pancreatic adenocarcinoma. It’s the first approval for a drug that addresses a genetic signature called an NRG1 gene fusion. Netherlands-based Merus will market the bispecific antibody under the brand name Bizengri. In a deal struck days prior to the approval announcement, Partner Therapeutics licensed U.S. commercialization rights to Bizengri. —The blockbuster AstraZeneca drug Imfinzi expanded its FDA-approved uses to include limited-stage small cell lung cancer that has not progressed following concurrent platinum-based chemotherapy and radiation therapy. The checkpoint inhibitor was first approved in 2017 for bladder cancer and added extensive-stage lung cancer as a new indication in 2020. The drug’s latest approval is based on Phase 3 results showing a 27% reduction in the risk of death compared to a placebo. AstraZeneca said the FDA decision makes Imfinzi the first immunotherapy approved for limited-stage small cell lung cancer. —Xcovery Holdings drug ensartinib, brand name Ensacove, was approved to treat adults with advanced cases of non-small cell lung cancer that is positive for ALK mutations. Patients prescribed the once-daily pill must not have previously received an ALK inhibitor. —Pfizer cancer drug Braftovi landed accelerated approval as a first-line treatment for metastatic colorectal cancer driven by the BRAF V600E mutation. The approval covers use of the drug in combination with Eli Lilly’s Erbitux and the chemotherapy regimen referred to as FOLFOX, both standard colorectal cancer therapies. Braftovi, a small molecule inhibitor of BRAF V600E, was initially approved in 2018 for advanced cases of melanoma. The drug came from Pfizer’s 2019 acquisition of Array Biopharma. —Tevimbra, a cancer immunotherapy developed by BeiGene, received FDA approval as a first-line treatment for gastric and gastroesophageal junction cancers when used in combination with chemotherapy. It’s the second FDA approval for the checkpoint inhibitor, which was approved last March for treating advanced or metastatic esophageal squamous cell carcinoma after prior treatment with chemotherapy. The new year means a new identity for BeiGene. The cancer drug developer is changing its name to BeOne Medicines. Starting Jan. 2, the company’s stock symbol on the Nasdaq will be “ONC.” Rejections, Warnings & More Bad News in Biotech —Astellas Pharma’s bid to bring patients less-frequent eye injections of its drug Izervay was rejected by the FDA. Izervay, approved for treating geographic atrophy in 2023, is administered monthly to slow progression of the vision-loss disorder. Astellas sought approval for every-other-month dosing based on two-year Phase 3 data. According to Astellas, no safety benefit/risk issues were cited but the FDA took issue with a statistical matter related to labelling language proposed by the company. The rejection will limit Izervay’s ability to compete against Apellis Pharmaceuticals’ geographic atrophy drug Syfovre, which is approved for both monthly and every-other-month dosing. —In other Astellas news, the label for menopause drug Veozah now sports a black box warning for the risk of serious liver injury. The warning follows a FDA safety communication issued in September after a postmarketing report of a patient who developed signs and symptoms of liver injury after taking the once-daily pill for about 40 days. Veozah won FDA approval in 2023 as the first in a new class of therapies for menopause. —Applied Therapeutics received a double dose of bad regulatory news. First the FDA rejected the biotech’s application for govorestat, a drug developed as a treatment for the rare metabolic disease galactosemia. According to Applied, the agency cited “deficiencies in the clinical application.” Days after the FDA complete response letter, the FDA sent Applied a warning letter. The trial and the drug are redacted in the public version of the letter, but in a regulatory filing, Applied acknowledged the FDA’s concerns are about the govorestat galactosemia trial. Applied said the warning letter identified issues with electronic data capture and a dosing error in the dose-escalation portion of the study — both of which the company believed it had already addressed with the agency. Applied said it would respond to the FDA warning letter. —Bad news keeps stacking up for Intercept Pharmaceuticals and its drug, Ocaliva, a treatment for the rare liver disease primary biliary cholangitis (PBC). On Dec. 12, the FDA issued a safety alert, warning of the risk of serious liver injury in patients without advanced liver cirrhosis. The alert came one month after the FDA turned down Intercept’s application seeking full approval for Ocaliva, which won its accelerated approval in PBC in 2016. The FDA’s rejection letter for the drug cited safety concerns. When Ocaliva first reached the market, it was the only FDA-approved second-line treatment for PBC. In the past year, drugs from Ipsen and Gilead Sciences have each won accelerated approvals as new second-line therapies for the rare disease. Two weeks after the FDA turned down full approval of Ocaliva, the European Commission revoked the conditional marketing authorization for the drug. Advanz Pharma holds rights to Ocaliva in Europe. The company said the commission decision is subject to an ongoing annulment procedure in the EU’s General Court and a ruling is expected in 2025. —The FDA turned down Zealand Pharma’s glepaglutide as a treatment for short bowel syndrome, a rare disorder that develops when the small intestine is damaged or shortened, making it difficult for the organ to absorb nutrients. The drug is a long-acting GLP-2 analog intended to enhance the intestine’s ability to absorb nutrients, reducing patients’ dependence on intravenous feeding. According to Zealand, the FDA said the application needed more evidence of efficacy and safety. The company said it would discuss the letter with the FDA and proceed with plans to seek European approval in 2025. —Lexicon Pharmaceuticals came up short in its bid to expand approval of its drug, sotagliflozin (brand name Zynquista), to include the treatment of adults with type 1 diabetes and chronic kidney disease. The FDA’s Dec. 20 rejection of the drug followed a negative FDA advisory committee vote in October. The FDA approved sotagliflozin last year as a treatment for heart failure; it’s marketed in this indication under the brand name Inpefa. —Johnson & Johnson received a complete response letter for its injectable version of Rybrevant, a drug that treats cancer driven by EGFR mutations. Intravenously infused Rybrevant was approved in 2021 as a treatment for non-small cell lung cancer. The injectable version is made with technology from Halozyme. J&J said the FDA letter flagged manufacturing issues and did not cite any concerns about the new formulation or its safety and efficacy.

点击蓝字 关注我们 黄雷，董秋石，武爱文（北京大学肿瘤医院暨北京市肿瘤防治研究所胃肠肿瘤中心三病区　消化系统肿瘤整合防治全国重点实验室，北京　100142） 基金项目：国家自然科学基金项目（82173156）、北京市医管局登峰人才培养计划（DFL20241105）、北京市自然科学基金京津冀基础研究项目（22JCZXJC00140） 通信作者：武爱文　E-mai ：wuaw@sina.com 通信作者 武爱文 教授 主任医师 教授 博士研究生导师 北京大学肿瘤医院 胃肠肿瘤中心三病区主任 中国抗癌协会理事 北京抗癌协会常务理事 北京抗癌协会大肠癌专业委员会主任委员 北京抗癌协会科普专业委员会主任委员 中国抗癌协会科普委员会副主任 中国抗癌协会肿瘤防治科普专业委员会常务委员 中国抗癌协会大肠癌专业委员会常务委员 中华医学会外科学分会实验和转化学组委员 中国医师协会外科医师分会结直肠医师专业委员会委员 中国医药教育协会腹部肿瘤专业委员会副主任委员 中国性学会结直肠肛门功能分会副主任委员 世界中医药联合会整合肿瘤专业委员会副会长 北京中医药医养协会肿瘤康复分会副主任委员 国家首批健康科普专家 【摘要】  结直肠癌是全球范围内最常见的恶性肿瘤之一，也是肿瘤研究的热点领域。结直肠癌治疗涉及内镜下治疗、外科手术、围手术期和转移性结直肠癌的综合治疗。整体而言，2024年结直肠癌领域中随机对照研究成果丰硕，转移性结直肠癌新药及组合探索活跃。重要成果继续集中在免疫治疗的应用，局部晚期直肠癌的新辅助治疗后病理学完全缓解比例进一步提高，对双免疫治疗及新药物组合的探索日渐增多。主要呈现以下发展趋势，结直肠癌外科治疗在早期和局部晚期更加趋向于简约有效，与围手术期相关学科的组合促进患者的加速康复；局部晚期结直肠癌的研究将趋向于精准分层的研究，以辨识可能的获益人群和场景；转移性结直肠癌的一线治疗相对固定，后线治疗将有更多融合基础研究领域的最新探索，如新型免疫治疗包括细胞治疗、疫苗、基因编辑治疗等。超加速康复、器官保留的新理念、中医药及肝移植等的加盟，为结直肠癌患者更好的生活质量和预后提供更多的动力和可能。本文旨在回顾2024年度结直肠癌治疗研究进展。 【关键词】 结直肠癌；内镜外科；加速康复；器官保留；免疫治疗 结直肠癌是世界上第三大常见的癌症，也是癌症相关死亡的第二大常见原因[1]。结直肠癌是一个主要的全球健康问题，在中国被诊断出的癌症中排名第2，严重影响了患者的生命健康[2]。此外，近年来，早发型结直肠癌（即＜50岁患者的结直肠癌）发病率显著增加，这引起了全球医学界的广泛关注。随着医学技术的不断进步和对疾病认识的持续深入，结直肠癌的治疗策略也在不断演变和优化。2024年结直肠癌治疗领域迎来了诸多令人鼓舞的研究进展，这些成果不仅推动了临床实践的发展，也为患者带来了新的希望。本文旨在汇总2024年度相关重要文献、学术会议报道，并征询部分专家的意见，围绕内镜及传统外科治疗、围手术期治疗、不可切除结直肠癌的治疗等进行总结，旨在为结直肠癌的多学科治疗提供最新进展信息。  1 外科治疗 1.1  内镜外科治疗 内镜治疗是结直肠息肉和部分早期结直肠癌的主要治疗方式，包括圈套法息肉切除、内镜下黏膜切除术和内镜下黏膜下层剥离术，其中前者应用较广泛，通常采用带有切割/凝固电流的热圈套器切除。2024年多项来自西方国家的有关冷圈套和热圈套的随机对照研究结果得以发表，分别比较不同直径的息肉冷圈套法和热圈套法切除的区别，主要关注点为息肉残留复发、出血及延迟穿孔。 一项大型随机对照试验对≤10 mm的有蒂结肠息肉进行了亚组分析，评估了冷圈套息肉切除术（cold snare polypectomy，CSP）和热圈套息肉切除术（hot snare polypectomy，HSP）治疗术后即时出血（即围手术期使用夹子止血）和延迟出血（术后2周内发生的出血）情况。共647个有蒂息肉和386例患者被纳入分析。结果发现，与HSP相比，CSP患者即时出血发生率显著更高（10.8%∶3.2%，P＜0.001），手术时间显著更短[（123.0±117.8）s∶（166.0±237.7）s，P＝0.003）]。尽管CSP与更多的即时出血事件有关，但未造成不良临床事件，亦无延迟出血发生，该研究结果支持冷圈套息肉切除术作为治疗≤10 mm的有蒂结肠息肉的标准治疗方法[3]。 另一项随机对照试验，比较了冷圈套法内镜黏膜切除术（cold snare endoscopic mucosal resection，C-EMR）和热圈套法内镜黏膜切除术（hot snare endoscopic mucosal resection，H-EMR）在治疗大型（≥15 mm）平坦非有蒂结直肠息肉的疗效和安全性。共纳入177例患者被随机分配至C-EMR组（n＝87）和H-EMR组（n＝90）。结果表明，C-EMR组患者的复发率显著高于H-EMR组（18.4%∶1.1%，RR＝16.6，P＜0.001），迟发性穿孔仅在H-EMR组发生（1.1%∶0，P＝0.320）。H-EMR组患者的延迟出血率显著高于C-EMR组（7.8%∶1.1%，RR＝6.77，P＝0.034）。C-EMR在治疗平坦非有蒂结直肠息肉更高的安全性和技术成功率，但内镜复发率更高，说明该技术仍存在局限性[4]。 对于直径＞20 mm的非有蒂息肉，Steinbrück等[5]的研究纳入363例患者（48.2%为女性）的396个息肉纳入了意向治疗分析，随机分配至冷切除组（采用无电流息肉切除术）和热切除组（采用切割凝固电流的标准内镜下粘膜切除术），主要结局为严重不良事件（如穿孔或内镜后出血）。结果表明，冷切除组的主要不良事件发生率（1.0%∶7.9%，P＝0.001）、穿孔后出血率（0∶3.9%，P＝0.007）和内镜后出血率（1.0%∶4.4%，P＝0.040）均显著低于热切除组，但术后残留腺瘤的风险显著高于热切除组（23.7%∶13.8%，P＝0.020）。表明冷切除大型非有蒂结直肠息肉较热EMR安全更高，但残留腺瘤率更高，进一步的研究须证实息肉大小和组织学在多大程度上可以决定个体化的治疗方法[5]。 上述研究多来自欧美的报告，以上研究表明，相比传统热圈套器法，冷圈套器法有省时、安全、后遗损伤小的优势，但需要保障一定距离的切缘，避免腺瘤残留和复发。目前而言，冷圈套器EMR应被视为选择较大结直肠息肉的新治疗选项，但仍需要进一步研究以提高其有效性。 1.2 传统外科治疗 全系膜切除手术是目前可切除结直肠癌的标准治疗方式。近年来，传统外科治疗对不同微创手术方式（腹腔镜和机器人辅助）、直肠癌手术不同入路（经腹和经肛入路）、不同淋巴结清扫范围（D2和D3）、荧光辅助技术等进行探讨，以期提供更多的治疗选择，也为改善患者手术相关不良结局提供线索和依据[6]。 低位直肠癌的保肛手术一直是外科关注的热点。经肛全直肠系膜切除术（transanal total mesorectal excision，TaTME）是近年来学界关注度较高的手术方式，经肛视野可显著改善下段直肠显露及肠壁切缘，在部分中心已较成熟。前期报告的TaTME术后局部复发率突增与术中癌细胞泄漏及学习曲线相关性更高。来自日本的一项前瞻性队列研究中，40例直肠癌患者接受了TaTME，在6个代表性步骤中进行手术区域细胞学评估，发现手术过程中仅观察到少数癌细胞，最终手术区域未检测到癌细胞。如仔细执行2次荷包缝合和随后的盆腔冲洗，术中癌细胞的播散风险较低[7]。2024年报告的北美洲一项多中心前瞻性观察试验[8]和加拿大单中心研究[9]也证实了在高容量中心进行TaTME手术的肿瘤学安全性和有效性。值得关注的是，对于超低位直肠癌，2个阶段Turnbull-Cutait吻合术可以成为外科手术的替代方案，可避免临时造口，且在并发症、排便失禁、患者满意度、生活质量和肿瘤学结果方面与联合回肠造口术的手工结肠肛管吻合术相近，但仍有较高的并发症发生率[10]。 近年来机器人辅助手术应用越来越广泛，在直肠癌手术中显示出明显优势[11-12]。2024年发表的一项双盲随机对照临床试验，比较了Ⅰ～Ⅲ期结肠癌患者接受机器人辅助（机器人辅助组）或腹腔镜结肠癌手术（腹腔镜组）的结果。研究发现，在术后第1天，机器人辅助组C反应蛋白水平显著低于腹腔镜组（平均差异为19.88 mg/L，95%CI为3.89～35.86 mg/L，P＝0.045），表明Ⅰ～Ⅲ期结肠癌患者采用机器人辅助手术可减少手术应激反应。然而，在术后恢复质量、疼痛强度或镇痛使用方面，两种手术方法无显著差异[12]。 右半结肠癌的淋巴结清扫范围多以全结肠系膜切除（complete mesocolic excision，CME）为常规，但RELARC研究并未证明CME优于D2[13]，故建议将标准D2切除术作为常规术式，而CME仅在患者有明显的结肠系膜淋巴结受累时才考虑，这与美国结肠和直肠外科医师学会指南一致。荷兰RIGHT研究则是针对临床指南依从性较差的现况，强调实施标准化手术培训的重要性[14]。在中国同样存在常规进行D3淋巴结清扫的现况，但如何做好D2手术的标准化以及如何做好选择性的D3淋巴结清扫，仍需要进一步研究和探讨。 结直肠手术后的吻合口漏是最常见的严重并发症，如何预防是一个重要的话题。传统意义上，吻合口应重视张力、血运、梗阻等相关因素。在此基础上，尚有辅助器具的方法探索。在一项前瞻性多中心随机试验中研究了改良氰基丙烯酸酯胶来加强吻合口的初步结果，结果表明改良氰基丙烯酸酯胶在预防吻合口漏（anastomotic leakage，AL），可以帮助减少严重的术后并发症[15]。另一项正在进行的国际随机对照研究则是希望使用结肠吻合口保护装置Colovac预防高风险结直肠AL的并发症，以保护高风险吻合口[16]。 1.3 围手术期管理 精细的围手术期管理可以有效降低手术并发症的发生率，缩短住院时间，改善患者的整体预后[17-18]。理论上减少手术应激的所有措施均有助于患者康复，整合型围手术期管理可加速患者康复，达到≤48 h出院，甚至当日出院[19-20]。 影响围手术期安全性和康复速度的因素较多。来自意大利的团队利用前瞻性队列结合人工智能，通过多治疗机器学习分析，对6 241例选择性结直肠切除手术患者的4种不同肠道准备方法进行了比较。结果显示，机械肠道准备显著增加AL风险，而口服抗生素组与非机械肠道准备组相当，机械肠道准备联合口服抗生素显著降低了手术部位感染的风险[21]。另一项多中心、双盲、安慰剂对照的随机临床试验表明，机械和口服抗生素肠道准备相比单独机械肠道准备能显著降低直肠癌术后并发症发生率（5.8%∶13.5%，OR＝0.39，95%CI为0.21～0.72），故可择期直肠切除手术的标准治疗方案[22]。 除肠道准备以外，在疼痛、麻醉药物用量、液体输注以及血糖波动控制方面均有一些研究成果被报道，反映了围手术期管理的精细化趋势。术前双侧超声引导下腰方肌阻滞能减少吗啡使用量，并延长首次患者自控镇痛需求的时间[23]。在麻醉深度方面，相比中度神经肌肉阻滞，深度神经肌肉阻滞能减少30%的瑞芬太尼使用，并改善手术条件和降低腹内压，提高手术满意度[24]。一项关于目标导向液体治疗在老年患者接受腹腔镜下结直肠癌根治性切除手术中的随机对照试验发现，脉搏压力变异度作为目标导向液体治疗的监测指标可以改善老年患者腹腔镜下结直肠癌根治性手术的短期预后[25]。还有研究提示，二甲双胍可降低非糖尿病患者结肠癌手术后高血糖发生率，但尚需评估二甲双胍治疗对术后并发症的影响[26]。 结直肠癌患者术后通常会经历持续的肠道功能障碍，饮食干预可能是管理症状和提高治疗后饮食质量的有效方法[27]。低位前切除综合征（low anterior resection syndrome，LARS）是直肠癌患者常见的术后肠道功能障碍，对LARS的长期管理和支持对于改善直肠癌幸存者的生活质量至关重要[28]。术后早期开始凯格尔运动对缓解直肠癌患者的术后排尿功能障碍可能有效，但需要进一步的研究[29]。患者随访是重要的，但增加随访的频率并不能显著降低10年总体死亡率或癌症特异性死亡率[30]。  2 围手术期治疗 2.1  新辅助治疗 近年来，结直肠癌的新辅助治疗目标发生了重要变化，除了传统的根治性手术外，还衍生出器官保留的新需求和新目标。 2.1.1 以手术为目标的新辅助治疗  新辅助治疗一直是局部进展期结直肠癌，尤其直肠癌的研究热点。2024年是新辅助治疗研究成果丰硕的1年。虽然以OPTICAL、FOXTROT为代表的研究并未在结肠癌证实新辅助治疗有生存获益，但在直肠癌的系列研究中则显示出新辅助治疗的显著优势[31-32]。 结直肠癌分为错配修复功能缺陷（deficient mismatch repair，dMMR）/微卫星高度不稳定（microsatellite instability-high，MSI-H）和错配修复功能良好（proficient mismatch repair，pMMR）/微卫星稳定（microsatellite stable，MSS）2类。对dMMR/MSI-H而言，单纯免疫检查点抑制剂可获得较好的肿瘤退缩。PICC试验中3个月疗程的亚组分析结果显示，新辅助特瑞普利单抗，无论是否联合塞来昔布，都有极佳的长期生存，仅在中位随访39个月时，单药组出现1例第二原发的乳腺癌、1例术后感染死亡和1例COVID-19感染死亡，联合组无不良事件。首个多中心Ⅱ期试验NEOPRISM-CRC研究表明，在意向治疗患者中，病理完全缓解（pathological complete response，pCR）率达到了53%，而在肿瘤突变负荷（tumour mutation burden，TMB）高或中等的患者中，pCR率达到了55%，表明早期高dMMR/MSI结直肠癌的帕博利珠单抗新辅助治疗有效且安全性高[34]。IMHOTEP Ⅱ期试验中，对dMMR/MSI型结直肠癌，帕博利珠单抗新辅助治疗的pCR率随其治疗周期数增加而提高，接受1次帕博利珠单抗新辅助治疗的pCR率为47.1%，接受2次帕博利珠单抗新辅助治疗的pCR率为68.0%。多变量逻辑模型显示，帕博利珠单抗新辅助治疗的次数与pCR率的增加显著相关（OR＝3.6，95%CI为1.2～11.3，P=0.026）[35]。在笔者中心进行的回顾性研究发现，新辅助单药可使初始难以切除的dMMR/MSI-H结直肠癌实现较高比例的肿瘤完全缓解（47.6%），在T4b结肠癌或低位直肠癌患者中使用新辅助免疫治疗可减少多器官切除，并实现器官功能保留[36]。 近年来，放射治疗（以下简称放疗）联合免疫治疗成为研究的热点。在不同研究中，患者人群选择、药物使用的不同时机、方案、周期存在显著差异。以手术为目标的新辅助治疗主要用于降低手术复杂性和改善局部疾病控制，特别是对于高风险复发患者[37]。与标准治疗（术前放化疗）相比，mFOLFIRINOX联合长程放疗（新辅助化疗组）显著提高了无病生存（disease-free survival，DFS）率[67.6%∶62.5%，限制性平均生存时间（restricted mean survival time，RMST）差异5.73个月，95%CI为0.05～11.41个月，P＝0.048]、7年无转移生存（metastasis free survival，MFS）率（79.2%∶72.3%，RMST差异6.1个月，95%CI为0.93～11.37个月，P＝0.021）和7年总生存（overall survival，OS）率（81.9%∶76.1%，RMST差异4.37个月，95%CI为0.35～8.38个月，P＝0.033）。使用mFOLFIRINOX进行新辅助化疗，然后进行放化疗，改善了局部晚期直肠癌（locally advanced rectal cancer，LARC）患者的OS，证实了长期DFS和MFS的益处，应被视为这些患者的最佳选择之一[38]。但有研究将抗血管生成药物阿柏西普加入mFOLFOX6新辅助化疗中，并未改善患者的3年DFS或OS[39-40]。 对未分层的LARC放疗联合免疫检查点抑制剂研究成果涌现。虽有质子放疗[41]和基于磁共振引导自适应放射治疗（magnetic resonance guided adaptive radiation therapy，MRgART）集成增强（simultaneous integrated boost，SIB）治疗的探索[42]，但目前主流仍将放疗分为短程放疗（short-course preoperative radiotherapy，SCRT）或长程放化疗（long-course preoperative radiotherapy，LCRT）2个大类。从目前数据看，SCRT联合免疫检查点抑制剂可获得更高的pCR率。来自华中科技大学同济医学院附属协和医院的UNION研究，将T3～4期/N阳性直肠癌患者随机分配至SCRT（试验组）或LCRT（对照组），后接受卡瑞利珠单抗和CAPOX方案（卡培他滨＋奥沙利铂）或单独CAPOX方案。结果表明，在此项研究的主要研究终点pCR上，试验组显著高于对照组（39.8%∶15.3%，P＜0.001）。UNION研究的阳性结果为新辅助SCRT序贯卡瑞利珠单抗联合化疗治疗LARC提供了强有力的临床证据[43]。北京友谊医院开展的LCRT（50 Gy/25f）联合卡培他滨和替雷利珠的研究，pCR率达到40%（20/50）[44]。笔者所在的北京大学肿瘤医院一项前瞻性、单臂、Ⅱ期试验（PKUCH-R04），采用全程新辅助治疗（total neoadjuvant therapy，TNT）结合诱导化疗免疫疗法后接受长程放化疗治疗高风险pMMR直肠癌患者，pCR率可达37.5%[45]。目前扩大样本量的PKUCH-R07研究正在进行。 2.1.2 以器官保留为目标的新辅助治疗 等待观察策略系指新辅助治疗后达到临床完全缓解（clinical complete response，cCR）的直肠癌患者，可选择暂不接受全直肠系膜切除术的等待观察策略以期保留器官。TNT可提高LARC的肿瘤退缩和器官保留比例[46]。接受TNT后，根据临床肿瘤反应等级评估器官保存[47]。TNT有诱导化疗（induction chemotherapy，INCT）后CRT/SCRT和CRT/SCRT后巩固化疗（consolidation chemotherapy，CNCT）2种模式，均能实现长期器官保留，且大多数肿瘤再生发生在等待观察的前2年内。此外，CRT-CNCT顺序治疗在器官保留方面更有效[48]。特定的磁共振成像（magnetic resonance imaging，MRI）影像特征可以独立预测残留肿瘤的存在[49]。NO-CUT试验的初步结果发现，25.5%的患者可选择非手术管理（non-operative management，NOM），无远处复发生存率高达96.9%，表明TNT后选择NOM是一种可行的治疗策略[50]。 美国纪念斯隆-凯特琳癌症中心在2024年欧洲肿瘤内科学会（European Society of Medical Oncology，ESMO）年会上更新了Ⅱ期临床研究的结果，发现100%的局部晚期dMMR直肠癌患者接受程序性死亡受体1（programmed death-1，PD-1）阻断剂单药治疗6个月后，全部达到持续的临床完全缓解和非手术治疗[51]。不仅在直肠癌中，在其他实体肿瘤中同样达到类似惊人的效果。Lordick等[52]报告了一项Ⅱ期开放标签、单中心试验最新进展显示，非手术治疗的患者持续影像学完全缓解和长期器官保留。经过3年随访，接受帕博利珠单抗治疗的手术和非手术治疗患者的DFS和OS均保持高水平（所有患者的3年DFS率和OS率分别为80%和94%）。 对pMMR/MSS的直肠癌而言，近年来，研究发现放疗结合免疫治疗可进一步促进肿瘤退缩，并可能通过“等待观察” 策略实现器官保留。来自复旦大学肿瘤医院的TORCH研究，纳入T3～4期和/或N阳性的直肠癌患者，接受短程放疗联合化疗和PD-1抑制剂联合治疗。在26名可评估的患者中，13名达到cCR并采用WW策略，其余13名患者进行了手术，其中6名局部切除且无残留肿瘤细胞（ypT0），7名接受了全直肠系膜切除术，4名确认原发肿瘤和淋巴结无残留肿瘤细胞（ypT0N0, TRG0）。因此，总的完全缓解率（CR）为88.5%，结果表明，iTNT方法有潜力成为保留器官的优选治疗方案[53]。值得注意的是，免疫检查点抑制剂的加入并非单纯的药物叠加，尚需要更多研究探索其发挥作用的机制。 2024年结直肠癌新辅助治疗的相关临床试验汇总如表1所示。 2.2 辅助治疗 目前，结直肠癌的标准辅助治疗方案包括氟尿嘧啶类药物（如5-氟尿嘧啶或卡培他滨）单独使用或与奥沙利铂联合使用，治疗周期为3个月或6个月[54]。法国国际辅助化疗持续时间评估协作组的研究奠定了结肠癌辅助治疗的方案和时长选择。2024年来自SCOT的报告关注了辅助化疗的最佳开始时间。该试验将244个中心接受手术的5 719例患者，随机分配至3个月或6个月的辅助化疗组，结果显示，早期开始组（手术后≤6周）与晚期开始组（手术后＞6周）相比，5年DFS率分别为78.0%和73.2%，辅助化疗开始时间＞6周患者DFS率较低（HR＝1.24）。故应督促患者术后早期恢复并开始辅助化疗[55]。来自荷兰的结肠癌患者队列研究显示，3个月CAPEOX方案（卡培他滨＋奥沙利铂）（1～4个周期，n＝2 108）和6个月CAPEOX方案（5～8个周期，n＝204）相比，两者3年OS率相似，但前者神经毒性、生活质量和工作能力方面表现更佳，支持在临床实践中使用3个月的辅助CAPEOX方案化疗[56]。基于机器学习的模型（COLOXIS）或可通过肿瘤转录组数据分析预测早期结肠癌患者对奥沙利铂的疗效[57]。此外，有研究表明，CD3/CD8 T淋巴细胞密度可作为分层预后指标，且显示高风险组在辅助化疗中获益更多[58]。 浆膜受累的结肠癌术后容易出现异时性腹膜转移，预防性HIPEC治疗或可有益。但遗憾的是，今年国际多中心的随机对照研究COLOPEC长期结果显示，对于T4或穿孔结肠癌患者，辅助性腹腔热灌注化疗与系统化疗相比，并未显示出生存益处[59]。 化疗的毒性反应影响其完成率及疗效，奥沙利铂的外周神经毒性成为限制性毒性反应之一。有研究报告，按照瘦体质量计算用药剂量，比传统按照体表面积计算，可显著减少奥沙利铂诱导的周围神经毒性，并改善患者生活质量，且不会影响无复发生存时间和OS时间[60]。传统中医药的价值一直缺少高质量的循证医学证据。值得关注的是，来自中国中医科学院西苑医院的多中心随机对照研究结果表明，在常规实践中使用中药健脾益肾方能显著提高化疗完成率，尤其在Ⅱ期和年龄≤65岁的患者亚组中效果更明显。这表明健脾益肾方作为一种辅助疗法，可能有助于提高特定结肠癌患者的化疗依从性和生活质量，但需要更多的研究来验证其长期效果和最佳应用策略[61]。  3 不可切除结直肠癌的治疗 3.1  转移性结直肠癌（metastatic colorectal cancer，mCRC）一线治疗 3.1.1 原发灶切除 mCRC标准治疗以全身药物治疗为主。除药物治疗方案的选择外，还涉及原发灶的切除与否，一直尚存在较大争议。2024年肿瘤学年鉴报告了CAIRO4研究的结果。在无原发性肿瘤严重症状的同步mCRC患者中，药物治疗前首先切除原发灶并无生存获益[62]。该研究在2012年8月至2021年2月共纳入206例患者，随机分为两组，中位随访时间69.4个月，前期原发灶切除组中位OS时间与未切除组比较差异无统计学意义（20.1个月∶18.3个月，P＝0.32）。因此，对无症状的Ⅳ期结肠癌患者，未接受化疗者，不建议常规先行切除原发灶[63]。 3.1.2 药物治疗选择 转移性结直肠癌的一线药物治疗包括化学药物、靶向治疗、免疫治疗等，主要是基于对肿瘤组织生物学特性的预判选择治疗方案。因此，对错配修复蛋白、微卫星状态、RAS、RAF等突变检测是必要的步骤。 对dMMR/MSI-H的mCRC，keynote 177研究奠定了免疫疗法一线治疗的地位。近年，对双免治疗在mCRC中的探索一直在进行中[64–67]。CheckMate 8HW是一项随机、开放标签、Ⅲ期临床研究，纳入初治的dMMR/MSI-H的不可切除或mCRC患者，按照2∶2∶1随机分为双免组（纳武利尤单抗＋伊匹木单抗）、单免组（仅纳武利尤单抗）和化疗组，2024年美国临床肿瘤学会（American Society of Clinical Oncology，ASCO）会议仅报告了双免组对比化疗组的中期结果，近期发表在New England Journal of Medicine。中位随访31.5个月，双免组和化疗组患者中位无进展生存（progression-free survival，PFS）时间分别为未达到和5.9个月，24个月PFS率分别为72%和14%。需要关注的是，双免组3～4级治疗相关的不良事件明显低于化疗组（23%∶48%）[68]。结果显示，纳武利尤单抗＋伊匹木单抗在MSI-H/dMMR mCRC患者中显示出较化疗更长的无进展生存时间，且安全性更高，健康相关生活质量更佳，在各个亚组包括年龄组中安全性和有效性均保持一致。以上研究结果与其他相关研究结果均支持纳武利尤单抗＋伊匹木单抗作为MSI-H/dMMR mCRC患者的标准一线治疗方案[69-71]。当然，我们更加期待未来的最终研究报告，尤其是双免对比单免的结果。 对于占mCRC大多数的pMMR/MSS型患者，免疫疗法能否提高标准治疗的疗效尚不明确，但对不同药物组合的研究非常活跃。研究表明，斯鲁利单抗联合治疗可能成为mCRC患者有前景的一线治疗选择[72-73]。信迪利单抗（全人源IgG4单克隆抗体）联合贝伐珠单抗和CapeOX（BBCAPX）也被证明在不可切除mCRC患者中具有较好的抗肿瘤活性和较高的安全性，且肝转移患者预后更佳[74]。 lvonescimab（针对PD-1和血管内皮生长因子的四价双特异性抗体）单独或联合ligufalimab（针对CD47的人源化IgG4单克隆抗体）与FOLFOXIRI方案联用作为mCRC患者的一线治疗显示出良好的疗效和可接受的安全性[75]。amivantamab（一种血管内皮生长因子-MET双特异性抗体）联合FOLFOX方案或FOLFIRI方案治疗RAS/RAF野生型mCRC展现出鼓舞人心的、持久的抗肿瘤活性和可控的安全性[76]。 人表皮生长因子受体2（human epidermal growth factor receptor-2，HER-2）靶向双特异性抗体zanidatamab联合化疗±贝伐珠单抗在HER-2＋mCRC中具有良好的抗肿瘤活性[77]。三药联合治疗（信迪利单抗＋西达本胺＋贝伐珠单抗）相比于双药治疗（信迪利单抗＋西达本胺）在MSS/pMMR结直肠癌患者中显示出更好的疗效，包括更高的18周PFS率、总响应率和疾病控制率，以及更长的中位PFS时间，可能是MSS/pMMR晚期结直肠癌患者的一个有希望的治疗策略[78]。 随着人口老龄化，老年mCRC患者的比例预计在未来将持续增长，因此选择更加合适的治疗方案也有不少探索，来自不同国家的研究有不同的选择。一项来自日本的多中心、随机、开放标签的Ⅲ期临床试验（JCOG1018），推荐FP/BEV作为≥70岁不可切除mCRC患者的标准治疗方案[79]。PANDA研究发现，mFOLFOX方案或5-氟尿嘧啶＋亚叶酸钙＋帕尼单抗均可作为老年RAS/BRAF野生型mCRC患者的初始治疗方案，两者在PFS和OS结果相当，但后者的毒性较低，可能更适合老年患者[80]。 2024年mCRC一线治疗的相关临床试验汇总如表2所示。 3.2 mCRC后线治疗 许多患者在接受标准治疗后仍面临较高的复发风险和死亡率[81]。因此，后线治疗的必要性更为重要[82]。针对不同患者的特征及其肿瘤的生物标志物，后线治疗的研究正在不断推进，以期找到更有效的治疗方案来应对这一复杂的疾病[83-84]。 一项单臂、开放标签、单中心Ⅱ期研究（NCT05435313）中纳入标准治疗失败的结直肠癌肝转移患者，给予呋喹替尼、替雷利珠单抗和肝动脉灌注化疗（hepatic artery infusion chemotherapy，HAIC）治疗4～6周期，随后使用呋喹替尼、替雷利珠单抗进行维持治疗，直至疾病进展、死亡或不可接受的毒性。更新的生存分析数据显示，呋喹替尼联合替雷利珠单抗和HAIC在标准治疗失败的MSS结直肠癌肝转移患者中具有生存益处，特别是对于右半结肠癌患者[85]。立体定向消融放疗联合呋喹替尼和PD-1抑制剂替雷利珠单抗在mCRC治疗中显示出有希望的效果和良好的安全性[86]。一项针对难治性MSS mCRC患者的Ⅱ期研究，药物包括免疫检查点抑制剂evorpacept（ALX148）、西妥昔单抗和帕博利珠单抗。初步发现，尽管evorpacept＋西妥昔单抗＋帕博利珠单抗显示出一些活性，但需要进一步优化evorpacept＋西妥昔单抗＋帕博利珠单抗剂量以确定在难治性MSS CRC患者中的推荐剂量[87]。 trastuzumab deruxtecan（DS-8201）作为单药治疗，对于HER-2阳性mCRC患者（包括RAS突变、之前接受过抗HER-2治疗的患者）显示出有希望的抗肿瘤活性和可控的安全性，研究结果支持trastuzumab deruxtecan 5.4 mg/kg作为这些患者的最佳剂量选择[88]。EP4拮抗剂vorbipiprant（也称为CR6086）与PD-1抑制剂药物balstilimab联合治疗的研究显示，这种联合疗法在提高免疫检查点抑制剂的疗效方面显示出有希望的效果，特别是在有肝转移的患者中[89]。HER-2靶向双特异性抗体NC410联合帕博利珠单抗疗法安全且耐受性良好，显示出在难治性晚期mCRC中的潜在临床活性。在MSS/MSI-L CRC患者中，观察到部分患者有持续的病情缓解和疾病稳定[90]。针对HER-2阳性mCRC患者的tucatinib（TUC）和trastuzumab（Tras）联合治疗具有良好的耐受性和持续的疗效[91]。 encorafenib和cetuximab（E+C）与标准疗法（伊立替康＋cetuximab或FOLFIRI方案＋cetuximab）在治疗BRAF V600E突变的mCRC患者中，显示E＋C联合疗法有效且耐受性良好，PFS时间显著长于标准疗法[92]。sotorasib联合帕尼单抗panitumumab在KRAS G12C突变的mCRC患者中作为化疗难治性KRAS G12C突变mCRC患者的潜在标准治疗选择[93]。另一项研究中，MSS mCRC患者在2～3线化疗方案后进展，接受多肽疫苗PolyPEPI1018（1.2 mg，皮下注射）和阿替利珠单抗（1 200 mg，静脉注射）1次/3周，直至疾病进展或不可接受的毒性。治疗后平均程序性死亡受体配体1表达和CD8+肿瘤浸润性淋巴细胞密度均显著增加。PolyPEPI1018联合阿替利珠单抗耐受性良好[94]。 值得关注的是，近年来嵌合抗原受体T细胞（chimeric antigen receptor T-cell，CAR-T）治疗取得了一定进展。鸟苷酸环化酶C（guanylyl cyclase C，GUCY2C）在mCRC细胞中GC-C的表达是正常肠上皮细胞的2～10 倍，且约80%的结直肠癌患者肿瘤中的GC-C表达为阳性。GUCY2C CAR-T疗法IM96治疗mCRC研究20例患者的研究结果在2024年ASCO年会上报告，结果显示，在19例可评估疗效的患者中，DCR为73.7%，ORR为26.3%[95]。 3.3 转移灶切除及肝移植 此外，对于永久性不可切除的肝转移患者，肝移植联合化疗提供一种新的治疗可能。来自法国的TransMet试验将患者随机分配到肝移植联合化疗组或单独化疗组。意向治疗人群中，5年OS率为肝移植＋化疗组显著高于化疗单独组（56.6%∶12.6%，HR＝0.37，P＝0.000 3）。与单独化疗相比，肝移植＋化疗显著提高了生存率，该结果支持将肝移植作为永久性肝转移患者的新标准选择[96]。这项结果为无法获得良好肝转移灶无瘤状态的患者提供了新的希望。  4 总结与展望 2024年结直肠癌治疗领域取得了显著进展[97]，特别是在外科技术、围手术期管理和系统治疗方面[98]。重要成果继续集中在免疫治疗的应用，在LARC的新辅助治疗领域成果丰硕，显示出更高的病理学完全缓解比例，对双免疫治疗及新药物组合的探索日渐增多。笔者认为，结直肠癌外科治疗在早期和局部晚期更加趋向于简约有效，与围手术期相关学科的组合促进患者的加速康复；局部晚期结直肠癌的研究将趋向于精准分层的研究，以辨识可能的获益人群和场景；mCRC的一线治疗相对固定，后线治疗将有更多融合基础研究领域的最新探索，如新型免疫治疗包括细胞治疗、疫苗、基因编辑治疗等。超加速康复、器官保留、中医药及肝移植等的加盟，为结直肠癌患者更好的生活质量和预后提供更多的动力和可能。 参考文献 向上滑动查看 [1] Association NHCOTPROCSOOCM. 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Nivolumab (NIVO) + 5-fluorouracil/leucovorin/oxaliplatin (mFOLFOX6)/bevacizumab (BEV) versus mFOLFOX6/BEV for first-line (1L) treatment of metastatic colorectal cancer (mCRC): Phase 2 results from CheckMate 9X8.[J]. J Clin Oncol, 2022, 40(Suppl 4): 8. 推荐阅读 ●   盘点2023 | 武爱文教授：2023年度结直肠癌治疗研究进展 ●   盘点2022丨武爱文教授：2022年度结直肠癌治疗进展 ●   2023年度肿瘤学科盘点集锦(共17个) 声明：本文由“肿瘤界”整理与汇编，欢迎分享转载，如需使用本文内容，请务必注明出处。 排版：lagertha 校对：松月