Zanzalintinib

多项Ⅲ期研究失败使错配修复正常(pMMR)/微卫星稳定(MSS)结直肠癌被视作“冷肿瘤”且对免疫治疗耐药。研究人员提出，这种耐药具有条件性，受疾病分期、转移解剖部位、空间免疫架构及治疗机制影响。反复Ⅲ期失败包括LEAP-017、IMblaze370和RELATIVITY-123在难治性pMMR/MSS人群中未达疗效终点；唯一阳性Ⅲ期研究STELLAR-303（atezolizumab联合zanzalintinib）较regorafenib仅显示有限总生存获益，免疫组分贡献不明确。研究人员指出，在早期疾病、无肝转移、空间筛选肿瘤以及可重塑肿瘤微环境(TME)的新疗法中，已出现免疫活性信号。这些观察支持统一概念：pMMR/MSS结直肠癌并非绝对免疫抵抗，而是具有条件性免疫敏感，其应答由时间、解剖、生物学和治疗因素塑造。认识上述原则可指导患者筛选、生物标志物分层和药物研发，以释放免疫治疗临床潜力。《TRENDS in Cancer》刊发的述评指出，结直肠癌(CRC)免疫治疗在错配修复缺陷(dMMR)/微卫星不稳定高(MSI-H)人群已取得突破，但占85%的错配修复正常(pMMR)/微卫星稳定(MSS)人群屡遭Ⅲ期失败，LEAP-017、IMblaze370、RELATIVITY-123均未达终点，STELLAR-303虽阳性但免疫贡献存疑。研究人员由此反思：pMMR/MSS结直肠癌并非先天“冷肿瘤”，其免疫抵抗是条件性的，由疾病分期、转移部位、空间免疫架构与治疗机制共同决定。该研究意义在于把“无效”重新框架为“条件性敏感”，为病人选择、生物标志物开发与新一代免疫药物设计提供路线图。 研究人员主要依托已发表临床试验数据、回顾性与汇总分析、空间转录组与免疫评分(Immunoscore-IC)等队列证据开展工作；新辅助治疗数据来自局部直肠/结肠癌患者队列，转移性人群来自难治性微卫星稳定转移性结直肠癌(MSS mCRC)临床试验队列，肝脏免疫浸润比较来自配对原发灶与肝转移样本，生物标志物验证来自AtezoTRIBE等一线转移性队列。 原则1：早期临床阶段结直肠癌对免疫治疗更脆弱。研究人员依据免疫编辑(immunoediting)与侵袭性增加伴随瘤内效应T细胞密度下降、癌相关成纤维细胞致密细胞外基质屏障、调节性T细胞(Treg)抑制、主要组织相容性复合体(MHC)丢失等机制，并结合UNION、SPRING-01、NRG-GI002等新辅助直肠腺癌队列说明：局部早期肿瘤保留更高基线免疫浸润，程序性死亡蛋白1(PD-1)阻断联合全程新辅助治疗可显著提高病理完全缓解(pCR)；差异可能来自免疫与放疗时序及人群生物学不同。NICHE-1、NEST等非随机研究进一步支持局部结肠癌新辅助免疫联合有客观缓解。 原则2：无肝转移患者可能具更高免疫检查点敏感性。肝脏具免疫耐受特性，肠静脉经门脉入肝使肝转移常见。研究人员引用药理与临床证据显示，MSS肝转移灶CD8+ T细胞浸润低于配对原发灶；botensilimab+balstilimab难治队列中无肝转移客观缓解率(ORR)22%对0%，汇总分析23.0%对4.8%，四项随机事后总生存 hazard ratio 0.33–0.69。AtezoTRIBE与STELLAR-303未见肝转移预测失效，研究人员解释为联合方案中非免疫组分可能主导疗效。 原则3：空间免疫生物标志物而非肿瘤突变负荷(TMB)可预测获益。pMMR/MSS中位TMB低且与PD-1获益关系弱，POLE/POLD1超高危除外。研究人员强调淋巴细胞向肿瘤微环境(TME)转运为限速步；dMMR有“免疫枢纽(immune hubs)”与强CD8+ T细胞浸润，pMMR/MSS则见细胞毒淋巴细胞被间质屏障和抑制群分隔。Immunoscore-IC在AtezoTRIBE高评分组总生存优势明显(hazard ratio 0.42)，AtezoTRIBE2正前瞻性验证。 原则4：克服TME介导免疫排斥的新一代免疫治疗显现潜力。增强滞留策略中，PD-1/血管内皮生长因子(VEGF)双抗ivonescimab联合FOLFOXIRI ORR 70.8%；细胞选择性策略中，PD-1/转化生长因子β受体2(TGFβR2)双抗INCA33890在难治人群ORR 15.2%、PD-1/白细胞介素-2(IL-2)双抗IBI363 ORR 12.7%，均可作用于PD-1+细胞；TME选择性活化策略中，掩蔽抗细胞毒性T淋巴细胞相关蛋白4(CTLA-4)抗体ADG126联合pembrolizumab ORR 17.6%，botensilimab、porustobart通过增强抗体依赖细胞介导细胞毒性(ADCC)清除瘤内Treg。三类策略均指向局部重编程TME。 讨论部分，研究人员总结：未加选择的pMMR/MSS结直肠癌中检查点抑制剂反复失败催生“内在耐药”叙事，但早期阶段、无肝转移、空间免疫架构与TME导向新药共同揭示条件性免疫敏感。未来研发应以分期和转移部位指导筛选、以空间生物标志物指导分层、以TME滞留/选择性活化/细胞选择性药物克服排斥。 结论部分译为：在未加选择的pMMR/MSS结直肠癌中，检查点抑制剂的反复失败导致一种内在免疫抵抗的观点；然而新兴信号揭示出由时间、解剖、生物学和治疗因素塑造的条件性免疫敏感。实现结直肠癌免疫治疗潜力，需要围绕分期与部位知情的患者选择、生物标志物引导的分层，以及被设计用于克服TME排斥的药物来构建开发策略。

Bayer has decided to offload its aging cancer drug Stivarga to German compatriot Grünenthal as competition mounts. Grünenthal announced Monday that it will pay up to 375 million euros ($431 million) to acquire Stivarga, an oral multikinase inhibitor. According to Grünenthal, patent protection for Stivarga is expected to last until 2029 in the European Union and by 2030 in the U.S. But loss of exclusivity in China has already taken a toll on sales. Citing impact from China’s centralized tender program for off-patent drugs, Bayer reported an 18% decline in Stivarga sales in the first half of 2026 to 148 million euros. To Grünenthal, CEO Gabriel Baertschi described the deal as “a strong strategic fit,” that reflects the company’s “disciplined M&A strategy of acquiring established medicines that address clear and ongoing medical needs and create long-term value.” Grünenthal expects the deal to close by the end of 2026 or the beginning of 2027. The company estimates that Stivarga may contribute about 100 million euros to its consolidated EBITDA for next year. “By leveraging the strength of our commercial and operational expertise, we see clear opportunities to maximize the value of the medicine and support Grünenthal’s long-term growth,” Baertschi said. In response to Fierce’s inquiry about potential personnel changes, a Bayer spokesperson said, “employee-related implications of the transaction are minimal and will be managed through the normal transition process in accordance with applicable local requirements and in close collaboration with Grünenthal.” Stivarga had been under pressure even before China’s volume-based procurement hit in 2025, when Bayer handed regional promotion rights for Stivarga and another older cancer drug, Nexavar, to local firm Yifan Pharmaceutical. In all three FDA-approved indications—namely, liver cancer, colorectal cancer and gastrointestinal stromal tumors (GIST)—Stivarga has been facing stiff competition. In Nexavar-pretreated liver cancer, Exelixis’ Cabometyx represents a formidable rival to Stivarga. Ayvakit, originally developed by Blueprint Medicines and now owned by Sanofi, targets certain mutations of GIST. And in colorectal cancer, the FDA is expected to rule on Exelixis’ investigational zanzalintinib, used alongside Roche’s Tecentriq, in March 2027, after the combo beat Stivarga in a head-to-head phase 3 trial. Bayer embarked on a multiyear transformation under CEO Bill Anderson in 2024, removing management layers to accelerate the commercial push for newer growth products like prostate cancer drug Nubeqa and kidney disease and heart med Kerendia. The Stivarga sale comes a few weeks after the German pharma inked a potential deal worth 3 billion euros to sell a minority stake in its long-acting reversible contraceptives business to asset management firm Apollo. “The divestment of Stivarga is part of Bayer's innovation-driven growth strategy and enables us to further focus our resources on advancing breakthrough innovations for patients,” the Bayer spokesperson said. For its part, Grünenthal has built a business model buying established, cash-generating brands to fund R&D and stabilize revenue. Some purchases it made in recent years include paying 500 million euros for Bayer’s hypogonadism drug Nebido in 2022 and buying Vaolinor Pharma and its opioid-induced constipation treatment Movantik for $250 million in 2024. For 2025, the company reported record-high adjusted EBITDA of 500 million euros and a 46% increase in operating cash flow to 309 million euros. In its full-year 2025 report issued in March, Grünenthal touted its net leverage of 2.24x and its financial position for future R&D investments and further acquisitions. Editor's Note: The story has been updated with colorectal cancer as the target indication for zanzalintinib and with additional statements from Bayer.