Dana-Farber Cancer Institute, Inc.

CHICAGO — A new type of targeted cancer drug that blocks a “DNA caretaker” protein called Werner helicase has captured the attention of several big pharma companies in recent years, and the first data appear to reinforce its potential. Cells are typically equipped with critical redundancies for important proteins, but when they mutate in cancer patients, a single protein can become the key to a cell’s life or death. By finding the proteins that aberrant cancer cells need to function and then blocking them, drug developers are building the next generation of targeted cancer treatments. Roche now has the first data for its experimental drug, which takes advantage of what’s known as synthetic lethality, in gynecologic and colon cancers. It was shared this week at the American Association for Cancer Research’s annual meeting in Chicago. In the span of six years, scientists and physicians took a promising drug target identified via CRISPR screening and created a handful of experimental treatments for cancer patients. There are now four different Werner helicase-targeting agents in early-stage clinical trials from Roche, Novartis, GSK and Nimbus Therapeutics — a private drug developer with a track record of doing big deals. “Werner helicase really and truly represents a synthetic lethal vulnerability and therefore a therapeutic opportunity in MSI cancers,” said Timothy Yap, a physician-scientist with the University of Texas MD Anderson Cancer Center, referring to cancers with a specific DNA signature. “That’s really the crux of it and why it was so exciting.” Synthetic lethality is a phenomenon that scientists are exploiting to develop new targeted cancer treatments. Their inspiration is PARP inhibitors (such as AstraZeneca’s Lynparza), a class of drugs used to treat a wide range of cancers including breast and ovarian. PARP inhibitors are a synthetic lethal therapy for cancers with BRCA mutations. In the Phase 1 study, Roche’s experimental drug led to four confirmed responses — two in endometrial cancer, one in colorectal cancer, and one in ovarian cancer — in 35 patients. There was also a fifth unconfirmed response in endometrial cancer. Yap presented the data Sunday at the AACR meeting. The responses mean the drug, which came from Roche’s partnership with Vividion Therapeutics in 2020, shrank the tumors in these patients at least 30%. It’s the first time that researchers have shown the effect of a Werner helicase blocker in people. Many of the patients in the study had gone through several previous treatment regimens. While their cancers were found in a wide range of locations, most of the tumors were considered microsatellite instable, which is a sign of DNA misrepair that physicians frequently look for in cancer diagnoses. The initial science that identified Werner helicase as a potential target showed that knocking it out was lethal to the microsatellite instable cells, and this piqued the interest of drug developers. Microsatellite instability-high cancers make up around 3% of all cancer cases, according to some estimates. The responses to Roche’s drug occurred at a range of doses, from 150 mg a day to 1,000 mg twice a day. In an interview, Ryan Corcoran, director of the gastrointestinal cancer center program at the Massachusetts General Hospital Cancer Center, said there’s not a clear correlation between the responses and dose levels. Researchers typically look for dose dependency (more drug equals better efficacy) in clinical studies as a green flag the treatment is working as intended. Corcoran, who chaired the session where Roche’s clinical trial results were presented, consults for Roche but not on the Werner helicase project. The primary side effects related to the drug were nausea, vomiting and diarrhea. There were no dose-limiting toxicities. Like Novartis had already reported, both GSK and Nimbus disclosed at the meeting that their molecules were non-covalent, meaning they do not permanently bind Werner helicase. This leaves Roche as the lone company developing a covalent, or permanently binding, agent in clinical trials. GSK suggested in its presentation that its drug could work in tumors that acquired resistance to Roche or Novartis’ compounds, but that’s based on animal model data and has not been shown in humans. GSK’s drug comes from a partnership with Ideaya Biosciences, a biotech company that’s focused on developing drugs against synthetic lethalities. In 2019, four papers were published showing Werner helicase could be a promising target for treating microsatellite instable cancers. These cancers tend to respond well to immunotherapy, but patients have few other options beyond those treatments. Of the two studies published in Nature on the same day, one was from Mathew Garnett’s lab at the Wellcome Sanger Institute, while the other was led by Adam Bass, who at the time was at the Dana-Farber Cancer Institute and now leads translational cancer research at Novartis. Using CRISPR screening, researchers from both groups found that Werner helicase was needed in microsatellite instable cancer models but dispensable in models that were microsatellite stable. “When you knock out Werner helicase, in 48 hours, the cells are dead,” Garnett said. “All their DNA is just shattered, and it’s really phenomenal. You had this sense when you saw this genome shattering, that there was something really profound happening to these cells.” There are several other synthetic lethality programs in early-stage trials. Corcoran said he has yet to see results from another class of synthetic lethal drugs that matches the success of PARP inhibitors, though many of these efforts are still early and have yet to report clinical data. One closely-watched effort to leverage synthetic lethality is targeting a protein called PRMT5 in cancers with mutations known as MTAP deletions. This is an area in which Bristol Myers Squibb, Amgen, Ideaya and others are all working on early-stage programs, though readouts so far have been mixed . Eli Lilly and Foghorn Therapeutics last year began a Phase 1 trial for a SMARCA2 inhibitor, which they are studying in patients with SMARCA4-mutated cancers. “Imagine you’re riding a bicycle — it’s a bicycle with two wheels — and one of the wheels is lost, and now you’re riding a unicycle,” Foghorn CEO Adrian Gottschalk said. And so giving a SMARCA2 inhibitor to one of these patients is like taking a stick to the cancer cell’s remaining wheel, he said.

Science最新研究解开大脑学习之谜、新研究揭示胆汁酸代谢在骨关节炎中起着关键作用、为什么我们的腰围总是在中年时变粗？Science论文揭示背后秘密 2025年4月份已经结束，4月份Science期刊又有哪些亮点研究值得学习呢？小编对此进行了整理，与各位分享。 1.突触可塑性新发现！Science最新研究解开大脑学习之谜 DOI: 10.1126/science.ads4706 我们如何学会新技能？大脑如何编码新信息？这些问题的答案指向了大脑的突触可塑性——神经元之间连接强度的变化。然而，长期以来，科学家们对大脑在学习过程中如何选择特定突触进行可塑性改变的规则知之甚少。如今，加州大学圣地亚哥分校的研究团队在《Science》杂志上发表了一项突破性研究，揭示了个中奥秘。 研究团队利用先进的双光子成像技术，对小鼠运动皮层中的突触活动进行了实时观测。他们发现，在学习过程中，神经元的不同树突区域遵循着截然不同的突触可塑性规则。具体来说，顶树突的可塑性是由局部突触的协同活动驱动的，而基底树突的可塑性则与神经元的动作电位活动密切相关。这种差异表明，单个神经元在学习过程中同时运用了多种可塑性规则，且这些规则在神经元的不同区域发挥作用。 “这一发现从根本上改变了我们对大脑如何解决‘学分分配问题’的理解。”研究通讯作者Takaki Komiyama教授说道，“我们过去认为突触可塑性在整个大脑内遵循统一的规则，但这项研究表明，单个神经元在不同的亚细胞区域并行执行不同的计算任务。” 2.Science：新研究揭示胆汁酸代谢在骨关节炎中起着关键作用 DOI: 10.1126/science.adt0548 骨关节炎（OA）是影响数千万美国成年人的最常见疾病之一，传统上被认为是一种主要由机械磨损引起的疾病。在一项新的研究中，耶鲁大学骨科与康复学系研究副主任Chuan-Ju Liu博士及其团队揭示了令人信服的证据，表明涉及胆汁酸代谢和胰高血糖素样肽 1（GLP-1）信号传导的肠道-关节轴在骨关节炎的发展过程中起着关键作用。这项研究标志着在理解骨关节炎的代谢基础方面取得了重大进展，为治疗开辟了令人兴奋的新途径。相关研究结果发表在Science杂志上。 肠道菌群-GUDCA-肠道FXR–GLP-1关节通路为骨关节炎提供了潜在的治疗方法 Liu认为，这项新的研究强调了胆汁酸，尤其是甘氨熊去氧胆酸（glycoursodeoxycholic acid, GUDCA），代谢在骨关节炎中的关键作用。他们的临床前研究表明，GUDCA的减少会加速骨关节炎的进展，而补充GUDCA则会减轻这些影响。这种保护作用主要是由于抑制了肠道法尼类固醇 X 受体（farnesoid X receptor, FXR）。 FXR是胆汁酸合成、脂质和葡萄糖代谢的关键调节因子，当它受到抑制时，会增强肠道干细胞的增殖。这导致分泌 GLP-1（一种进入血液并到达关节的激素）的肠内分泌细胞数量增加，从而通过调节产生软骨的软骨细胞和其他关节细胞来防止骨关节炎。 肠道微生物组，尤其是鲍氏梭菌（Clostridium bolteae），在 FXR 信号传导和 GLP-1 调节中发挥着重要作用。Liu 指出，这项研究证实鲍氏梭菌破坏了胆汁酸平衡，影响了 GLP-1 的分泌，并改变了骨关节炎进展。肠道微生物组与关节健康之间的这种错综复杂的联系强调了通过靶向肠道衍生途径治疗骨关节炎的潜力。 3.为什么我们的腰围总是在中年时变粗？Science论文揭示背后秘密：脂肪祖细胞在衰老时大量产生新的脂肪细胞 DOI: 10.1126/science.adj0430 脂肪组织在调节各种激素和代谢过程中起着至关重要的作用，并表现出实质性的成分和表型可塑性。从中年到衰老早期，成年人的内脏脂肪组织质量通常会显著增加。内脏脂肪过多被认为是各种代谢紊乱的重要危险因素。脂肪组织的积累通过两种主要机制发生：脂肪细胞肥大和脂肪生成。然而，早期衰老导致脂肪组织积累的机制仍然知之甚少。 如今，来自希望之城和加州大学洛杉矶分校的一项临床前研究揭示了与年龄相关的腹部脂肪背后的细胞罪魁祸首，为为什么我们的腹部随着中年而变宽提供了新的见解。这一发现也为未来预防腹部松弛和延长健康寿命的疗法提供了一个新的靶点。相关研究结果发表在《Science》杂志上。 脂肪生成有助于与年龄相关的内脏脂肪组织积累 通过与论文共同通讯作者、加州大学洛杉矶分校的Xia Yang博士及其团队合作，Wang及其团队进行了一系列随后在人类细胞上得到过验证的小鼠实验。Wang 和她的同事们专注于白色脂肪组织（WAT），这是与年龄相关的体重增加的脂肪组织。虽然众所周知，脂肪细胞会随着年龄的增长而变大，但是Yang团队和Wang团队猜测白色脂肪组织也会通过产生新的脂肪细胞而膨胀，这意味着它可能具有无限的生长潜力。 为了验证他们的假设，他们专注于脂肪祖细胞（adipocyte progenitor cell，APCs），这是白色脂肪组织中产生脂肪细胞的一个干细胞群体。Wang团队首先将来自年轻和年老小鼠的APC细胞移植到第二组年轻小鼠中。来自年老小鼠的APC细胞迅速产生了大量的脂肪细胞。然而，当他们将年轻小鼠的APC移植到年老小鼠体内时，这些APC细胞并没有产生许多新的脂肪细胞。他们的研究结果证实，无论宿主的年龄如何，较老的APC细胞都有能力独立制造新的脂肪细胞。 4.Science：新突破！阻断癌症中的EPO信号传导可有效根除小鼠体内的肝脏肿瘤 DOI: 10.1126/science.adr3026 在一项新的研究中，斯坦福大学医学中心病理学和医学教授Edgar Engleman医学博士及其团队发现近40年前发现的一种能刺激红细胞生成的蛋白质在抑制免疫系统对癌症的反应方面发挥着令人惊讶的关键作用。相关研究结果发表在Science杂志上。论文第一作者是David Kung Chun Chiu博士。 巨噬细胞中的EPO/EPOR信号介导非炎症性肿瘤免疫型 阻断这种蛋白质的活性会使小鼠以前的免疫耐受性肝脏肿瘤（冷肿瘤）变成充满抗癌免疫细胞的“热”肿瘤。当与进一步激活这些免疫细胞对抗癌症的免疫疗法相结合时，这会导致大多数小鼠的现有肝脏肿瘤完全消退。这些接受治疗的小鼠在实验期间存活。相比之下，对照组小鼠只存活了几周。 Engleman说，“这是我们对癌症免疫系统如何开启和关闭的理解的一个根本性突破。我对这一发现感到非常兴奋，我希望靶向我们发现的这一机制的治疗方法能够迅速进入人体试验。” 尽管这项研究是在小鼠身上完成的，但有强有力的迹象表明，这种称为促红细胞生成素（erythropoietin, EPO）在许多类型的人类癌症中起着类似的作用。 5.Science：挑战常规！新研究揭示一条神经免疫回路介导癌症恶病质中的"冷漠" DOI: 10.1126/science.adm8857 许多癌症患者在生命即将结束时所经历的疲劳和缺乏动力被视为他们身体健康下降和体重极度减轻的不可避免的后果。但是一项来自华盛顿大学医学院的新研究挑战了这一长期以来的假设，表明这些行为变化源于大脑中特定的炎症感应神经元（inflammation-sensing neuron）。为此，他们确定了癌症相关炎症与晚期癌症中的动机丧失之间的直接联系。相关研究结果发表在Science杂志上。 癌症相关恶病质（cancer-linked cachexia）是一种导致肌肉萎缩和体重减轻的典型疾病。研究人员研究了患有癌症相关恶病质的小鼠，发现了大脑中一种以前未被识别的通路。这条通路感知炎症并积极抑制多巴胺——动机的关键驱动因素，从而导致冷漠和动力丧失。阻断该通路恢复了动力，尽管癌症和体重减轻仍在继续。这表明冷漠可以与癌症本身分开治疗。 论文共同通讯作者、华盛顿大学医学院神经科学教授和精神病学教授Adam Kepecs博士说，“这项研究的意义是深远的。我们发现了一种直接的大脑机制，炎症通过该机制驱动癌症患者的冷漠，我们能够在患有恶病质的小鼠中恢复正常的动机，尽管随着癌症的进展，炎症仍在持续。” 6.帕金森的幕后黑手找到了？Science封面研究解密：帕金森病溶酶体调控枢纽Commander复合体 DOI:10.1126/science.adq6650 你有没有注意到，身边的老年人中，有些人手会不由自主地颤抖，走路时步伐变得缓慢而僵硬，甚至拿筷子夹菜都会显得吃力？这些看似普通的衰老现象，其实可能是帕金森病（Parkinson’s Disease, PD）的早期信号。帕金森病作为一种常见的神经退行性疾病，正在悄悄影响全球超过1000万人的生活。而更令人揪心的是，这种疾病目前无法治愈，患者只能通过药物或手术延缓病情进展。 COMMD3敲除降低溶酶体GCase活性 然而，科学的探索从未停止。近年来，科学家们发现，帕金森病的发病机制与细胞内的“垃圾处理系统”——溶酶体的功能障碍密切相关。而这篇发表在《Science》杂志上的研究，更是揭示了一个令人兴奋的新发现：一个名为COMMD3的基因及其相关的蛋白质复合体，可能是解开帕金森病谜团的关键线索。这篇文章不仅为帕金森病的发病机制提供了全新的视角，还为未来的治疗策略打开了新的大门。 帕金森病的发病机制复杂，目前已知的一个重要风险因素是GBA1基因的突变。GBA1基因编码的是一种名为葡萄糖脑苷脂酶（GCase）的溶酶体酶，它负责分解细胞内的脂质垃圾。如果GBA1基因出了问题，溶酶体的“清洁能力”就会下降，导致垃圾堆积，最终引发神经细胞的死亡。 然而，科学家们发现，GBA1基因突变并不是帕金森病的唯一原因。许多携带GBA1突变的人并没有发病，而一些没有GBA1突变的人却患上了帕金森病。这说明，一定还有其他基因在“帮凶”角色。为了找到这些隐藏的“帮凶”，研究团队采用了CRISPRi基因筛选技术，在全球范围内扫描了数万个基因，试图找出那些能够调节溶酶体功能的关键基因。 7.Science：打破常规！CD8 T细胞启动涉及两个不同的阶段 DOI: 10.1126/science.adq1405 在一项新的研究中，来自维尔茨堡大学马克斯-普朗克系统免疫学研究小组的一个团队发现了免疫反应的一个以前未知的阶段。他们的研究结果挑战了关于T细胞启动（T-cell priming）过程的长期假设。这些新的见解对疫苗和细胞免疫疗法的开发具有重要意义。相关研究结果发表在Science期刊上。 CD8 T细胞启动涉及两个不同的阶段 这个由Wolfgang Kastenmuller和Georg Gasteiger领导的研究团队采用了创新的显微镜技术来观察特定的免疫细胞（称为T细胞）在病毒感染期间是如何被激活和增殖的。他们的发现揭示了新的机制：免疫系统以比以前认为的更有针对性的方式扩增它的防御细胞。 免疫系统面临着一项艰巨的任务，即从极其多样化的T细胞库中迅速识别出能够特异性识别特定病原体的T细胞。这些选定的T细胞然后在“T细胞启动”过程中进行克隆扩增。 论文共同第一作者Deeksha Seetharama解释说，“我们发现T细胞激活不仅涉及一个阶段，还涉及两个不同的阶段。” 论文共同第一作者Katarzyna Jobin详细阐述道，“虽然T细胞启动的第一阶段用于激活一系列特定T细胞，但我们新发现的第二阶段负责选择和特异性扩增能够最有效识别病原体的T细胞。这确保了免疫反应达到最佳效率。” 8.Science：将微生物疫苗与竞争菌株组合使用可有效杀死肠道中的致病菌 DOI: 10.1126/science.adp5011 在一项新的研究中，苏黎世联邦理工学院和牛津大学病理学院的教授Emma Slack与巴塞尔大学生物中心教授Médéric Diard领导的一个国际研究团队展示了如何配制出针对肠道病原体的高效口服疫苗：即不仅要接种疫苗，还要将其与无害细菌结合，这些细菌与致病微生物竞争食物，从而饿死它们。他们在小鼠中证实了这一点。相关研究结果发表在Science杂志上。 通过他们的综合方法，该研究团队不仅能够防止沙门氏菌在小鼠体内定植，而且能够有效地对付已经建立的大肠杆菌。在这两种情况下，接种疫苗或单独使用无害细菌的影响都要小得多。 为了使竞争菌株成功地与致病微生物竞争，至关重要的是它们必须在尽可能相似的条件下生长，即它们必须生活在肠道的同一部分，能够应对相同的酸度和氧气水平，并使用相同的营养物。 该研究团队相应地选择或生产了合适的竞争菌株。在这项研究的框架内，他们在实验室证明，在基因工程的帮助下，有可能产生一种高效的沙门氏菌竞争菌株。不过，如果巧妙地选择和组合天然存在的菌株，这也可以在没有基因工程的情况下完成，正如他们用三种天然存在的大肠杆菌菌株的混合物所证明的那样。 9.Science：雌激素可刺激脑膜Treg细胞产生阿片类物质来抑制疼痛 DOI: 10.1126/science.adq6531 在一项新的研究中，来自加州大学旧金山分校的研究人员发现了一种通过免疫细胞起作用的新机制，并指出了治疗慢性疼痛的不同方法。他们指出，雌激素可以通过使脊髓附近的免疫细胞产生阿片类物质（opioids）来抑制疼痛。这会在疼痛信号到达大脑之前阻止它们。这一发现可能有助于开发治疗慢性疼痛的新方法。这也可能解释为什么一些止痛药对女性比男性更有效，以及为什么绝经后的女性会经历更多的疼痛。相关研究结果发表在Science杂志上。 这项研究揭示了调节性T细胞（Treg）的全新作用，而Treg细胞以减少炎症的能力而闻名。论文第一作者、加州大学旧金山分校博士后Elora Midavaine博士说，“这些细胞受到雌激素和黄体酮的性别依赖性影响，并且与任何免疫功能都无关，这一事实非常不寻常。” 当神经元（通常靠近皮肤）感觉到可能引起疼痛的东西时，这种交流就开始了。然后，这些神经元向脊髓发送信号。Kashem及其团队发现，脊髓下部周围的脑膜含有丰富的Treg细胞。为了了解它们的功能，他们用毒素清除了这些细胞。由此取得的效果是惊人的：没有Treg细胞，雌性小鼠对疼痛变得更加敏感，而雄性小鼠则没有。这种性别特异性差异表明，雌性小鼠更依赖Treg细胞来控制疼痛。Kashem说，“这既令人着迷又令人费解。这实际上让我最初持怀疑态度。” 进一步的实验揭示了Treg细胞与雌激素之间的关系，这是以前没有人见过的：雌激素和黄体酮促使Treg细胞大量产生止痛的脑啡肽（enkephalin）。 10.Science：利用Perturb-multiome方法确定转录因子如何驱动血细胞生长和成熟 DOI: 10.1126/science.ads7951 在一项新的研究中，来自丹娜法伯癌症研究院和波士顿儿童癌症与血液疾病中心的一个研究团队确定了一种新的方法来理解某些称为转录因子的蛋白质如何决定哪些基因程序将驱动血细胞生长和成熟。相关研究结果发表在Science杂志上。 这种称为Perturb-multiome的方法使用CRISPR一次敲除许多血细胞中单个转录因子的功能。然后，研究团队对每个细胞进行单细胞分析，以测量这种基因编辑的效果，包括确定哪些基因开启或关闭，哪些基因是可访问的（基于表观遗传标记）。他们将该工具应用于未成熟的血细胞，以识别重要的转录因子和编码它们的DNA区域，其中这些转录因子和DNA区域强烈影响血细胞的发育。 他们发现，他们确定的许多对驱动血细胞生产很重要的DNA区域也是已知携带与血液疾病相关的突变的区域。他们确定为重要的DNA区域占基因组的不到0.3%，但它们解释了对血细胞特征和特化的不成比例的很大一部分遗传影响。

Keytruda's Keynote-689 marks the first positive trial in more than two decades in resected locally advanced head and neck squamous cell carcinoma. Ending a 20-year-plus drought, Merck & Co.’s Keytruda demonstrated that its use around surgery can reduce the risk of certain head and neck cancers from returning.Continuous use of Keytruda—both before and after surgery—reduced the risk of recurrence or death by 27% in patients with stage 3 or 4a, resected, locally advanced head and neck squamous cell carcinoma (HNSCC), according to results from the phase 3 Keynote-689 trial presented at the American Association for Cancer Research Annual Meeting 2025.In the study, Keytruda was added to postoperative radiotherapy with or without chemo. Investigators compared the perioperative Keytruda regimen with the sans-Keytruda standard treatment.Keynote-689 marks the first positive trial in more than two decades in resected locally advanced HNSCC, making Keytruda the first PD-1 inhibitor to mount such a benefit.The study’s findings suggest that the Keyturda regimen represents a new standard of care in this disease setting, Ravindra Uppaluri, M.D., Ph.D., from Brigham and Women’s Hospital and Dana-Farber Cancer Institute, said during a press conference Sunday. Uppaluri is a co-principal investigator of Keynote-689.The 27% event-free survival (EFS) improvement, though statistically significant, isn’t numerically among Keytruda’s best performances in its use around surgery, an approach known as perioperative treatment. In 2023, Keytruda won its perioperative non-small cell lung cancer approval after slashing the risk of disease recurrence, worsening or death by 42% when added to presurgical chemo alone.The 27% number is still clinically meaningful, Marjorie Green, M.D., Merck’s head of oncology global clinical development, said in an interview with Fierce Pharma.At three years, 57.6% of patients in the Keytruda arm remained recurrence free, versus 46.4% in the control arm. That 11.2-percentage-point absolute difference is also clinically meaningful for patients, she added.“There have been uptakes and adoptions of therapies for 2% to 3% absolute difference in outcomes, because we know most of the recurrences that have happened on the study were distant,” which increases the risk of death, she said.Further, Keytruda’s 51.8-month median EFS time was notably longer than the control arm’s 30.4 months. Despite the overall trial win, there remains a question about whether Keytruda is appropriate for patients whose tumors have low to no expression of PD-L1.The magnitude of Keytruda’s EFS benefit deteriorated as patients with lower levels of PD-L1 were included in the analysis. In patients with PD-L1 expression at a combined positive score (CPS) of 10 or above, the EFS risk reduction reached 34%. The number dropped to 30% when those with at least 1 CPS score were included, and then to 27% when PD-L1-negative disease was also counted.Green wouldn’t disclose what level of PD-L1 coverage Merck is seeking in the drug’s FDA label. She did note that Keytruda’s existing perioperative indications in other curative disease settings are broad approvals across the PD-L1 spectrum. In this HNSCC setting, patients with CPS of 10 or greater make up about 65% of the population, and only 5% have CPS below 1. Because of the small number of patients, it would be hard to draw conclusions about the PD-L1-negative group, Uppaluri said during the press conference.“Given that as a whole, I would say yes, this should be for all participants,” Uppaluri said.Another question that Keynote-689 cannot conclusively answer is whether Keytruda is necessary both before and after surgery. That question is even more relevant because Roche’s PD-L1 inhibitor Tecentriq failed in its own study when used as an adjuvant therapy after head and neck cancer surgery.Uppaluri admitted that the contribution of components is clearly a limitation of the study. Before Keynote-689 was launched, some investigator-initiated studies showed the potential of a perioperative regimen. Plus, there’s been a theory that giving a checkpoint inhibitor early before surgery—when the immune system is more robust and the tumors intact—may lead to better outcomes, Green noted.On a key secondary endpoint, Keytruda recorded a 9.4% major pathological response rate—defined as 10% or lower residual invasive cancer cells in resected tissues—versus 0% in the standard-of-care arm.Green acknowledged that 9.4% is a fairly small number. But it could indicate that adjuvant Keytruda provided some contribution to the EFS benefit.Neoadjuvant treatment with Keytruda appeared to have led to fewer uses of chemo in the adjuvant setting because more patients were deemed to have lower risk post-surgery.Green called that element out because removing the need for chemo could mean better tolerability. In Keynote-689, the Keytruda arm recorded numerically fewer chemo-related side effect incidents such as severe skin reactions.Finally, data on whether Keytruda could extend patients’ lives remained immature. Keytruda showed a favorable 28% reduction in the risk of death in the CPS 10 or above population. Because the statistical significance bar was not met, testing of this endpoint in the rest of the study population was not formally performed, and additional follow-up is ongoing. Merck’s application based on Keynote-689 is under FDA priority review with a target decision date of June 23, 2025.