Ivonescimab

iStock, Sean Pavone Beginning this week in Chicago, the American Association for Cancer Research’s annual conference will feature presentations that could have far-reaching implications for breast and blood cancers and more. Kicking off Friday and running through June 3 at McCormick Place Convention Center in Chicago, the 2025 annual meeting of the American Association for Cancer Research will include some of the most cutting-edge developments in cancer, which experts believe could have far-reaching implications across the industry and for medical practice. “As we head into the 2025 ASCO Annual Meeting, there are several key breast cancer trials that reflect major advancements in how we approach treatment,” Jason Mouabbi, assistant professor of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center, told BioSpace in an email. Meanwhile, Lore Gruenbaum, chief scientific officer of The Leukemia & Lymphoma Society, is looking forward to a host of blood cancer-related presentations, including those that explore minimal residual disease (MRD) testing in multiple myeloma—a development she called “exciting.” MRD testing, Gruenbaum added, “will likely change clinical development strategies for novel agents and may provide significant time savings” for drugmakers. Besides breast and blood cancers, many of the late-breakers at ASCO 2025 are focused on melanoma, gastric, prostate and lung cancers. Breast and Blood Cancers Amid the variety of presentations at ASCO 2025, the buzz around breast and blood cancers stands out. One such attention-grabber is Takeda and Protagonist Therapeutics’ investigational hepcidin mimetic rusfertide, which the partners are developing for polycythemia vera, a rare but potentially deadly blood malignancy. “Rusfertide is a promising emerging treatment option,” Gruenbaum told BioSpace, noting that the molecule could provide an effective alternative for patients who do not adequately respond to standard therapies. In March, Takeda and Protagonist released topline data from their Phase III VERIFY study, which showed that rusfertide met its primary efficacy endpoint, eliciting treatment responses in 77% of patients versus 33% of placebo counterparts. Rusfertide likewise aced key secondary endpoints, including reducing phlebotomies, boosting hematocrit control and improving patient-reported outcomes. While Gruenbaum had not yet seen the ASCO abstract , “the data available so far indicate the potential for Rusfertide to significantly reduce the need for phlebotomies and improve hematocrit control in patients with polycythemia vera,” she said, adding that an improvement in quality of life data “could be very meaningful to patients.” VERIFY has been granted a plenary spot at the conference. In breast cancer, several presentations have drummed up considerable pre-conference interest. One of these is AstraZeneca’s Phase III SERENA-6 trial, which MD Anderson’s Mouabbi said is “one of the most anticipated studies at ASCO.” SERENA-6 combines the pharma’s oral SERD camizestrant with a CDK4/6 blocker to treat patients with HR-positive, HER2-negative advanced breast cancer with emergent ESR1 mutations. High-level outcomes posted in February showed the camizestrant regimen significantly improved progression-free survival in these patients versus standard-of-care aromatase inhibitors. AstraZeneca did not reveal specific data at the time—but will do so now at ASCO. “This trial is especially compelling because it’s the first to show a statistically significant improvement in progression-free survival in this setting, without requiring radiographic progression,” Mouabbi told BioSpace . “It’s a potential paradigm shift in how we manage endocrine resistance.” Like VERIFY, SERENA-6 is also a plenary presentation . AstraZeneca will also have additional Phase III data from DESTINY-Breast09, which will be “another standout” presentation, according to Mouabbi. The trial centers on the antibody-drug conjugate Enhertu—which AstraZeneca is developing in partnership with Daiichi Sankyo—testing it with or without Roche’s Perjeta as a first-line option in patients with HER2-positive metastatic breast cancer. Last month, the partners announced that Enhertu significantly improved progression-free survival in Destiny-Breast09, though again without providing specific data. “This is a significant development for HER2+ patients, offering a less chemotherapy-intensive option with robust efficacy,” Mouabbi said. Other notable breast cancer presentations, according to Mouabbi, include Merck and Gilead’s ASCENT-04/KEYNOTE-D19 , which combines the anti-TROP2 ADC Trodelvy with the mega-blockbuster Keytruda, and Pfizer and Arvinas’ VERITAC-2 trial, which in March returned mixed results for their investigational PROTAC degrader vepdegestrant. Bi – and Trispecifics Aside from specific presentations, experts are also looking forward to advancements in various treatment modalities. Such developments could give rise to new treatment opportunities for what Scott Kopetz, professor of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center, called “cold tumors”—those that are unlikely to elicit an immune response and are, in turn, less susceptible to immunotherapies. In particular, Kopetz has his eye on bispecific antibodies, which he said could usher in “a new era in VEGF-targeted therapies.” These emerging therapies “not only inhibit angiogenesis [the formation of new blood vessels] but also enhance immune responses,” he continued, noting that such a mechanism could lead to “promising efficacy and safety in advanced solid tumors.” As a result, bispecific antibodies could yield “potential breakthroughs” in the treatment of immunologically cold tumors, such as castration-resistant prostate and gallbladder cancers, Kopetz said. According to Gruenbaum, bispecifics, and now also trispecific antibody platforms, could likewise open up new treatment avenues for blood cancers. ASCO, she continued, will witness initial clinical data for two trispecifics, including Johnson & Johnson’s JNJ-5322 and Ichnos Glenmark Innovation’s ISB-2001, both of which are being developed for relapsed/refractory multiple myeloma. There is also now a growing number of bispecific therapies for blood cancers, some of which are inching toward regulatory approval, which they could secure “in the near future,” Gruenbaum said. Drug developers are also starting to move these agents into earlier lines of therapy, she added. For David Piwnica-Worms, chair of Cancer Systems Imaging at MD Anderson, ASCO 2025 will be an opportunity to learn about some of the latest developments in radiopharmaceuticals. “We’re really seeing two trends,” he told BioSpace in an email. The first deals with identifying biomarkers for cancers earlier in the disease cycle, while the second is focused on identifying novel isotopes. Both of these trends, Piwnica-Worms said, underscore that “this is an exciting time” for the radiopharma space, since “the field is rapidly expanding with new isotopes and new molecular targets.” China in Focus In a May 21 note to investors, analysts at Truist Securities made an astute observation: nearly a third of presentations at ASCO involve assets that came from Chinese companies. The considerable presence of China at the conference reflects “the country’s increase in R&D efforts, as per the Truist note. “China’s biotech innovation footprint has clearly expanded on the global stage.” Christiana Bardon, co-managing partner at biotech investment firm MPM BioImpact, made a similar observation. In an email to BioSpace , she pointed out that whereas Chinese companies “historically have focused on making ‘fast-follower drugs,” they are now taking an active leadership role in innovation and are advancing “disruptive, first-in-class medicines.” Bardon pointed to Summit Therapeutics’ and its Chinese partner Akeso’s PD-1/VEGF bispecific ivonescimab, “which may displace Keytruda’s dominant position in cancer immunotherapy.” According to Bardon, many Big Pharma players have been playing catch-up to Summit and Akeso in this space: “Since Summit Therapeutics in-licensed ivonescimab from Akeso, we have seen BioNTech, Merck, and Pfizer reach for additional PD(L)1 x VEGF assets from China.” Bardon sees no real problem with this, however. “Increasing innovation will ultimately benefit patients, regardless of where it originates,” she said. Paul Moore, chief scientific officer at Zymeworks, agreed, noting that China’s ascent as a worldwide leader in cancer innovation creates a “more competitive environment” across the oncology space, in turn pushing U.S. companies to be more “innovative and efficient.” Drugmakers, Moore offered, should become more “intentional” about their pipelines, look for opportunities to differentiate themselves and “prioritize thoughtful trial design.” Studies should pay particular consideration to the underlying biological mechanisms of diseases, while also taking advantage of companies’ respective “unique areas of expertise,” he added. Such an approach, Moore explained, is likely to result in drug candidates “with novel biological mechanisms and strong clinical potential.” Development efficiency will no longer be enough, Moore added. “Real progress will come from therapies...that offer something new and impactful for patients.” In all, he said that healthy competition between global leaders in biopharma innovation could lead to a “steel-sharpens-steel phenomenon.”

▎追溯HER3 ADC在第一三共开发HER3-DXD后，行业内有不少跟进，在百利天恒EGFR/HER3 ADC被重金引进后，该双抗也成为开发重点。HER3这个靶点表达不高，几乎是研发界的共识，而ADC对于抗原表达有一定要求，又有这么多开发的，跟风式开发或引进，成为影响企业决策的主要因素。第一三共在2025年ASCO，公布HER3-DXD相关数据：Patritumab deruxtecan（HER3-DXd）用于第三代EGFR TKI治疗后耐药的EGFR突变型（EGFRm）晚期非小细胞肺癌（NSCLC）患者：HERTHENA-Lung02 III期研究背景：在接受第三代EGFR酪氨酸激酶抑制剂（TKI）治疗后出现疾病进展的EGFR突变型晚期NSCLC患者中，现有疗法疗效有限。HER3-DXd 是一种抗体药物偶联物（ADC），由靶向HER3的人源化单克隆抗体与拓扑异构酶I抑制剂通过稳定的四肽可切割连接子连接组成，在 HERTHENA-Lung01 研究中显示出有前景的疗效。方法：HERTHENA-Lung02（NCT05338970）为一项III期、随机、开放标签研究，比较HER3-DXd与以铂类为基础的化疗（PBC）在EGFR突变型（Ex19del或L858R）NSCLC患者中在第三代EGFR TKI治疗失败后的疗效。主要终点为独立影像评估委员会（BICR）评估的无进展生存期（PFS），采用分层log-rank检验。关键次要终点为总生存期（OS）。结果：共586名患者被随机分配至HER3-DXd或PBC组（中位年龄64岁，女性占61%，亚洲人占60%）。截至2024年5月31日的PFS主要分析数据截止时间，中位随访时间为10.7个月（范围5.2-21.9个月），HER3-DXd组与PBC组的治疗持续时间分别为5.5个月（0.7-16.8）和4.6个月（0.7-16.5）。HER3-DXd在PFS方面相较PBC具有统计学上的显著改善（HR=0.77；95% CI：0.63-0.94；P=0.011）。HER3-DXd组与PBC组的中位PFS分别为5.8个月（95% CI：5.5-6.8）和5.4个月（95% CI：5.0-5.6）。HER3-DXd与PBC在不同时间点的PFS率如下：6个月：50% vs 38%；9个月：29% vs 19%；12个月：18% vs 5%。客观缓解率（ORR）为：HER3-DXd：35.2%（95% CI：29.7%-40.9%）；PBC：25.3%（95% CI：20.4%-30.6%）。中位缓解持续时间（DOR）分别为：HER3-DXd：5.7个月（95% CI：5.1-7.3）；PBC：5.4个月（95% CI：4.1-5.6）。OS数据仍不成熟。在基线伴有脑转移的患者中（由中枢神经系统BICR评估）：HER3-DXd组（n=105）中位颅内PFS为5.4个月（95% CI：4.0-5.9）PBC组（n=95）为4.2个月（95% CI：2.8-5.0）（HR=0.75；95% CI：0.53-1.06）安全性结果：HER3-DXd组所有患者（100%）和PBC组的99%均出现了治疗相关不良事件（TEAE）因TEAE导致停药的比例：HER3-DXd为11%（33例），PBC为10%（27例）最常见的不良事件包括：恶心：HER3-DXd 57.9%（168例），PBC 42.1%（118例）血小板减少：HER3-DXd 52.1%（151例），PBC 27.1%（76例）疲劳：HER3-DXd 50.3%（146例），PBC 42.1%（118例）3级及以上TEAE发生率：HER3-DXd：73%，PBC：57%。主要由于HER3-DXd中3级及以上血小板减少较多（30% vs 7.9%）每组各有1例3级以上出血事件与3级血小板减少相关。HER3-DXd组中有14例患者（5%）出现了被判定与药物相关的间质性肺病（ILD），包括：11例1/2级，1例3级，2例5级（致命）。以上数据展现出来的HER3-DXD有一定效果，但很难在一众ADC中有出彩，同时其OS本身可能也很难有统计学意义。PFS优势并不明显，HER3-DXd组与PBC组的中位PFS分别为5.8个月和5.4个月。做过ADC，大概都会对HER3的表达有一个大概的概念，这并不算是一个表达十分优异的靶点。但不得不承认ADC，在一定程度上是依赖于抗原的表达量的。众所周知，HER2阳性乳腺癌中的HER2是非常高的表达量，目前少有靶点可以与其匹敌，因此它在临床上就表现得非常亮眼。而目前HER3  DXD在OS上的获益还要等后期数据的披露。2024年9月17日，第一三共和默沙东公布HER3-DXD（ patritumab deruxtecan ）HERTHENA-Lung02 三期临床数据。Patritumab deruxtecan 在 EGFR 突变的非小细胞肺癌患者中表现出统计学上显著的无进展生存期改善，这些患者在接受 EGFR TKI 治疗后，尚未得到充分的治疗需求。HERTHENA-Lung02三期临床试验评估了Patritumab deruxtecan在接受过EGFR TKI治疗的局部晚期或转移性EGFR突变非小细胞肺癌（NSCLC）患者中的疗效。该试验达到了无进展生存期 (PFS) 的主要终点，与铂类加培美曲塞诱导化疗和培美曲塞维持化疗相比，有统计学上显著改善。总生存期 (OS) 数据尚不成熟，试验将继续进一步评估次要终点 OS。非小细胞肺癌约占全球所有肺癌的85%，其中高达70%的病例在晚期阶段确诊，全球14%至38%的非小细胞肺癌肿瘤发生EGFR激活突变。在接受EGFR突变转移性NSCLC的初次治疗后，许多患者经历疾病进展，当前可用的二线治疗非常有限。HERTHENA-Lung02试验中的安全性特征与之前在肺癌临床试验中观察到的Patritumab deruxtecan一致，未发现新的安全信号。大多数间质性肺疾病（ILD）事件为低级别（1级和2级）。观察到两例5级ILD事件。HERTHENA-Lung02是一项全球多中心、开放标签的3期试验，评估帕曲妥珠单抗德鲁昔单抗（每三周5.6   mg/kg）与四个周期的培美曲塞和铂类化疗在EGFR激活突变（外显子19缺失或L858R）的转移性或局部晚期NSCLC患者中的疗效和安全性。这些患者在接受第三代EGFR  TKI治疗（如奥希替尼、拉泽替尼等）失败后纳入研究。ADC具有较为明显的PFS获益，但OS是否获益逐步成为一个悬而未决的答案。如今对待ADC的看法也逐渐成熟，单纯的ORR，PFS，已经不足以证明ADC的对于OS的获益。或许未来还要进一步验证联合PD1抑制剂作为一线治疗是否能够超越PD1抑制剂联用化疗的效果，如果收益较小，可能还是会影响ADC的市场推广。目前，单药ADC仍然以末线治疗为主，走向前线治疗需要联用。如今第一三共和默沙东只公布了初步的PFS获益，OS获益还未成熟，使得HER3 DXD能否完全被接受认可还有一段路要走。不过凭借二期HERTHENA-Lung01研究数据，2023年12月22日，第一三共和默沙东共同宣布HER3-DXd（patritumab  deruxtecan）的生物制品许可申请（BLA）获FDA受理并予以优先审评，适应症为既往至少接受过两种系统治疗的EGFR突变型局部晚期或转移性非小细胞肺癌（NSCLC）。但很不幸，2024年7月，第一三共/默沙东的靶向HER3的抗体偶联药物（ADC）HER3-DXd（patritumab deruxtecan）的上市申请被FDA延期批准，其适应症为用于治疗既往至少接受过两种系统治疗的EGFR突变型局部晚期或转移性非小细胞肺癌（NSCLC）患者。据悉，被延期的原因主要是由于第三方制造设施检查相关的调查结果，其疗效和安全性数据并未存在问题。TROP2 DXD在非小细胞肺癌OS的失利，给ADC赛道蒙上一种不确定性。当然一定程度上还是靶点的因素，占据主要地位。2025年5月20日，辉瑞60.5亿美元引进三生制药PD-1/VEGF双抗，引爆行业，顺便提起一起陈年旧事，当年三生要剥离PD-1/TGFB双抗，PD-1/LAG-3双抗和PD-1/VEGF双抗几条管线出来，成立丹生生物，后来投资机构放弃这次投资机会，这笔交易因此就没有达成。如今成为很多人口中的笑谈。在当时的背景下，估值一亿美元，不投也是在情理之中，尤其PD-1/TGFB双抗这条管线，M7824都失败了，吸引力下降，PD-1/LAG-3双抗也没有很强的证据，包括PD-1/VEGF双抗在2022年也饱受争议，22年我写文章，夸AK112，评论区不少质疑我的，biotech不同于药企，药企有持续现金流，而biotech需要不断融资，试错机会并不多。而在这里面，康方起了非常重要的作用，其实该赛道都占了康方的光，也就是说，没有康方，几乎就没有现在PD1/VEGF双抗这些交易。但如果信达的363，再走出来，或者更优化的药物走出来，现在的交易，或许又是笑话，谁也不能保证。公众号内回复“ADC”或扫描下方图片中的二维码免费下载《抗体偶联药物：从基础到临床》的PDF格式电子书！公众号已建立“小药说药专业交流群”微信行业交流群以及读者交流群，扫描下方小编二维码加入，入行业群请主动告知姓名、工作单位和职务。