Ivonescimab

氨基观察-创新药组原创出品作者 | 武月2024年，吉利德堪称水逆王者。重金收购的Trodelvy，在非小细胞肺癌和尿路上皮癌的三期临床试验中接连失利，并撤回尿路上皮癌适应症的加速批准，一度被贴上“水逆”标签。戏剧性的是，在2025年，这款Trop2 ADC却在三阴性乳腺癌（TNBC）领域接连取胜：2025年4月21日，Trodelvy联合K药一线治疗转移性TNBC的ASCENT-04试验成功；5月23日，单药一线治疗PD-L1阴性TNBC的ASCENT-03试验再传捷报。这两项关键3期临床的胜利，有可能让Trodelvy成为一线mTNBC所有患者的骨干疗法，巩固其在首发适应症三阴乳腺癌的优势，更让吉利德的肿瘤管线重燃希望。但这并非终点。在ADC赛道“内卷”加剧的当下，Trodelvy既要面对同靶点竞品的围剿，又要警惕HER2 ADC的“跨界打击”。更紧迫的是，吉利德必须尽快突破乳腺癌的“舒适区”。Trodelvy在肺癌领域的失利阴影尚未消散，而小细胞肺癌、子宫内膜癌等新战场的开拓能否成功，将决定其能否真正走出水逆。当然，这不只决定Trodelvy处境，可能决定了Trop2 ADC的命运。/ 01 /一线突破三阴性乳腺癌因缺乏治疗靶点、预后极差，号称“乳腺癌之王”，给年轻女性的健康造成极大威胁。过去20年，化疗始终是标准疗法，但中位生存期仅1-2年。Trodelvy的崛起，始于2021年ASCENT试验中二线治疗的突破，而2025年的两项三期临床胜利，则将其推向了更前线的战场。4月21日，吉利德宣布，Trodelvy+K药联合一线治疗转移性三阴乳腺癌的ASCENT-04试验获得成功。该研究针对既往未接受过治疗的PD-L1高表达（CPS≥10）不可切除局部晚期或转移性三阴性乳腺癌（mTNBC）患者，结果显示，相较于K药联合化疗，Trodelvy+K药的方案在无进展生存期（PFS）方面展现出统计学及临床意义的显著改善，OS作为关键次要终点其数据尚未成熟，但呈现早期积极趋势。安全性方面，联合疗法未出现新的安全信号，与单药已知特性一致，具体数据将在即将举行的ASCO会议上披露。这也是mTNBC首个达到PFS终点的PD-1+Trop2 ADC联合治疗的三期临床试验。5月23日，吉利德再次宣布，Trodelvy单药一线治疗PD-L1阴性TNBC的ASCENT-03试验成功，与化疗相比，在不适合PD-1/PD-1的mTNBC患者中，经过Trodelvy治疗的患者PFS具有高度统计学意义和临床意义的改善。安全性方面也与之前的试验表现相同。传统化疗一直是mTNBC早期治疗的标准护理，但是化疗的效果亟待改善，并且吉利德表示，在mTNBC中，大约50%的患者没有接受超过1线的治疗，这表明需要额外的有效早线治疗选择。吉利德首席医疗官Dietmar Berger表示：“与化疗相比，ASCENT-03结果代表了20多年来这一患者群体的首次临床上有意义的进步。通过更早地解决这种侵袭性和难以治疗的疾病，我们有可能改善转移性三阴性乳腺癌患者面临的高未满足需求的治疗方案。”更重要的是，这两项关键三期临床的成功，使Trodelvy有望覆盖所有一线TNBC患者，成为新的“骨干疗法”。2024年，Trodelvy的销售额为13.15亿美元，若成功拓展至一线三阴乳腺癌，对吉利德显然是一大步。花旗分析师甚至预测，2030年Trodelvy的峰值销售额或达32亿美元。/ 02 /TNBC攻防战2025年一季度，Trodelvy的销售额出现了下滑，尽管吉利德表示这是库存调整所导致的，但市场竞争的压力不言而喻。能否借临床胜利保持增势，将是吉利德的下一个考验。毕竟，TROP2这个靶点在乳腺癌中的前景并不是十分明朗，不仅要面对同靶点药物的竞争，还要担心HER2 ADC的“背刺”，后来者的超车。即使是在Trodelvy已经建立先发优势的TNBC领域，HER2 ADC、后来者的攻势已箭在弦上。首先是双抗药物的进击。康方生物的PD-1/VEGF双抗AK112，普米斯/BioNTech的PD-L1/VEGF双抗PM8002以及康宁杰瑞的PD-1/CTLA-4双抗KN046，也正在加速探索TNBC适应症，AK112、PM8002已在2期试验中展现出对PD-L1高/低表达TNBC的强势疗效，并启动三期临床。在去年底召开的圣安东尼奥乳腺癌研讨会(SABCS)会上，AK112、PM8002更新了其一线治疗三阴乳腺癌的数据，前者的mPFS为9.3个月，后者为13.5个月。由于研发进度更快，PM8002已经读出部分OS数据，12个月和15个月的OS率分别为80.8%和78.1%。如果能够延续这样的临床表现，双抗无疑将为TNBC患者带来新的选择。除此之外，BioNtech还在全速推进PD-L1/VEGF+ADC策略，这无疑也会对吉利德的PD-1+TROP-2 ADC联用造成冲击。其次是HER2 ADC的“背刺”。虽然TNBC不适用于传统HER2靶向药，但有着旁观者效应的HER2 ADC，能对其中占比约30%的HER2低表达TNBC患者发挥作用。DS-8201率先在HER2低表达中取得突破。在一项3期临床DESTINY-Breast04中，纳入既往接受过1-2线化疗的低表达HER2的不可切除性或转移性乳腺癌患者，结果表明相比化疗组，DS-8201组ORR达50%，接受化疗的患者仅为16%，PFS更是增长了近3倍，OS也获益翻倍。尽管该研究样本数有限，但虑到目前TNBC治疗选择的有限性，以及DS-8201在低水平表达HER2的TNBC患者中的显著疗效，这也为TNBC提供了新方向。作为首发阵地，吉利德围绕三阴乳腺癌进行了全方位布局，除了前述的两项3期临床，还在开展PD-1+Trop2 ADC用于三阴乳腺癌术后辅助治疗的3期临床试验。除此之外，吉利德表示，正在对Trodelvy开展的一系列Trop-2高表达的肿瘤3期试验进行评估，包括单药及与K药的联用，涉及TNBC和HR+/HER2-乳腺癌的早期治疗。但是，在强手林立的世界，真正的护城河不在于数量，而是临床数据的深度，能否在OS/PFS最终分析中保持优势，并证明其在真实世界中的成本效益，将决定Trodelvy的长期竞争力。/ 03 /不能止于乳腺癌作为自己重金收购而来的ADC，吉利德没有理由、也不能放弃对它的潜力挖掘。换句话说，Trodelvy不能止于乳腺癌，倘若能在肺癌领域取得突破，必将开拓更大的市场。只不过，在非小细胞肺癌（NSCLC）领域，Trodelvy已经有了一次重大失利。2024年1月22日，名为EVOKE-01的研究没有达到OS的主要终点。在与对照组化疗相比，Trodelvy并未为晚期NSCLC患者带来OS改善，这也导致市场对Trodelvy预期的走低。目前其进度大为落后对手，科伦博泰的SKB264已经获批用于三线EGFR突变NSCLC，成功突围肺癌；第一三共的Dato-DXd也在失败之后，从广泛探索到“锚定”EGFR突变的NSCLC，并重新提交了新的上市申请，也获得了FDA的突破性疗法认定。对于Trodelvy来说，EVOKE-01研究也并非一无所获。通过该研究，吉利德发现患者此前接受PD-(L)1抑制剂治疗时的应答状态，会对Trodelvy治疗效果产生影响。简单来说，对于PD-(L)1抑制剂无应答的患者，相比经过PD-(L)1抑制剂治疗达成完全缓解或部分缓解的患者，或许能够在Trodelvy的治疗中获益更多。这也为TROP2 ADC在肺癌领域的应用提供了新的思路和方向。默沙东则在开展Trodelvy联合K药对比K药单药一线治疗PD-L1≥50%的NSCLC患者的3期临床。此前，联合治疗组在治疗PD-L1高表达患者的ORR达到69%，疾病控制率达到86%。Trodelvy能否在细分人群中扳回一城，仍是未知数。与此同时，吉利德也在推进Trodelvy在肺癌领域的其他研究。2024年国际肺癌研究协会世界肺癌大会上，吉利德公布了2期临床试验TROPiCS-03中广泛期小细胞肺癌（ES-SCLC）队列的结果。结果显示，43例小细胞肺癌患者，均为一线化疗联合免疫治疗耐药，该临床经确认的缓解率为41.9%，即43例患者中有18例达到PR，mPFS为4.4个月，中位OS为13.6个月。2024年底，FDA授予Trodelvy突破性疗法认定，用于治疗接受铂类化疗后疾病进展的ES-SCLC患者；今年2月份，Trodelvy已经登记了二线小细胞肺癌3期临床。小细胞肺癌约占肺癌病例的15%，其中约70%的患者在确诊时处于广泛期。对于ES-SCLC患者来说，当疾病对当前一线标准治疗（铂类化疗或免疫疗法）无应答时，预后通常较差且治疗选择有限。这意味着，若最终临床成功，吉利德无疑会开辟一片新市场，也能让市场重拾对Trodelvy的预期。/ 04 /总结肺癌领域足够宽广，但也已经足够内卷。去年7月，吉利德还启动了Trodelvy在子宫内膜癌患者中的三期临床，此外，其在胃癌、膀胱癌的早期探索也在进行中，只不过前路漫漫。总体来看，Trodelvy的三阴乳腺癌连续胜利，为吉利德赢得了喘息之机，但远非终局。在ADC赛道，既有DS-8201这样的超级明星，也有SKB264等本土黑马。若不能尽快在肺癌、妇科肿瘤等领域复制成功，Trodelvy恐难逃被替代的宿命。这就是ADC江湖的生存法则，不进则退。PS：欢迎扫描下方二维码，添加氨基君微信号交流。

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.”