▎追溯
一直以来,默沙东对于K药地位的维护,从未停歇。从过去的联用,如TIGIT等,别人做,默沙东也做,做好也不错,做坏更受益,K药仍然是肿瘤一哥。
对于旗下PD1/VEGF,默沙东更是前脚骂完,后脚接着买入。可见免疫治疗就是默沙东的命根所在。
2026 ASCO之后,默沙东在两次的投资者交流活动中的对话会议内容已经被披露出来。其中更受关注的仍然是其对PD1/VEGF的看法。
甚至出现先前说的话,过几天又反悔。我想可能是在行业对于AK112巨大争议之后,默沙东内部又重新组织了对外宣传的口径。集体否认具备三期开启条件。
6月4日的一场。(节选)
Akash Tewari - Jefferies LLC - Analyst阿卡什·特瓦里 - 杰富瑞有限责任公司 - 分析师
Understood. Now, maybe going into ASCO, and I'd love to give you know, you obviously have a PD-1 VEGF in development that's Phase 3 ready.明白。现在,也许切入到ASCO的话题,我很想了解,你们显然拥有一款正在研发中且已经具备3期临床条件的PD-1/VEGF(双特异性抗体)。
And your team has been very prudent in terms of where you want to develop that asset.并且你们的团队在想要把该资产开发到哪些方向上一直非常谨慎。
But I'd love to get your take, as you've said, we want to get more data from the field externally before we figure out our own development program.但我很想听听您的看法,正如您所说,在我们确定自己的开发计划之前,我们希望从外部领域获得更多的数据。
Obviously, we've got some important data sets from HARMONI-6, the ROSETTA data from BioNTech, and then also the lack of a PFS hit on HARMONI-3.显然,我们已经获得了来自HARMONI-6的一些重要数据集、来自百欧恩泰(BioNTech)的ROSETTA数据,以及在HARMONI-3研究中未能达到PFS(无进展生存期)显著统计学意义的结果。
How is Merck's view on where PD-1 VEGFs fit a role, particularly in lung, change post-ASCO?在ASCO之后,默克对于PD-1/VEGF(双抗)在何处发挥作用(尤其是在肺癌中)的看法发生了怎样的变化?
Marjorie Green - Merck & Co Inc - Senior Vice President and Head of Oncology, Global Clinical Development马乔里·格林 - 默克公司 - 高级副总裁兼全球临床开发肿瘤学负责人
This is such an interesting development for all of us as we think about how to optimize therapy for people with different kinds of malignancies.当我们思考如何为患有不同类型恶性肿瘤的患者优化治疗时,这对我们所有人来说都是一个非常有趣的进展。
Through the KEYTRUDA program, we have more than 20 studies that we have done with different combinations of KEYTRUDA with VEGF inhibitors, including bevacizumab, where we have two approvals, Lenvatinib where we've seen some compelling data in endometrial cancer, as well as in renal cell, other VEGF TKIs.通过KEYTRUDA项目,我们已经开展了20多项研究,探索KEYTRUDA与不同的VEGF抑制剂的组合,包括贝伐珠单抗(我们已获得两项批准)、乐伐替尼(我们在子宫内膜癌以及肾细胞癌中看到了令人瞩目的数据),以及其他VEGF TKI(酪氨酸激酶抑制剂)。
And so we've learned a great deal about the combinations over time.因此,随着时间的推移,我们对这些组合疗法了解了很多。
And historically, it's not been a one-size-fits-all approach for these kinds of combinations.而且从历史上看,这类组合疗法从来都不是“一刀切”的方法。
And what has really been the question, and I think people are more excited after ASCO is could the bispecific of putting these two together and potentially improving the therapeutic index by putting them together because the safety appears to be a little more tolerable, and maybe you can increase the efficacy actually of the PD-1 as well by the structure.而真正的核心问题——并且我认为人们在ASCO之后更加兴奋的是——将这两者结合在一起的双特异性抗体,是否能通过把它们组合在一起来潜在地提高治疗指数,因为安全性似乎更加耐受,并且也许你还可以通过这种结构实际上来提高PD-1的疗效。
Is that going to be what it takes to open up VEGF more broadly across multiple tumor types?这是否会是将VEGF在多种肿瘤类型中更广泛地打开局面的关键?
And I think we're still left with more questions than answers. So HARMONI-6 was great data.而且我认为我们仍然留下的问题比答案多。所以HARMONI-6是非常棒的数据。
I want to congratulate Akeso, the investigators. It is clinically compelling information.我想祝贺康方生物(Akeso)和研究人员。这是临床上非常令人瞩目的信息。
It's the first Phase 3 randomized data set we've seen with the bispecific that shows consistency between PFS and OS.这是我们见过的第一个使用双特异性抗体、并显示出PFS(无进展生存期)和OS(总生存期)之间一致性的3期随机数据集。
But open questions remain regarding the translatability into global studies, the translatability into different subsets of non-small cell lung cancer, referring back to what you said with even look at HARMONI, and you look at HARMONi-2, where you didn't necessarily see that same correlation between PFS and OS.但是,关于其向全球研究的外推性、向非小细胞肺癌不同亚群的外推性,仍存在悬而未决的问题,这可以回溯到你刚才提到的,甚至看看HARMONI研究,当你观察HARMONI-2时,你在那里不一定能看到PFS和OS之间存在同样的关联性。
There are also open questions about -- in that particular HARMONI-6 study about the differences in age that was seen, where you saw most of the benefit for those people who were less than 65. In a different magnitude, people keep talking about 407, KEYNOTE-407, and I'd like to point out that that study, the control arm, there was 60% crossover.在那项特定的HARMONI-6研究中,关于所观察到的年龄差异也存在悬而未决的问题,你看到大部分获益集中在那些小于65岁的人群中。在不同的层面上,人们一直在谈论407,即KEYNOTE-407,而我想指出的是,在该研究中,对照组有60%的患者进行了交叉换药(crossover)。
I don't know if people remember that 60% of the control arm crossed over to pembrolizumab.我不知道人们是否还记得,对照组有60%的人交叉转换到了帕博利珠单抗治疗。
And the age hazard ratios, there was a small difference, definitely between those who were less than 65 and those who were older, but the magnitude of difference was not the same that was seen in HARMONI-6.至于年龄的风险比(hazard ratios),在小于65岁和年龄更大的人群之间确实存在微小的差异,但这种差异的幅度与在HARMONI-6中所看到的截然不同。
And so I'm excited because the curve separated and they stayed separated. Will they continue that way?因此我很兴奋,因为(生存)曲线分开了,而且它们保持着分离状态。它们会一直保持这样吗?
I don't know the answer to that. When we look at the HARMONI, the HARMONi-2, they didn't seem to do that from the data we know to date.我不知道这个问题的答案。当我们看HARMONI,即HARMONI-2时,从我们目前已知的数据来看,它们似乎并没有表现出这样(持续分离)的特征。
So I'm curious and it's an area where we want to continue to develop and explore, but how these agents will combine in different tumor types is to be determined.所以我很好奇,这是一个我们想要继续开发和探索的领域,但这些药物在不同的肿瘤类型中将如何组合使用仍有待确定。
So we're always, as you said, we're data-driven, we're very disciplined, and we will go where there's opportunity where we think the science and the clinical need makes sense.因此,正如你所说,我们始终是数据驱动的,我们非常严谨,并且我们会走向有大机会、且我们认为在科学和临床需求上都合理的地方。
Akash Tewari - Jefferies LLC - Analyst阿卡什·特瓦里 - 杰富瑞有限责任公司 - 分析师
Understood. Now, last one on just speeding PD-1 VEGF and then I actually want to go broader.明白。现在,最后一个关于加速PD-1/VEGF(双抗)的问题,然后实际上我想谈谈更广泛的话题。
LaNova asset, I think the term Merck adopted was we're Phase 3 ready at ASCO.礼新医药(LaNova)的资产,我认为默克在ASCO上采用的说法是“我们已经具备3期临床条件”。
I will say the one question I think I've certainly thought of and I've heard this from investors as well is like it's unusual for Merck to present unconfirmed responses.我要说的是,我肯定思考过、并且我也从投资者那里听到的一个问题是,默克展示“未确认的疗效缓解(unconfirmed responses)”是很不寻常的。
I mean, you guys are very straight and narrow. You give confirmed responses, you give proper durability.我的意思是,你们一向非常死板和严谨(规规矩矩)。你们通常只给出确认的缓解,给出恰当的持久性。
And at AACR, I think both in the poster and in the abstract, it was the same data cutoff.而且在美国癌症研究协会(AACR)年会上,我认为无论是在海报还是在摘要中,采用的都是相同的数据截止日期。
And so the question I've always had is really how did that data mature over time, really encouraging 55% response rate, but it was unconfirmed.因此我一直想问的问题是,随着时间的推移,那些数据究竟是如何成熟的,虽然55%的客观缓解率确实非常鼓舞人心,但它之前是未确认的。
Is there any qualitative color you can give us in terms of as you've given that therapy for a longer duration because that's really what you have internally, how that profile has evolved over time?随着你们给药持续时间的延长,在数据方面您能否给我们提供一些定性的细节描述,因为这正是你们内部所掌握的信息,这个数据特征随时间推移是如何演变的?
Marjorie Green - Merck & Co Inc - Senior Vice President and Head of Oncology, Global Clinical Development马乔里·格林 - 默克公司 - 高级副总裁兼全球临床开发肿瘤学负责人
Yeah. I don't like to talk about data that's not public yet in any kind of forum.是的。我不喜欢在任何形式的论坛上讨论尚未公开的数据。
And so we have confidence in the data that we presented.因此,我们对我们所展示的数据是有信心的。
Otherwise you wouldn't have seen us present information like that.否则,你是不会看到我们展示那样的信息的。
And also we wouldn't call an asset Phase 3 ready unless we thought that what you would see is what you would get.而且,除非我们认为“你所见即你所得”,否则我们也不会称一项资产已经具备3期临床条件。
6月9日的一场(节选)
Asad Haider阿萨德·海德尔
Let's maybe unpack another big theme coming out of ASCO, which you were very much at the center of as well, which is the progress on the PD-1/VEGF bispecific class.让我们也许来拆解一下来自ASCO的另一个大主题,你也非常深处这一主题的核心,那就是PD-1/VEGF双特异性抗体品类的进展。
So I guess first, Dean, externally on the HARMONI-6 data that you saw from Akeso.所以我想首先,迪恩,从外部来看,关于你看到的来自康方生物的HARMONI-6数据。
I would just love to get your thoughts on the issues that were raised by the discussant on the stage after the data were presented that fueled some substantial discussion and debate among investors.我只是很想听听数据展示后台上特邀评论员(discussant)提出的那些问题,在投资者中间引发了一些实质性的讨论和辩论,您对这些问题有什么看法。
I mean are these really substantial concerns around the global translatability in terms of differences and age or is this just skeptics trying to poke holes in the data?我的意思是,关于在年龄差异方面的全球外推性,这些真的属于实质性的担忧吗?还是这只是怀疑论者试图在数据中挑刺(找漏洞)?
Dean Li - Merck & Co Inc - Executive Vice President, President - Merck Research Laboratories李迪恩 - 默克公司 - 执行副总裁兼默克研究实验室总裁
So I think everything the discussant said is legitimate and we take them seriously.所以认为特邀评论员所说的一切都是合乎情理的,并且我们严肃认真地对待它们。
I think the person who spoke was very clear of the things one had to think through.我认为发言的那位人士非常清楚人们必须通盘思考的那些事情。
But just stepping back, one of the things that's been very clear when you add PD-1 and VEGF, whatever the VEGF part has been, has been, you can hit PFS, but it's been hard to hit OS. That's been a constant sort of theme.但是仅仅退一步来看,当你把PD-1和VEGF加在一起时(无论VEGF部分具体是什么药物),一直以来非常明确的事情之一是,你可以达到PFS(显著性),但一直很难达到OS(显著性)。这在某种程度上是一个恒久的主题。
We've seen it in our own pipeline. Other people have seen it in their pipeline as well.我们在我们自己的管线里见识过这种情况。其他人在他们的管线里也同样见识过。
But you need to step back and sit there and say, is this a clean PFS to OS?但你需要退一步并坐在那里说,这是一个从PFS到OS的完美转化吗?
You'd have to say that it's clean in relationship to the OS appear to hold.你不得不说,就OS结果似乎能够站得住脚而言,它是干净利落(完美)的。
There are all the other caveats that one has to think about, and so one has to be very thoughtful how one advances it.这里面存在着所有其他人们必须思考的警告说明,因此人们在如何推进它时必须非常深思熟虑。
And so when we look at that data, we sit there and go, on one hand, there haven't been many things that have translated for PFS and OS, and this one is.因此当我们审视那个数据时,我们坐在那里心里想,一方面,过去并没有太多的东西能同时在PFS和OS上实现转化,而这一个做到了。
We do not we think that's an important contribution.我们并不——我们认为这是一个重要的贡献。
But I think the caveats that the discussant said informs us as to how do we think to move it forward, and in what partner should we move it forward, and in precisely what indications we would move it forward.但我认为特邀评论员提到的那些警告说明,提示了我们应当如何考虑去推进它、我们在联合什么药物(合伙伙伴)的情况下应当推进它,以及我们究竟应该在哪些适应症里去推进它。
Clearly, if you look at PD-1s and VEGFs, there are opportunities in lung, but it's not just in lung.显然,如果你观察PD-1和VEGF,在肺癌中存在着机会,但它不仅仅是在肺癌中。
It's in HCC, it's in RCC, it's in cervical, it's in a variant.它还在肝细胞癌(HCC)、肾细胞癌(RCC)、宫颈癌(cervical)、以及卵巢癌(原文a variant应为ovarian卵巢癌之误)中。
There's many places where PD-1 and a VEGF works. So we're doing the hard work to sort of sort out where and when we should target those different indications.在许多地方PD-1和VEGF组合都能发挥作用。因此我们正在做艰苦的工作,来在某种程度上梳理出我们应该在何时何地去针对那些不同的适应症。
But equally important for us is not just where we put the PD-1/VEGF, but what's the combination partner.但对我们来说同样重要的一点是,不仅在于我们将PD-1/VEGF应用在哪里,还在于什么是联合用药的伙伴。
Should it be chemo? Should it be sac-TMT? Should it be a different ADC? Should it be a different molecule?它应该是化疗吗?它应该是sac-TMT吗?它应该是一款不同的ADC吗?它应该是一个不同的分子吗?
Asad Haider阿萨德·海德尔
So let's unpack that a little bit more. At ASCO, just regarding your own PD-1/VEGF program that you alluded to a little bit right now, you noted that it was Phase 3-ready, which was intriguing and suggests it's moving potentially at a more rapid speed than certainly I think a lot of us have thought.那么让我们再多拆解一下这个问题。在ASCO上,单就你刚才略微提及的你们自己的PD-1/VEGF项目,你指出它已经具备了3期临床条件,这非常引人入胜,并且暗示它的移动推进可能正处于一个比我们许多人原以为的更快速的节奏上。
So I guess we'll just ask the question. Like, what data are you waiting for externally or internally before you get comfortable, in your words, to let the dogs out, I think you phrased it as that.所以我猜我们只想问这个问题。就像,在让你感到踏实之前,你正在等待外部或内部的哪些数据,用你的话来说,叫“关门放狗”(意指大展身手/全力推进),我想你是像那样措辞的。
Dean Li - Merck & Co Inc - Executive Vice President, President - Merck Research Laboratories李迪恩 - 默克公司 - 执行副总裁兼默克研究实验室总裁
I'm going to have to live that one down a little bit.我不得不为那句话(过头的俏皮话)承受一点小代价(承担点尴尬)了。
Asad Haider阿萨德·海德尔
But what indications can be seen in those?但在那些里面能看到什么适应症呢?
Dean Li - Merck & Co Inc - Executive Vice President, President - Merck Research Laboratories李迪恩 - 默克公司 - 执行副总裁兼默克研究实验室总裁
Yeah. So clearly, we work extremely closely with Kelun. So us understanding where some of the other agents are will be really important because it's not just around the PD-1/VEGF.好的。所以很显然,我们与科伦极其密切地合作。因此,我们去了解其他某些药物处于什么阶段将非常重要,因为这不仅仅围绕着PD-1/VEGF。
We believe that PD-1/VEGF could be an accelerant to other novel molecules, whether they're antibody drug conjugates, whether they're precision-targeted.我们相信PD-1/VEGF可以作为其他新型分子的加速剂,无论它们是抗体偶联药物,还是精准靶向药物。
So it is about PD-1/VEGF. There is more information that will be coming out.所以它关系到PD-1/VEGF。未来会有更多的信息公布出来。
我们从以上的对话中,可以看到默沙东高管微妙而又拧巴的态度。甚至不想给对手增加任何分值。
虽然,默沙东的高管极具违心地祝贺康方生物(Akeso)。但他们都对全球重复性,不同NSCLC亚群中的一致性,年龄差异,产生同样质疑。总结而言:全球可重复性(Global Reproducibility):目前的数据主要来自特定地区研究。未来是否能够在全球III期研究中得到重复验证?仍需观察。不同NSCLC亚群中的一致性:不同患者亚群是否同样获益?这一点也尚未完全明确。年龄差异:HARMONi-6中,65岁以下患者获益明显更大。而65岁以上患者获益幅度明显较小。这种年龄相关差异:是否真实存在?是否具有生物学基础?仍然需要进一步研究。PD1/VEGF还远未成为一种所谓的标准疗法的同时,对于其其它适应症的探索,和联用的探索,未来都会成为其必经之路,而默沙东更相信PD-1/VEGF可以作为其他新型分子的加速剂。除此之外,PD1/VEGF仍未解决PD1抗体耐药的问题。但一场新的免疫治疗浪潮无疑又一次被掀起。如果默沙东有可以选择的一个结果,我想,PD1/VEGF的失败,这样对于K药地位的维护似乎更有利。
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