Eli Lilly and Company (NYSE:LLY) Lilly Oncology ASCO Investor Event June 2, 2024 8:30 PM ET

Eli Lilly and Company (NYSE: LLY) 莉莉肿瘤 ASCO 投资者活动 2024 年 6 月 2 日 晚上 8:30 点 ET

Company Participants 公司参与者

Jake Van Naarden - Executive VP & President of Loxo

杰克·范纳登 - Loxo 执行副总裁兼总裁

Lillian Smyth - Senior Vice President and Global Development Head for Breast Cancer at Loxo

Lillian Smyth - Loxo 乳腺癌全球发展负责人，高级副总裁

John Pagel - Vice President and Head of Global Hematology at Loxo

约翰·佩格尔 - Loxo 全球血液学副总裁兼负责人

Geoff Oxnard - VP of Clinical Development, Global Head Thoracic Cancer at Loxo

Geoff Oxnard - Loxo 公司全球胸部癌症临床发展副总裁

Arjun Balar - MD, Vice President, Global Clinical Development at Loxo

阿尔琼·巴拉-医学博士，洛克索全球临床发展副总裁

Barry Taylor - Chief Scientific Officer of Loxo

Barry Taylor - Loxo 首席科学官

Kara Clinton - Senior Vice President Oncology Medical Affairs

Kara Clinton - 肿瘤医学事务高级副总裁

Winselow Tucker - Senior Vice President & Chief Commercial Officer for Loxo

Winselow Tucker - Loxo 公司高级副总裁兼首席商务官

Conference Call Participants

电话会议参与者

Evan Seigerman - BMO Capital Markets

伊万·塞格曼 - BMO 资本市场

Seamus Fernandez - Guggenheim Securities

西莫斯·费尔南德斯 - 古根海姆证券

Geoff Meacham - Bank of America

杰夫·米查姆 - 美国银行

Steve Scala - TD Cowen

史蒂夫·斯卡拉 - TD 科温

Chris Schott - JPMorgan

克里斯·施特 - 摩根大通

Akash Tewari - Jefferies

阿卡什·特瓦里 - 杰弗里斯

Dave Risinger - Leerink Partners

戴夫·赖辛格 - 利灵合伙人

Jake Van Naarden  杰克·范纳登

All right. Can everyone hear me, yes. Okay. I think we're going to get started. All right. Thanks, everyone, for coming tonight. And for those online, thanks for being patient as we let people get in and take their seats. I know we're starting a little bit late. My name is Jake Van Naarden. I lead the oncology unit here at Lilly, which, in the case of oncology, actually spans our discovery efforts all the way through our commercial medicines, and you'll see that reflected actually in what we walked through here tonight.

好的。大家都能听到我说话吗，好的。好的。我想我们要开始了。好的。谢谢大家今晚过来。对于在线参与的人，感谢你们的耐心等待，让大家进场并就座。我知道我们开始有点晚。我叫杰克·范纳登。我在莉莉公司领导肿瘤学部门，实际上在肿瘤学领域，我们的发现工作一直延伸到我们的商业药品，你们将在今晚的介绍中看到这一点。

Over the past couple of years, we've been working to modernize the portfolio and strategy in oncology here at Lilly. And we're doing this event tonight because I think we're really entering a new phase. And so tonight, we're going to tell you a little bit about how we think our philosophy about [indiscernible] creation, what we've been up to over the past couple of years in these efforts, walk through the portfolio itself and importantly, actually introduce you to a bunch of members of the team who don't do as much IR and don't do so much media but are actually the ones doing all the hard work, getting our medicines built and bringing them to patients. So I'm excited for you to meet them here tonight.

在过去的几年里，我们一直在努力现代化 Eli Lilly 在肿瘤学领域的产品组合和战略。今晚我们举办这个活动是因为我认为我们正在进入一个新阶段。所以今晚，我们将告诉您一些关于我们对[不可辨]创造的哲学的看法，我们在过去几年中所做的努力，浏览产品组合本身，更重要的是，实际上向您介绍一些团队成员，他们不太参与 IR 工作，也不太参与媒体工作，但实际上是在做所有艰苦的工作，研发我们的药物并将其带给患者。我很高兴今晚能让您见到他们。

This is the safe harbor provision. So in terms of agenda, I'm going to start and kick things off, talk a little bit about our strategy, our vision, the kinds of medicines we make, tell you a little bit about [indiscernible] the changes in both the research and development portfolio and philosophy over the past couple of years, give an update on the commercial performance of our approved medicines. And then hand it over to my teammates, my colleagues who are going to walk through a bunch of the actual medicines in the portfolio that we're excited about. And then we'll take some Q&A at the end.

这是安全港条款。所以在议程方面，我将开始并启动事务，谈一下我们的战略、愿景，我们生产的药物类型，告诉您一些关于过去几年研发组合和理念变化的情况，更新我们已批准药物的商业表现。然后将其交给我的队友，我的同事们将详细介绍我们对组合中一些实际药物感到兴奋的情况。然后我们会在最后进行一些问答。

Speaking of the team, really excited about the team we've built here in Lilly Oncology. This is a group of people who the vast majority of whom are new to the company over the past couple of years. Many of them are new to industry. I just couldn't be more thrilled with the kind of talent that we've been able to attract, which we think is a big reflection actually of the medicines we're working on. Great people want to work on great medicines. We've had the bring a really great team together that I think rivals the best, frankly, among our peer set. And so you'll hear from them tonight as we talk through the portfolio.

说到团队，我对我们在礼来肿瘤学部门建立的团队感到非常兴奋。这是一群人，其中绝大多数人在过去几年里都是新来的。他们中的许多人都是新手。我们成功吸引了各种人才，这让我感到非常高兴，我们认为这实际上也反映了我们正在研究的药物。优秀的人才愿意为优秀的药物工作。我们已经组建了一个非常出色的团队，我认为在同行中可以与最优秀的团队相媲美。今晚在我们讨论投资组合时，你们将会听到他们的发言。

So a couple of years ago, in 2019, Lilly bought Loxo and I came to the company from that acquisition. And in the ensuing year, A bunch of us had the opportunity to take on increasing roles in leadership we were reporting an opportunity to reshape what oncology look like here at the company.

所以几年前，2019 年，Lilly 收购了 Loxo，我也是从那次收购中加入了公司。在接下来的一年里，我们中的许多人有机会承担更多的领导角色，我们有机会重塑这家公司的肿瘤学领域的面貌。

But Lilly's have a long history in oncology. This is our first gambit. Some of the first chemotherapies ever invented or Lilly products, there, many of them are in use today are still standard of care in tens of thousands, hundreds of thousands of patients globally as generic medicines. Some of the first model antibodies in oncology or Lilly products still in today. And of course, Verzenio medicine has made a huge impact for people with breast cancer has, of course, been an important business contributor as well.

但是 Lilly 在肿瘤学领域有着悠久的历史。这是我们的第一个筹码。一些最早发明的化疗药物或者 Lilly 的产品，其中许多至今仍在全球数以万计、数以十万计的患者中作为仿制药物使用。一些最早的肿瘤学模型抗体或者 Lilly 的产品至今仍在使用。当然，Verzenio 药物对乳腺癌患者产生了巨大影响，当然，它也是一个重要的商业贡献者。

So starting with strategy. How do we think about oncology medicine creation and delivery? Really, 3 things. And it starts with a conviction in biology. The entire effort is biology oriented. It's not around where the tumor rose inside of the body. It's not around some categories of biology. It's about -- it starts with identifying targets, proteins or other parts of the cell in, on around a cancer cell that we think that if you build the right medicine, step 2, that you can actually get the tumors out of die and you observe that both preclinically and eventually, you can observe that clinically on conventional imaging.

所以从战略开始。我们如何看待肿瘤学药物的创造和交付？实际上，有 3 个要点。首先是对生物学的信念。整个工作是以生物学为导向的。它不是围绕肿瘤在体内的位置。也不是围绕某些生物学类别。它是关于——首先是识别目标，蛋白质或其他细胞部分，位于癌细胞内外，我们认为如果你制造正确的药物，第二步，你实际上可以使肿瘤消失，你可以在临床前和最终在常规成像中观察到这一点。

Monotherapy activity clinically is what we're looking for in the right patients. We beat these medicines up a ton preclinically, and we build them to pretty exacting standards. Of course, they're not always going to be perfectly replicable when you put it in the clinic, but we think that through this approach, we can build a portfolio with a reasonably high probability of delivering medicines come the end of clinical trials.

单药疗法在临床上的活性是我们在寻找合适患者时所追求的。我们在临床前对这些药物进行了大量研究，并按照相当严格的标准进行了设计。当然，当你将其应用于临床时，它们并不总是能完全复制，但我们认为通过这种方法，我们可以建立一个在临床试验结束时有相当高概率提供药物的投资组合。

And so when we enter the clinic, yes, we're looking for monotherapy activity. Sometimes it's going to be robust enough to allow for an accelerated approval in a late-line population where there's a significant unmet need. We've done those. Sometimes it's just enough to tell you have something real that you can invest more capital into in randomized trials and prove out through other endpoints, and we've done that as well. And so this is the approach we take. And it really centers on biologic conviction, target selection and building the right medicines.

所以当我们进入诊所时，是的，我们正在寻找单药疗效。有时它会足够强大，以便在晚期人群中获得加速批准，那里存在重大未满足需求。我们已经做过这些。有时仅仅告诉你有一些真实的东西，你可以投入更多资本进行随机试验，并通过其他终点证明，我们也做到了。所以这就是我们采取的方法。它真正侧重于生物学信念、靶点选择和构建正确的药物。

How do we do it? We do it through a combination of our internal discovery efforts and business development. A couple of years ago, we recognize that we really needed business development to help accelerate this modernization effort. And so we've done a lot of deal making since the Loxo acquisition. We've purchased companies both public and private. We've done discovery partnerships. We've done licensing transactions. We've gravitated towards earlier-stage deals. That's where we think the biggest opportunity is to actually create value. And I think we will continue to be active in business development.

我们是如何做到的？我们通过内部发现努力和业务发展的结合来实现。几年前，我们意识到我们确实需要业务发展来帮助加速这一现代化努力。因此自从收购 Loxo 以来，我们进行了许多交易。我们收购了公共和私人公司。我们进行了发现合作伙伴关系。我们进行了许可交易。我们倾向于较早阶段的交易。我们认为这是实际创造价值的最大机会所在。我认为我们将继续积极参与业务发展。

It's really a philosophy of agnosticism as to where good medicines come from. Our discovery teams are actually at the table with our business development professionals and identifying these opportunities. We don't sort of have a first principle about where a good medicine comes from. We have a lot of smarter people here. There's a lot of smart people out there in the external environment. And if we can find programs that we otherwise wouldn't have the ability to make or can de-risk things we're already working on forward, integrate things we're already working on, we love to be able to bring those things in from the outside world.

这实际上是一种不可知论的哲学，关于良药的来源。我们的发现团队实际上与我们的业务发展专业人员一起坐在一起，识别这些机会。我们并没有关于良药来源的第一原则。我们这里有很多更聪明的人。外部环境中也有很多聪明人。如果我们能找到我们本来没有能力制造的项目，或者能够降低我们已经在进行的工作的风险，整合我们已经在进行的工作，我们很乐意能够从外部世界引进这些项目。

So let's talk about the portfolio. So in late 2019, early 2020, this was the portfolio of approved and investigational medicines that we inherited and had to decide to do it.

让我们谈谈投资组合。所以在 2019 年末、2020 年初，这是我们继承并必须决定如何处理的已批准和调查中药品组合。

Unfortunately, most of the medicines, certainly in the first 2 columns on this slide we're either sort of already failing or we thought were destined to do so. And so we took the bold initiative in the first couple of months of assuming these roles to terminate nearly the entire pipeline. And we made a bet. And we made a bet that in the ensuing years, through a combination of internal discovery efforts, leveraging the philosophy I just talked about, through business development and through extreme focused, we could build back to a pipeline of size that would rival what we inherited, if not larger, with a portfolio probability that had a much higher chance of delivering real medicines that made a big impact to patients come the end of their journey while at the same time taking the handful of medicines that did look real and actually progress them through the development portfolio and get them approved launch, et cetera.

不幸的是，在这张幻灯片的前两列中，大多数药物要么已经失败，要么我们认为注定会失败。因此，在担任这些角色的头几个月里，我们采取了大胆的举措，几乎终止了整个研发管线。我们打了一个赌。我们打赌，在接下来的几年里，通过内部发现努力的结合，利用我刚才谈到的理念，通过业务发展和极度专注，我们可以重建一个规模庞大的研发管线，与我们继承的相媲美，甚至更大，具有更高概率的组合，以提供对患者产生重大影响的真正药物。在他们旅程结束时，同时将那些看起来真实的少数药物推进到开发管线，并获得批准上市等。

And I'm excited tonight to report in this way that I think we're well on our way to doing that. Now do we yet have the portfolio of clearly working medicines in the clinic that resulted from these efforts? No, we're not there yet. But I think we're entering a new phase of what that could look like. Importantly, as you can see on this slide, that dotted box on the upper left represents entirely new projects since that 2019, 2020 time frame. These were literally like ideas on a sheet of paper that we either brought in from the outside world and perfected or we built from scratch. And of course, we've moved important medicines from the left to the right. You'll hear about a lot of those later this evening.

我很高兴今晚以这种方式报告，我认为我们正在朝着这个方向取得进展。现在，我们是否已经拥有了清晰有效的临床药物组合，这些努力取得了成果？不，我们还没有达到那一步。但我认为我们正在进入一个新阶段，看起来会是什么样子。重要的是，正如您在这张幻灯片上所看到的，左上角的虚线框代表自 2019 年、2020 年以来完全新的项目。这些项目实际上就像是纸上的想法，要么是我们从外部引进并完善的，要么是从零开始构建的。当然，我们已经将重要的药物从左边移到右边。您晚些时候将听到更多关于这些药物的信息。

We've also diversified the modalities. A couple of years ago, if you wanted to make a cancer medicine at Lilly, you could make a small molecule or you can make a vacant antibody, and that was basically it. And our observation and looking at the increasingly complex landscape, patient need and biologic opportunities was that we needed the ability to diversify the modalities for which we could make cancer medicines, which meant diversifying the technology toolkit that we actually had. And I'm proud to say we've been doing this. Of course, we're continuing to make selective potent oral small molecules. You'll hear about a bunch of them tonight. We're putting our first antibody drug conjugates into the clinic, where we'll have our first T-cell redirector into the clinic next year. And by way, at least initially of the POINT Biopharma acquisition, we're now making radioligand therapies with our first one of those in a wholly owned way in the clinic now as well. So I expect over the ensuing years, the color diversity will continue, in fact, perhaps even get more balanced over time. But I'm excited that we -- when we identify a target now, we identify a product profile that we think can work in a patient and be differentiated, we now have a technologic toolkit that we can apply in a diverse way of how to make that medicine.

我们还多样化了模式。几年前，如果你想在礼来制造一种癌症药物，你可以制造一个小分子，或者你可以制造一个空抗体，基本上就是这样。我们观察到，随着日益复杂的景观、患者需求和生物机会，我们需要多样化制造癌症药物的模式，这意味着我们需要多样化我们实际拥有的技术工具包。我很自豪地说我们一直在做这个。当然，我们继续制造选择性强效口服小分子。今晚你会听到很多关于它们的信息。我们正在将我们的第一个抗体药物结合物投入临床试验，明年我们将把我们的第一个 T 细胞重定向剂投入临床试验。顺便说一下，至少最初通过 POINT 生物制药的收购，我们现在也在全资拥有的方式下制造放射配体疗法，其中我们的第一个已经在临床中了。因此，我预计在未来几年，色彩多样性将继续，事实上，随着时间的推移，可能会变得更加平衡。 但我很兴奋，当我们现在确定一个目标时，我们确定了一个产品概况，我们认为可以在患者身上起作用并具有差异化，我们现在有一个技术工具包，我们可以以多种方式应用如何制造这种药物。

While we were retooling the discovery portfolio, we, of course, were trying to jump-start pivotal development for the medicines that we thought warranted late-stage development kickstarted a suite of late-stage development for a handful of different programs a couple of years ago when this all happened, and interestingly, this resulted in a pretty concentrated clustering of readouts, 8 randomized trial readouts in the span of 12 months. It's probably the most concentrated number of late-phase readouts in oncology that Lilly have ever had. And most of them have been successful. Of course, they're never all going to be successful. That's just not the way this business works. I wish it were, but it usually isn't. But most of them have been, and that's really great for patients. It's really great for advancing our medicines towards approvals and new indications. There's still one more coming soon. This is the imlunestrant EMBER-3 Phase III study, the first Phase III study for the oral SERD in second-line ER-positive metastatic breast cancer. We'll hear a little bit more about that later tonight from Lillian. Important Phase III study coming later this year for that medicine.

在我们重新调整发现组合产品的同时，当然，我们试图为我们认为值得进行后期开发的药物启动关键性开发，几年前，当所有这些发生时，我们为几个不同项目启动了一系列后期开发，有趣的是，这导致了一系列相当集中的结果，12 个月内有 8 个随机试验结果。这可能是莉莉在肿瘤学领域拥有的最集中的后期结果数量。其中大多数都取得了成功。当然，并非所有都会成功。这就是这个行业的运作方式。我希望它是，但通常不是。但其中大多数都成功了，这对患者来说真的很棒。这对推动我们的药物获得批准和新适应症真的很有帮助。还有一个即将到来。这是 imlunestrant EMBER-3 第 III 期研究，是第二线 ER 阳性转移性乳腺癌口服 SERD 的第 III 期研究。今晚晚些时候我们将从莉莉安那里听到更多相关信息。今年晚些时候将有一项重要的第 III 期研究针对该药物。

And of course, all of the discovery retooling has led to an unusually active agenda for new clinical trial starts in calendar 2024, 8 new clinical trial starts for new molecular entities this year, 3 of whom have already dosed their first patients. The rest are still on track to happen throughout the remainder of the year. Perhaps not coincidental that this is such a robust year for new clinical starts. We started this process, as I mentioned about 4 years ago. That's roughly how long it takes in sort of a best-case scenario to make a new medicine from scratch against the standards that we hold ourselves to. And so it's really this bolus of early phase momentum that I think allows us to feel like we're starting a new chapter for oncology R&D here at Lilly.

当然，所有的发现重组工作已经导致了 2024 年日历中新临床试验启动日程异常活跃，今年有 8 个新的分子实体的临床试验启动，其中 3 个已经给他们的第一个患者注射了剂量。其余的仍然按计划将在今年余下的时间内进行。也许这对于新临床启动来说是一个如此强劲的一年并非巧合。正如我大约 4 年前提到的那样，我们开始了这个过程。这大致是在最理想情况下从零开始制造一种新药物所需的时间，符合我们自己设定的标准。因此，我认为这真的是早期阶段动力的一股潮流，让我们感觉我们正在为 Lilly 的肿瘤学研发开启新篇章。

While we've been doing this on the R&D side, of course, we've been busy [indiscernible] launching new indications for other medicines. And that's been going pretty well, especially as of late. The growth that we've seen commercial in the portfolio has been pretty robust, especially across our 3 key growth brands, Verzenio, Retevmo and Jaypirca. Verzenio bemaciclib, a medicine that we all know well, has really had a tremendous couple of years for patients, particularly those with high-risk early breast cancer. We're about 2 years into the launch of that indication for this medicine, and it is very clearly now the standard of care for these patients. It's a 2-year regimen and then patients are finished that I think has really bent the curve for patients with high-risk EBC, especially with the increased follow-up that we've had on the monarchE study and the duration and frankly, expansion of benefit even when patients have finished the regimen.

在我们在研发方面一直在进行这项工作的同时，当然，我们一直在忙于为其他药物推出新适应症。而且，最近情况一直不错。我们在组合产品的商业增长方面表现相当强劲，尤其是在我们的三个关键增长品牌 Verzenio、Retevmo 和 Jaypirca。Verzenio 贝马西利，这是我们都非常熟悉的一种药物，对于患有高危早期乳腺癌的患者来说，过去几年真的是非常了不起。我们已经推出了这种药物的这种适应症约 2 年时间，现在很明显已经成为这些患者的标准治疗。这是一个为期 2 年的疗程，然后患者就完成了，我认为这确实为患有高危早期乳腺癌的患者改变了疾病进展的曲线，尤其是我们在 monarchE 研究中增加了随访时间以及受益的持续时间和扩展，即使患者完成了疗程。

Uptake in this indication has been fairly brisk. We estimate that about 60% of the eligible population now receives this regimen, which is sort of an interesting work shack test of how you think that is. If there were any other therapeutic area, 60% 2 years into a launch, we feel pretty good. Unfortunately, in oncology, especially in a curative setting, we're not satisfied with that. So we have work to do to make sure that every eligible patient in the curative setting of high-risk EBC has the potential to benefit from this regimen. And we're going to continue working until we get as close to 100% as we can.

在这个适应症中，吸收速度相当迅速。我们估计大约 60%的符合条件的人群现在接受这种方案，这在某种程度上是一个有趣的工作枷锁测试，看看你认为如何。如果是其他治疗领域，推出 2 年后达到 60%，我们会感到相当满意。不幸的是，在肿瘤学中，特别是在治愈设置中，我们对此并不满意。因此，我们需要努力确保每位符合条件的高危早期乳腺癌患者都有可能从这种方案中受益。我们将继续努力工作，直到我们尽可能接近 100%。

Jaypirca, pirtobrutinib is our newest approved medicine in oncology. This is the non-covalent BTK inhibitor. We have 2 indications under accelerated approval that were both approved last year, first in relapsed mantle cell lymphoma; second, in relapsed CLL both admittedly small indications to start. Although interestingly, we found that the CLL indication, which is for patients who've already received at least a covalent BTK inhibitor and venetoclax or BCL-2 inhibitor, it's probably a larger indication than we initially thought. The growth in those medicines over the past couple of years have led to an increasing population of patients who've now relapsed those medicines and have extremely poor outcomes that Jaypirca can really offer a nice durable disease control for them. So we're continuing to execute commercially to bring this medicine to patients.

杰派卡，皮托布鲁替尼是我们在肿瘤学领域最新获批准的药物。这是一种非共价 BTK 抑制剂。我们有两个适应症在加速批准下，去年都获得了批准，第一个是复发性套膜细胞淋巴瘤；第二个是复发性慢性淋巴细胞白血病，起初都是较小的适应症。有趣的是，我们发现慢性淋巴细胞白血病适应症，针对的是那些已经至少接受过共价 BTK 抑制剂和维诺替克拉或 BCL-2 抑制剂的患者，可能比我们最初想象的更大。过去几年这些药物的增长导致了一个不断增加的患者群体，他们现在复发了这些药物，并且预后非常糟糕，而杰派卡可以为他们提供良好持久的疾病控制。因此，我们将继续商业化推广，将这种药物带给患者。

It's been interesting. We've gotten a lot of anecdotal feedback from patients and from physicians about their initial experience with this medicine, particularly those who weren't involved in the clinical trial program. So this is really their first experience and just great things to say about what the medicine has been able to do for patients in terms of both efficacy and tolerability. I say that because we're still really in the earliest innings of the overall life cycle of this brand. You'll hear from John a little bit later tonight about the large development portfolio here. Most of which hasn't actually read out yet. So there's a lot more indications to come for this drug. And the early signs of its adoption as well as just the experience that patients and physicians have had, I think, bode really nicely for the medicine's potential future.

这是非常有趣的。我们收到了许多关于患者和医生对这种药物的初次体验的趣闻反馈，特别是那些没有参与临床试验计划的人。所以这确实是他们的第一次体验，他们对这种药物在疗效和耐受性方面对患者所能做到的事情有很多好话要说。我这么说是因为我们仍然处于这个品牌整体生命周期的最早阶段。今晚稍后你会听到约翰关于这里的大型开发组合的介绍。其中大部分实际上还没有公布。所以这种药物还有更多适应症要推出。以及患者和医生们的早期接受迹象，我认为，这对于药物未来的潜力非常有利。

So you're going to hear now from the team about our investigational portfolio for the most part. And as we've been working over the past couple of years to speed our medicine delivery to patients. We have worked tirelessly to squeeze out every ounce of efficiency from every part of the drug development cycle and yet we still face a pretty significant bottleneck, which is actually clinical trial enrollment. It remains by far biggest bottleneck to getting our medicines to patients. Our trials just do not enroll as quickly as we want them to. And yet ironically, particularly in the United States, clinical trial enrollment is not a priority for the health care system. 7% of U.S. cancer patients ever enroll in a clinical trial despite it being a great way to access great care, to access standard of care oftentimes to access new investigational medicine. So I mentioned it here tonight because you're going to be hearing more from us in the future about this.

所以现在您将从团队那里听到我们大部分的调查组合。 正如我们在过去几年中一直在努力加快向患者提供药物的速度。 我们不知疲倦地努力从药物开发周期的每个部分中挤出每一丝效率，但我们仍然面临一个相当重要的瓶颈，那就是临床试验招募。 它仍然是将我们的药物送到患者手中的最大瓶颈。 我们的试验并没有像我们希望的那样快速招募。 然而具有讽刺意味的是，特别是在美国，临床试验的招募并不是卫生保健系统的优先事项。 尽管临床试验是获得优质护理、通常是获得标准护理的绝佳途径，也是获得新的调查性药物的途径，但美国只有 7%的癌症患者曾参与临床试验。 我今晚在这里提到它，因为您将在未来听到更多关于这方面的信息。

We are -- we've initiated a new effort this year to try and change perceptions about clinical trials in the United States, in particular, and really do more to broaden clinical trial access for patients in this country. You'll hear a little bit later tonight about the first Phase III trial for olomorasib, or KRAS G12C inhibitor in lung cancer, which is really the first study where we're piloting actually a lot of new ideas for trial implementation to try and broaden access. So I'll just give you a flavor for what that's like and you hear about the study from Jeff in a bit.

我们今年启动了一项新的努力，试图改变美国临床试验的看法，特别是真正为了扩大本国患者参与临床试验的机会。您稍后将听到关于奥洛莫拉西布（或 KRAS G12C 抑制剂）在肺癌中的第三期试验的消息，这实际上是我们正在试点许多新的试验实施理念的第一项研究，以扩大参与机会。所以我只是给你一点点味道，稍后您将从杰夫那里听到有关这项研究的信息。

We're allowing entirely local biomarker testing. So whatever patients and providers are using to identify let's say, PD-L1 levels or KRAS mutations, that liquid biopsy or solid tumor biopsy makes them eligible for the study.

我们允许完全本地生物标志物测试。因此，无论患者和医生使用什么来识别，比如 PD-L1 水平或 KRAS 突变，液体活检或实体肿瘤活检都使他们有资格参加研究。

We're allowing a cycle of standard of care medicines prior to even coming on to the study because we recognize that for patients who are newly diagnosed, they may be waiting for those biomarker results. They may be nervous about a clinical trial and not know how to think about it. They may be going through the study screening procedures. We're allowing a cycle of standard of care before coming on to our program.

我们允许在进入研究之前使用标准护理药物周期，因为我们意识到对于新诊断的患者来说，他们可能正在等待生物标志物结果。他们可能对临床试验感到紧张，不知道如何思考。他们可能正在进行研究筛查程序。在加入我们的计划之前，我们允许使用标准护理周期。

And interestingly, we're doing something that I think is a first, actually, certainly a first at Lilly, I think, a first for industry, which is that we're actually paying for all standard of care procedures on the study in addition to the medicines themselves. So CAT scans, labs, all of the things that would normally just be built to insurance, we're actually paying for. This is actually the normal course for every other disease that we work on at Lilly. We probably should have implemented this in oncology years ago, but we're doing it now because it's the right thing to do to. and if we're going to change the way that patients and providers think about clinical trials, particularly in the community, we really need to eliminate every barrier we possibly can. So you'll be hearing more about this from us over the coming months and years. I hope we're able to make it dent here.

有趣的是，我们正在做一件我认为是第一次的事情，实际上，至少在 Lilly，我认为是第一次在行业中，那就是我们实际上支付了研究中所有标准护理程序的费用，除了药物本身。因此，CAT 扫描、实验室检查，所有通常只需向保险公司报销的费用，我们实际上都在支付。这实际上是我们在 Lilly 从事的其他每种疾病的正常做法。我们可能应该在多年前在肿瘤学中实施这一做法，但现在我们正在这样做，因为这是正确的做法。如果我们要改变患者和医疗提供者对临床试验的看法，特别是在社区中，我们确实需要尽可能消除每一个障碍。因此，在未来几个月和几年里，您将会从我们这里听到更多相关信息。我希望我们能够在这里取得进展。

And in the meantime, I'm going to hand the mic over to my colleague, Dr. Lillian Smyth, who's going to walk us through our breast cancer portfolio.

与此同时，我将把麦克风交给我的同事，Lillian Smyth 博士，她将为我们介绍乳腺癌产品组合。

Lillian Smyth 莉莲·斯密斯

Thanks, Jake. Hi, everyone. Good to see you. I'm Lillian Smyth. I'm a medical oncologist. I was previously on faculty with the breast medicine and early drug development service of Memorial Sloan Kettering. So I used to see breast cancer patients in my [indiscernible]. I was also a clinical trial investigator enrolling to many studies. In the last few years, I joined Lilly, and now I lead development of our breast cancer medicines.

谢谢，杰克。大家好。很高兴见到你们。我是莉莲·斯密斯。我是一名医学肿瘤学家。我之前在纪念斯隆凯特琳癌症中心的乳腺医学和早期药物开发服务担任教职。所以我过去常常看乳腺癌患者。我也是临床试验研究者，参与了许多研究。在过去几年里，我加入了礼来公司，现在我负责我们乳腺癌药物的开发。

So let's jump right into Verzenio. So as you know, abemaciclib is our oral potent CDK4/6 inhibitor with greater selectivity for CDK4 than 6, which allows us to continually dose this medicine due to less myelosuppression. Shown here are the pivotal studies that we've conducted across the entire hormone-positive HER2-negative breast cancer continuum that have led to key indications for abemaciclib. We know that abemaciclib is approved in advanced breast cancer is monotheraphy with a combination with [indiscernible] therapy, and abemaciclib is the first and only CDK4/6 inhibitor approved for the treatment of patients with high-risk early breast cancer.

让我们直接进入 Verzenio。正如您所知，abemaciclib 是我们口服强效 CDK4/6 抑制剂，对 CDK4 的选择性更高于 6，这使我们能够持续给药这种药物，减少骨髓抑制。这里展示了我们在整个激素受体阳性 HER2 阴性乳腺癌连续谱上进行的关键研究，这些研究为 abemaciclib 的关键适应症提供了依据。我们知道 abemaciclib 在晚期乳腺癌中作为单药治疗或与[无法辨认]治疗联合使用获得批准，abemaciclib 是首个也是唯一一个获批用于治疗高危早期乳腺癌患者的 CDK4/6 抑制剂。

I'm also going to talk to you a little bit about the post-MONARCH study, which you may have seen was presented at ASCO yesterday, addressing a very important question for the community about CDK4/6 inhibitor sequencing with fulvestrant and abemaciclib after progression on a CDK4/6 inhibitor.

我还会跟你们谈一下关于 MONARCH 后研究的一些内容，你们可能已经看到昨天在 ASCO 上发布的内容，这个内容针对社区关于 CDK4/6 抑制剂在 CDK4/6 抑制剂进展后与 fulvestrant 和 abemaciclib 的顺序进行了回答非常重要的问题。

So obviously, there's been a lot of noise about the evolving adjuvant CDK4/6 inhibitor landscape. So I just wanted to remind you about the data that we have with monarchE. As you know, monarchE was the only adjuvant CDK4/6 inhibitor study designed actually for patients with high-risk disease. And we now have a very mature data set with all patients off therapy and in long-term follow-up.

显然，关于不断发展的辅助性 CDK4/6 抑制剂领域已经有很多讨论。我只是想提醒您我们在 monarchE 研究中所获得的数据。正如您所知，monarchE 是唯一一个专为高危疾病患者设计的辅助性 CDK4/6 抑制剂研究。我们现在拥有一个非常成熟的数据集，所有患者都已停止治疗，并处于长期随访中。

Shown here is the 5-year outcome data, which is a really important landmark for this disease. And you can see clear separation of the curves well beyond the treatment period. This is what we call carryover effect that we're seeing from abemaciclib Ultimately, of 5 years, we have seen a 32% reduction in the risk of developing an IDFS event, which translates to almost an 8% absolute difference in the risk of IDFS at 5 years.

这里展示的是 5 年的结果数据，这对于这种疾病来说是一个非常重要的里程碑。您可以看到曲线在治疗期之后有明显的分离。这就是我们所说的从阿贝曲唑带来的延续效应。最终，在 5 年的时间里，我们看到发生 IDFS 事件的风险降低了 32％，这意味着在 5 年时 IDFS 风险减少了近 8％的绝对差异。

Abemaciclib and endocrine therapy is the globally approved standard adjuvant therapy for high-risk early breast cancer, with the category 1 NCCN designation and a strong ASCO guideline recommendation.

Abemaciclib 和内分泌治疗是全球批准的高危早期乳腺癌辅助治疗的标准，具有 1 类 NCCN 指定和强烈的 ASCO 指南推荐。

Now let's touch on the post-MONARCH study. So we saw these data presented by Kevin Klinsky yesterday. And to remind you, the post-MONARCH study addressed a question about continuing CDK4/6 inhibition beyond progression on a CDK4/6 inhibitor first line. Patients received abemaciclib plus fulvestrant or fulvestrant alone. And you can see here at the primary analysis, abemaciclib added to fulvestrant, improved investigator-assessed progression-free survival with a hazard ratio of 0.73. And just to put these data in context, we know that there is a really high unmet need to optimize therapy in that post-CDK4/6 inhibitor setting. And when you look at these data and when you consider that the standard care is quite fractured actually in the second line with CDK setting. Targeted therapy options are limited and are associated with varying toxicity.

现在让我们谈一下 MONARCH 研究后续研究。昨天我们看到了 Kevin Klinsky 提出的这些数据。提醒一下，MONARCH 后续研究探讨了关于在 CDK4/6 抑制剂一线治疗进展后继续使用 CDK4/6 抑制剂的问题。患者接受了阿贝曲单抗加富马酸雌二醇或仅富马酸雌二醇。在主要分析中，阿贝曲单抗加入富马酸雌二醇，改善了研究者评估的无进展生存期，风险比为 0.73。仅仅将这些数据放在背景中，我们知道在 CDK4/6 抑制剂后续治疗中有一个非常高的未满足需求，需要优化治疗。当您查看这些数据并考虑到标准护理实际上在第二线 CDK 设置中相当分散时。靶向治疗选择有限，并且与不同的毒性有关。

Fulvestrant and abemaciclib offers a simple treatment solution with an observed treatment effect that is at least directionally similar to what we've seen with approved targeted therapies. The conclusions from this study is that post-MONARCH is the first Phase III randomized placebo-controlled study to demonstrate the benefit of continued CDK4/6 inhibition after progression on a CDK4/6 inhibitor. In this trial, abemaciclib improved progression-free survival despite the control arm performing better than expected with a 27% risk reduction for developing a PFS event, consistent benefit across multiple prespecified and clinically relevant subgroups, including key biomarker subgroups and a consistent improvement across key efficacy endpoints. Safety in this study was consistent with what we know about abemaciclib and discontinuation rate importantly was low at 6%.

富马酸氟维司特和阿贝曲唑提供了一个简单的治疗方案，观察到的治疗效果至少在方向上与我们在已批准的靶向治疗中看到的类似。这项研究的结论是，MONARCH 后是第一个展示在 CDK4/6 抑制剂进展后继续 CDK4/6 抑制的益处的 III 期随机安慰剂对照研究。在这项试验中，阿贝曲唑改善了无进展生存期，尽管对照组表现优于预期，发生 PFS 事件的风险降低了 27％，在多个预先指定和临床相关亚组中保持一致的益处，包括关键生物标志物亚组，并在关键疗效终点上保持一致的改善。这项研究的安全性与我们对阿贝曲唑的了解一致，而且停药率低，仅为 6％。

Abemaciclib and fulvestrant offers a targeted therapy option after disease progression on a CDK4/6 inhibitor for patients with hormone positive HER2-negative advanced breast cancer not selected for biomarker status. And we think that these results really have the opportunity to complement EMBER-3 as what Jake mentioned, which is our Phase III study, which will read out later next year or later this year with our oral third imlunestrant.

阿贝曲唑和富维司替联合使用，为激酶 4/6 抑制剂治疗后疾病进展的激素受体阳性 HER2 阴性晚期乳腺癌患者提供了一种靶向治疗选择，未选择生物标志物状态。我们认为这些结果确实有机会作为 Jake 提到的 EMBER-3 的补充，这是我们的 III 期研究，将在明年晚些时候或今年晚些时候公布我们的口服第三代伊姆鲁内斯特。

Now talking about imlunesterant. This is our brain-penetrant oral search designed for continuous ER target inhibition, including an ESR1 mutant breast cancer. As I mentioned, there is no clear standard of care after receipt of a CDK4/6 inhibitor in the first-line setting, although I've shown you just some evidence for abemaciclib from post-MONARCH-in this setting.

现在谈论 imlunesterant。这是我们设计的可穿透大脑的口服药物，用于持续抑制 ER 靶点，包括 ESR1 突变的乳腺癌。正如我所提到的，在接受第一线治疗后，尚无明确的护理标准，尽管我已经向您展示了一些关于 abemaciclib 的证据，这些证据来自于 MONARCH 后的这种情况。

There is also no SERD approved in combination with the CDK4/6 inhibitor or indeed in the adjuvant setting. So the thesis of our program was twofold: to develop an oral SERD that could differentiate in the advanced breast cancer setting by combining with abemaciclib, including in that pretreated CDK4/6 population. And then secondly, to displace standard of care adjuvant endocrine therapy in the adjuvant setting.

目前也没有与 CDK4/6 抑制剂联合使用或者在辅助治疗中获批准的 SERD。因此，我们项目的论点有两个：一是开发一种口服 SERD，通过与阿贝曲唑联合治疗，包括在已接受 CDK4/6 抑制剂治疗的晚期乳腺癌患者中进行区分。其次，是在辅助治疗中取代标准的内分泌治疗。

In terms of the Phase I data that we've generated from our EMBER Phase I study with imlunestrant, we've seen encouraging clinical efficacy, particularly in that second line post-CDK4/6 inhibitor setting, which is the subject of our ongoing Phase III EMBER study and we've seen efficacy of imlunestrant alone but also in combination with standard of care targeted therapies shown here on the far right panel, we've evaluated imlunestrant with abemaciclib with everolimus and alpelisib, all therapies that we use in the clinic.

就我们从 EMBER I 期研究中使用 imlunestrant 生成的数据而言，我们看到了令人鼓舞的临床疗效，特别是在 CDK4/6 抑制剂后的第二线治疗中，这也是我们正在进行的 EMBER III 期研究的主题。我们不仅看到了 imlunestrant 单药的疗效，还看到了与标准治疗靶向疗法结合使用时的疗效，我们评估了 imlunestrant 与 abemaciclib、everolimus 和 alpelisib 的联合应用，这些都是我们在临床中使用的治疗方案。

From a safety perspective, imlunestrant's monotherapy is well tolerated, and importantly, it safely combines with standard of care targeted therapies.

从安全性的角度来看，伊姆鲁内斯坦的单药疗法耐受性良好，并且重要的是，它可以安全地与标准治疗靶向疗法结合使用。

As I mentioned, our pivotal registration studies are ongoing, and include EMBER-3, which is our first Phase III study in the advanced breast cancer setting. This study enrolls patients who have received an imlunestrant inhibitor with or without a CDK4/6 inhibitor across 3 study arms: imlunestrant alone, investigator's choice endocrine therapy or imlunestrant in combination with abemaciclib. We have dual end point evaluation in both the ITT and ESR1 mutant population. And this study represents the first evaluation of [indiscernible], in combination with the CDK4/6 inhibitor in a Phase III study in the second-line setting. This should position us for dual approval, both as monotherapy and in combination with Verzenio. And although we are aware of the risks of studies like this, we are looking forward to seeing the data later this year. And if positive, this study positions imlunestrant to be the second oral third to market and the first in combination with the CDK4/6 inhibitor.

正如我所提到的，我们的关键注册研究正在进行中，包括 EMBER-3，这是我们在晚期乳腺癌领域的第一项 III 期研究。该研究招募接受过 imlunestrant 抑制剂治疗的患者，分为 3 个研究组：单独使用 imlunestrant、研究者选择的内分泌治疗或 imlunestrant 与 abemaciclib 联合使用。我们在 ITT 和 ESR1 突变人群中进行双重终点评估。该研究代表了第一次评估[indiscernible]与 CDK4/6 抑制剂联合在第二线治疗中的 III 期研究。这将使我们有望获得双重批准，既作为单药疗法，又与 Verzenio 联合使用。尽管我们意识到这类研究的风险，但我们期待今年晚些时候看到数据。如果结果积极，这项研究将使 imlunestrant 成为第二种口服第三代市场药物，也是第一种与 CDK4/6 抑制剂联合使用的药物。

EMBER-4 is our adjuvant study, enrolling early breast cancer patients who have already received 2 to 5 years of adjuvant endocrine therapy, which may have included a CDK4/6 inhibitor. We are randomizing 6,000 patients across 2 study arms, 5 years of imlunestrant or 5 years of continued standard adjuvant endocrine therapy. This trial evaluates a sequencing strategy for patients who write increased risk of recurrence and really positions us to address the full continuum of the adjuvant treatment journey. And you can envisage a future state if EMBER-4 is positive, where patients are sequencing from up-front abemaciclib and endocrine therapy then to imlunesterant to complete their adjuvant therapy journey, which for many patients is 7 to 10 years, particularly for those that increased risk. This is the largest oncology trial we have ever conducted it clearly, and we're looking forward to see this study complete in 2027.

EMBER-4 是我们的辅助研究，招募已接受 2 至 5 年辅助内分泌治疗（可能包括 CDK4/6 抑制剂）的早期乳腺癌患者。我们将在 2 个研究分组中随机分配 6,000 名患者，其中一个组接受 5 年伊姆卢内斯坦治疗，另一个组继续标准辅助内分泌治疗 5 年。该试验评估了一种适用于有复发风险的患者的顺序治疗策略，真正使我们能够处理辅助治疗旅程的全部连续过程。如果 EMBER-4 结果积极，您可以设想未来状态，患者从最初的阿贝马西利和内分泌治疗开始，然后转为伊姆卢内斯坦以完成他们的辅助治疗旅程，对于许多患者来说，这个旅程需要 7 至 10 年，特别是对于那些有增加风险的患者。这是我们迄今为止进行的最大的肿瘤学试验，显然，我们期待着在 2027 年看到这项研究的完成。

So finally, ending on LOXO-783. This is our highly mutant selective H1047R allosteric inhibitor. And just to grant you in the landscape, we know that these H1047R mutation, they're actually the most common [indiscernible] mutations that we see in our clinic. They occur in 15% of breast cancer. And the limitation of current therapies, current AKT and PI3-kinase inhibitors are not wild-type sparing, are not mutant selective same thing, meaning that they lead to wild-type mediated toxicities, particularly hybrid lycemia, skin toxicity and GI toxicity. And so the thesis of our program was to develop a mutant selective inhibitor that spares wild type entirely and would lead to superior tolerability and efficacy in the clinic.

最后，以 LOXO-783 结束。这是我们高度突变选择性的 H1047R 变构抑制剂。只是为了让您了解，我们知道这些 H1047R 突变实际上是我们诊所中看到的最常见的[不可辨识]突变。它们在乳腺癌中发生率为 15%。目前治疗的局限性在于，目前的 AKT 和 PI3-激酶抑制剂不是野生型保留的，也不是突变选择性的，这意味着它们会导致野生型介导的毒性，特别是混合性白血病、皮肤毒性和胃肠道毒性。因此，我们项目的主旨是开发一种突变选择性抑制剂，完全保留野生型，并在临床上具有更优越的耐受性和疗效。

783 preclinically shown on the far right panel here achieves significant tumor regression as monotherapy when compared to [indiscernible] but importantly, does not lead to increases in insulin or C peptide.

在这里最右侧的面板上显示，783 在单药治疗时实现了显著的肿瘤减退，与[不可辨识]相比，但重要的是，它不会导致胰岛素或 C 肽的增加。

We've also generated other preclinical data of 783 in combination with endocrine therapy and CDK4/6 inhibitors, and here, we see additive efficacy with those combinations.

我们还生成了 783 与内分泌治疗和 CDK4/6 抑制剂联合应用的其他临床前数据，在这里，我们看到这些组合具有附加疗效。

Our Phase I study the [indiscernible] trial is ongoing, and we're looking forward to sharing data later this year and [indiscernible] to say that LOXO-783 is part of a broad discovery campaign that we have against this target. And in fact, we're continuing to advance next-generation molecule to be clinic ready in 2025 as we continue to find the clinical profile of 783. As you know, we've been planning for a little while now, evaluating 783 as monotherapy and in combination and continuing to refine our understanding of the efficacy profile.

我们的 I 期研究[不可辨识]试验正在进行中，我们期待在今年晚些时候分享数据，并且[不可辨识]很高兴地说 LOXO-783 是我们针对这一靶点进行的广泛发现活动的一部分。事实上，我们正在继续推进下一代分子，以便在 2025 年准备进入临床，同时继续发现 783 的临床特征。正如您所知，我们已经计划了一段时间，评估 783 作为单药疗法和联合疗法，并继续完善我们对疗效特征的理解。

Really, the first important goal of this program was to establish have we developed a truly mutant selective inhibitor that spares wild type and avoids hyperglycemia? We have. LOXO-783 does not cause hyperglycemia in the clinic.

这个项目的第一个重要目标实际上是建立我们是否开发出一种真正的突变选择性抑制剂，它能保留野生型并避免高血糖？我们已经做到了。LOXO-783 在临床上不会引起高血糖。

From an efficacy perspective, this medicine has efficacy, and we're continuing to refine whether that efficacy is good enough in the context of the evolving therapeutic landscape and also the advances we've made in our own discovery campaign with molecules that are near clinic-ready for 2025. So with that, I'll hand you over to Dr. John Pagel to continue the portfolio review.

从疗效的角度来看，这种药物具有疗效，我们正在继续完善在不断发展的治疗格局和我们自己的发现活动中，对于 2025 年即将进入临床的分子是否足够有效的问题。因此，我将把话题转交给约翰·佩格尔博士，继续进行投资组合审查。

John Pagel 约翰·佩格尔

Good evening, everyone. I'm the guy that brought the water up, struggling a bit with my voice. So bear with me if you could. Thanks for joining us. I am the Global Head of Development for Hematology here at Lilly. I'm going to give you a little bit more about the development of Jaypirca, although, of course, Jake's introduced that a little bit for us tonight. And I'm going to tell you about a new drug that's just entered the clinic targeting the full receptor using a novel antibody drug conjugate.

大家晚上好。我是那个提水上来的家伙，我的声音有点吃力。如果可以的话，请大家谅解。感谢大家的参与。我是 Lilly 公司这里血液学全球发展负责人。我将为大家介绍更多关于 Jaypirca 的发展情况，当然，Jake 今晚已经为我们做了一点介绍。我将告诉大家关于一种新药物，它刚刚进入临床阶段，使用一种新型抗体药物结合物靶向完整受体。

About 2.5 years ago, I joined Lilly, but before that time, I spent more than 20 years in academia doing translational research. I had a research lab, and I saw patients with blood cancers. And it was during that time where I was an investigator on the Phase I/II BRUIN study exploring the use of Jaypirca in patients with relapsed peel malignancies. And I saw firsthand on what this drug did for patients. And because of that, I wanted to be closer to its development.

大约 2.5 年前，我加入了 Lilly，但在那之前，我在学术界从事了 20 多年的转化研究。我有一个研究实验室，并且看诊血液癌症患者。就在那段时间，我是 BRUIN 研究的一期/二期调查员，探索 Jaypirca 在复发性皮肤恶性肿瘤患者中的应用。我亲眼见证了这种药物对患者的作用。正因为如此，我希望更接近它的发展。

Of course, you know a lot about Jaypirca. I'll remind you that it is a Bruton's tyrosine kinase inhibitor, but it's a different type of BTK inhibitor. It is very highly selective, but importantly, it is a noncovalent BTK inhibitor, and it's really been designed to overcome the limitations of the covalent BTK inhibitors. And as you have heard and based on our strong efficacy and well-tolerated safety results from the Phase I/II BRUIN study, the FDA-approved Jaypirca for relapsed mantle cell lymphoma patients after 2 prior lines of therapy, including a BTK inhibitor, and in CLL after 2 prior lines of therapy after both a BTK and BCL-2 inhibitor.

当然，您对 Jaypirca 了解很多。我提醒您，它是一种 Bruton 酪氨酸激酶抑制剂，但它是一种不同类型的 BTK 抑制剂。它非常高度选择性，但更重要的是，它是一种非共价 BTK 抑制剂，实际上是为了克服共价 BTK 抑制剂的局限性而设计的。正如您所听到的，基于我们在 I/II 期 BRUIN 研究中强大的疗效和良好的耐受性结果，FDA 批准了 Jaypirca 用于在经历了 2 种先前治疗方案（包括 BTK 抑制剂）后复发的外套膜细胞淋巴瘤患者，以及在经历了 2 种先前治疗方案（包括 BTK 和 BCL-2 抑制剂）后的 CLL 患者。

And you can see on this slide, we have a comprehensive suite of Phase III studies, and I'm going to mention a little bit more in detail in just a subsequent slide. But first, I want to tell you a little more again about the efficacy of Jaypirca. These are the waterfall plots showing tumor size reduction in patients on the left with CLL. All of these patients had received prior covalent BTK inhibitor and in mantle cell lymphoma, which is on the right. And again, all of these patients had received prior BTK inhibitor.

在这张幻灯片上，您可以看到我们有一套全面的三期研究，我将在接下来的幻灯片中详细介绍一些内容。但首先，我想再次向您介绍一下 Jaypirca 的疗效。这些是显示慢性淋巴细胞白血病患者肿瘤大小减小的瀑布图，左侧是已接受过共价 BTK 抑制剂治疗的患者。右侧是辅助细胞淋巴瘤患者。同样，所有这些患者都曾接受过 BTK 抑制剂治疗。

These patients are very difficult patients. Not only had they received prior BTK inhibitor therapy, but many other classes of therapy. And in particular, if you see on the left, those CLL patients, all again, who had received a covalent BTK inhibitor, many of them had received as well a BCL-2 inhibitor, venetoclax. And that's represented by all the aspects that are at the bottom of those vertical bars representing an individual patient tumor size reduction. That's important because that is a patient population that historically has been of high unmet need due to actually very poor survival.

这些患者是非常困难的患者。他们不仅接受过先前的 BTK 抑制剂治疗，还接受过许多其他类别的治疗。特别是，如果您看到左边，那些 CLL 患者，再次，他们中的许多人已经接受了共价结合的 BTK 抑制剂，其中许多人也接受了 BCL-2 抑制剂 venetoclax。这由那些垂直条底部的所有方面代表，这些方面代表了个体患者肿瘤大小的减小。这很重要，因为这是一个历史上存在高度未满足需求的患者群体，实际上生存率非常低。

Similarly, on the right, we see a pattern of patients treated again with a covalent BTK inhibitor, but also many other lines of therapy, including lines of chemo immunotherapy as well. And this is also a patient of high unmet need. This patient population historically has had survival of 6 months or less.

同样，在右侧，我们看到一组患者再次接受共价结合的 BTK 抑制剂治疗的模式，但也有许多其他治疗线，包括化疗免疫疗法等。这也是一个高度未满足需求的患者。这一患者群体在历史上的存活期通常为 6 个月或更短。

We have built on these robust responses from this study to develop a comprehensive advanced series of Phase III studies, and those are shown here. We have tried to explore the use of Jaypirca through multiple different treatment settings. This includes first-line second line using continuous therapy as well as fixed duration therapy.

我们已经基于这项研究中的强有力反应，开展了一系列全面的第三阶段研究，这些研究结果显示在这里。我们尝试探索在多种不同治疗设置中使用 Jaypirca。这包括一线和二线使用持续疗法以及固定疗程疗法。

We recognize that there's a need for improving on the therapies and as well as improving on the tolerability profile of the medicine. And therefore, we are comparing Jaypirca to globally established combination therapies, including covalent BTK inhibitors or chemoimmunotherapy.

我们意识到需要改进治疗方法，以及改善药物的耐受性概况。因此，我们正在将 Jaypirca 与全球已建立的联合疗法进行比较，包括共价 BTK 抑制剂或化疗免疫疗法。

Also, we recognize that there are some patients who, where a fixed duration approach might be important for them. So we are enrolling patients in a relapsed CLL trial using Jaypirca in combination with venetoclax. That study is now continuing to enroll.

此外，我们意识到有些患者可能需要采用固定疗程方法。因此，我们正在招募患有复发性 CLL 的患者，使用 Jaypirca 与维诺替克拉合并治疗。该研究目前正在继续招募患者。

The other 4 company-sponsored studies shown here have all completed enrollment. We expect to enroll about 2,200 patients over these company-sponsored studies and look forward to them reading out over the next couple of years.

这里显示的其他 4 项由公司赞助的研究已经完成了招募。我们预计在这些由公司赞助的研究中招募约 2200 名患者，并期待它们在接下来的几年内公布结果。

I will note the BRUIN 321 study, that will be our first readout of a randomized Phase III study that's our study comparing Jaypirca to idelisiband rituximab or bendamustine and rituximab and we anticipate those results being reported again later this year.

我将注意 BRUIN 321 研究，这将是我们首次读取的随机 III 期研究，这是我们比较 Jaypirca 与 idelisiband 利妥昔单抗或苯达莫司汀和利妥昔单抗的研究，我们预计这些结果将在今年晚些时候再次报告。

Lastly, I want to point out on the far right, the BRUIN CLL-18 trial. We're excited about this trial. This is a trial that will be run through the German CLL study group. It's anticipated to begin later this year. This is a trial using Jaypirca in combination with venetoclax and a fixed duration approach in the first line.

最后，我想指出在最右边的 BRUIN CLL-18 试验。我们对这项试验感到兴奋。这是一项将通过德国 CLL 研究小组进行的试验。预计将于今年晚些时候开始。这是一项在一线使用 Jaypirca 与 venetoclax 和固定疗程方法结合的试验。

Overall, I think you can see that these studies show the confidence not only in relapsed/refractory CLL of Jaypirca but also in the first line and with fixed duration therapy.

总的来说，我认为您可以看到这些研究不仅显示了对 Jaypirca 复发/难治 CLL 的信心，也显示了对首选治疗和固定疗程的信心。

Okay. I told you that I've lead development in hematology. However, we have lots of medicines that are entering the clinic as you can see and many of them simultaneously. So I do lead other programs, and this is one of them.

好的。我告诉过你，我在血液学方面领导开发。然而，正如你所看到的，我们有许多药物正在进入临床试验，而且其中许多是同时进行的。因此，我也领导其他项目，这就是其中之一。

Of course, we also are very aware that recently, the FDA-approved an antibody drug conjugate targeting the full receptor for patients with relapsed ovarian carcinoma and that's Elahere. Elahere was shown to be superior to investigator's choice of chemotherapy in third-line ovarian cancer patients, but only those who have high folate receptor expression. We also know that Elahere has some significant toxicities, including ocular toxicity. So we recognize that there's an opportunity to establish a new standard of care, not only targeting those patients who might have a high folate expression, but low and moderate expression levels as well. And hopefully, that would be relatively well tolerated.

当然，我们也非常清楚最近 FDA 批准了一种靶向全受体的抗体药物结合物，用于复发性卵巢癌患者，这就是 Elahere。Elahere 被证明优于第三线卵巢癌患者的化疗选择，但仅限于那些具有高叶酸受体表达的患者。我们也知道 Elahere 具有一些显著的毒性，包括眼部毒性。因此，我们认识到有机会建立一个新的护理标准，不仅针对那些可能具有高叶酸表达的患者，还包括叶酸表达水平低和中等的患者。希望这种治疗相对耐受。

This is an antibody drug conjugate that uses a topoisomerase payload and has a drug antibody ratio that's high, and we have significant excitement around this product, and it's actually now just entered the clinic.

这是一种抗体药物结合物，使用拓扑异构酶荷载，药物抗体比高，我们对这个产品感到非常兴奋，它实际上已经进入临床阶段。

And I just want to show you a little bit of preclinical data to support our conviction that this drug will be active in those patients with perhaps low and moderate folate receptor expression levels. On the left, you can see a model of high folate expression, but in the middle 2, our moderate and low folate expression tumor models where Elahere is much less sensitive. And even in a model on the right of a non-ovarian cancer or colorectal where we see significant activity with our fully directed antibody drug conjugate.

我只想展示一些临床前数据，以支持我们的信念，即这种药物在那些可能具有低和中等叶酸受体表达水平的患者中将会起作用。在左侧，您可以看到高叶酸表达的模型，但在中间的两个模型中，我们的中等和低叶酸表达肿瘤模型对 Elahere 的敏感性要低得多。甚至在右侧的一个非卵巢癌或结直肠癌模型中，我们看到我们的全向抗体药物结合物具有显著活性。

As I said, this program has now entered the clinic, and we're excited to see where this goes over the next many months. And I think with that, I'll turn it over to my colleague, Dr. Jeff Oxnard. Thank you.

正如我所说，这个项目现在已经进入临床阶段，我们对接下来的几个月发展感到兴奋。我想现在我将把话题交给我的同事杰夫·奥克斯纳德博士。谢谢。

Geoff Oxnard

Good evening. I'm Geoff Oxnard. I lead lung cancer clinical development at Lilly. I'm going to tell you about a couple of molecules focused in GI and thoracic cancers. I'm a lung cancer doc, myself. I still see patients part time at Boston Medical Center, a safety net hospital in Boston. I joined Lilly last year, previously lone faculty at Dana-Farber and Harvard Medical School for about 10 years, where I was deeply involved in targeted therapy development and biomarker development. And I was one of the lead investigators of the first in human in the positive patients over the years and to see its impact. That's one of the joint Lilly last year.

晚上好。我是杰夫·奥克斯纳德。我在礼来公司负责肺癌临床开发工作。我将向您介绍一些关注胃肠道和胸部癌症的分子。我本身是肺癌医生。我仍然在波士顿医疗中心以兼职身份看病人，这是波士顿的一个安全网医院。我去年加入了礼来公司，之前在达纳·法伯和哈佛医学院担任独立教职大约 10 年，在那里我深度参与了靶向治疗和生物标志物开发工作。多年来，我是首位对阳性患者进行人体试验的主要研究人员之一，并见证了其影响。这就是我去年加入礼来公司的原因。

Retevmo, I think, nicely demonstrates the 3 principles that Jake told you about earlier, find a target that is important in cancer, RET develop a drug that differentiates compared to the available therapies. We know multi-kinase inhibitors had their limitations in terms of tolerability and potency limitations that Retevmo overcomes. And three, develop the drug into the need. Retevmo has been exhaustively developed. This drug has tumor-agnostic approval in RET-positive cancers in the U.S. and in the EU. It recently received pediatric approval in the U.S. It's the only RET inhibitor indicated in patients aged 2 and above with RET-positive cancers. It's underdeveloped in adjuvant lung cancer, a timely space for targeted therapy development. And finally, we've just described 2 positive first-line trials in RET-positive non-small cell lung cancer and RET-positive thyroid cancer. These are those 2 trials, both were reported last year at ESMO, both were co-published in the England Journal of Medicine and both demonstrate the impact of this drug when given first line compared to standard of care, PFS hazard ratio of 0.47 on the left in lung cancer of 0.28 on the right in RET-positive thyroid cancer.

Retevmo，我认为，很好地展示了 Jake 之前告诉你的 3 个原则，找到在癌症中重要的靶点，RET 开发一种与现有疗法有所区别的药物。我们知道多激酶抑制剂在耐受性和效力方面存在局限性，而 Retevmo 克服了这些局限性。第三，将药物开发到需要的地步。Retevmo 已经得到充分的开发。这种药物在美国和欧盟对 RET 阳性癌症具有肿瘤不可知批准。最近在美国获得了儿童批准。它是唯一一种适用于 2 岁及以上患有 RET 阳性癌症的患者的 RET 抑制剂。它在辅助肺癌治疗方面尚未开发，这是靶向治疗发展的一个及时空间。最后，我们刚刚描述了 2 个 RET 阳性非小细胞肺癌和 RET 阳性甲状腺癌的阳性一线试验。这两个试验，去年在 ESMO 报告，都在《英格兰医学杂志》上共同发表，都展示了该药物在一线使用时与标准治疗相比的影响，肺癌左侧的 PFS 危险比为 0.47。右侧 28 例 RET 阳性甲状腺癌。

This is the activity one would expect from an effective RET-targeted therapy, but these were difficult trials. People said these trials couldn't be done. We are proud to have completed these first-line trials in rare biomarker positive populations to demonstrate the impact of the drug and to enable access to this drug globally where randomized trial data is really important.

这是人们对有效的 RET 靶向治疗所期望的活动，但这些是困难的试验。人们说这些试验是不可能完成的。我们很自豪地完成了这些罕见生物标志物阳性人群的一线试验，以展示药物的影响，并使全球范围内能够获得这种药物，其中随机试验数据非常重要。

Of course, a RET inhibitor only works if you test for RET. And so enabling access and adoption of molecular testing is critical for this molecule and other molecules in our programs, and we continue to advocate for this.

当然，只有在检测到 RET 时，RET 抑制剂才能发挥作用。因此，促进分子检测的获取和采用对于这种分子以及我们项目中的其他分子至关重要，我们将继续为此进行倡导。

If you do cell molecular testing, the most common result you get back is KRAS. I'm going to tell you about our KRAS portfolio. These are 3 drugs on the left, olomorasib, a second-generation potent KRAS G12C selective targeted therapy in the middle, KRAS G12D targeted therapy, and only bioavailable drug. This drug is more focused in GI cancers, G12D is the most common KRAS variant. And finally, a pan-KRAS inhibitor, an ambitious drug also orally bioavailable. Olomorasib is entering late phase clinical development. The other 2 drugs are entering the clinic later on this year. I'll tell you more in a moment.

如果您进行细胞分子检测，您得到的最常见结果是 KRAS。我将向您介绍我们的 KRAS 产品组合。左侧有 3 种药物，olomorasib，中间是第二代强效 KRAS G12C 选择性靶向疗法，KRAS G12D 靶向疗法，也是唯一可生物利用的药物。这种药物更专注于 GI 癌症，G12D 是最常见的 KRAS 变体。最后，是一种泛 KRAS 抑制剂，也是口服可生物利用的雄心勃勃的药物。Olomorasib 正在进入晚期临床开发阶段。另外两种药物将于今年晚些时候进入临床试验。稍后我会告诉您更多信息。

Let's start with G12C. G12C is 15% of non-small cell lung cancer discovery of G12C inhibitors create enormous excitement about the ability to target KRAS. The FDA approval of these has moved the bar. And yet some of that optimism has not come to fruition. These drugs are mostly making an impact in previously treated non-small cell lung cancer. First-line lung cancer remains a meaningful unmet need where we think we can make a difference.

让我们从 G12C 开始。G12C 占非小细胞肺癌发现的 15%，发现 G12C 抑制剂引起了巨大的兴奋，因为可以瞄准 KRAS。这些药物获得 FDA 批准已经提高了标准。然而，一些乐观情绪并未实现。这些药物主要在先前治疗过的非小细胞肺癌中产生影响。一线肺癌仍然是一个有意义的未满足需求，我们认为我们可以做出改变。

Our thesis was that by developing a selective potent, tolerable drug with a wide therapeutic index would allow us to do the difficult thing that has not yet been done in lung cancer, combined a targeted therapy up-front with immunotherapy. Something we think we are well positioned to do.

我们的论点是，通过开发一种选择性强效、耐受性良好的药物，具有广泛的治疗指数，将使我们能够在肺癌领域做到迄今为止尚未完成的困难事情，即将靶向治疗与免疫疗法结合起来。我们认为我们有能力做到这一点。

On the upper right, I'm showing you the target inhibition or targeted occupancy of this second-generation G12C inhibitor compared to first-line -- first generation inhibitors, where we see more consistent and more effective target inhibition.

在右上方，我向您展示了这种第二代 G12C 抑制剂相对于一线--第一代抑制剂的目标抑制或靶向占据，我们看到更一致和更有效的目标抑制。

And on the bottom right, I show you pan-tumor activity. We recently showed at ASCO, demonstrating the effect of this drug. But the real reason to believe is data like this, this is new data of olomorasib after treatment with a prior G12C inhibitor.

在右下角，我向您展示泛肿瘤活性。我们最近在 ASCO 展示了这种药物的效果。但相信的真正原因是像这样的数据，这是在先前使用 G12C 抑制剂治疗后 olomorasib 的新数据。

What you see on the left is patients who discontinued due to toxicity or on the right patients who discontinued progression. Most of these patients, they're immediate prior therapy, was a G12C inhibitor, and we see a response rate above 40%. We see in PFS of 8 months in this heavily pretreated population. We don't think this drug is overcoming resistance. We think this drug is overcoming the target inhibition and PK limitations of first-generation drugs.

左侧所见为因毒性停药的患者，右侧为因疾病进展停药的患者。这些患者中，大多数之前接受的治疗是 G12C 抑制剂，我们看到超过 40%的应答率。在这个经过大量治疗的人群中，我们看到 PFS 为 8 个月。我们认为这种药物并非克服了耐药性，而是克服了第一代药物的靶点抑制和 PK 限制。

Importantly, it has differentiated tolerability. The predominant AE range is grade 1. 1 patient discontinued due to treatment-related adverse events even in patients who have intolerance to prior drugs, we see tolerance of this drug. [indiscernible]investigators in the study tell me that this is a drug people can be on for durable periods. We think this is a differentiated tolerability that will enable first-line combination with [indiscernible] therapy.

重要的是，它具有不同的耐受性。主要的不良事件范围是 1 级。1 名患者因与治疗相关的不良事件而停止治疗，即使是之前对药物不耐受的患者，我们也看到对这种药物的耐受性。[不可辨识]研究中的调查人员告诉我，这是一种人们可以持续使用的药物。我们认为这是一种不同的耐受性，将使其能够与[不可辨识]疗法进行首线联合应用。

This is CNS activity we just reported. As we know with Retevmo, CNS activity is important to enable durable response and durable impact in advanced non-small cell lung cancer, developing drugs with CNS activity, you can imagine is a principle across all of our early phase programs.

这是我们刚刚报告的中枢神经系统活动。正如我们所知，对于 Retevmo，中枢神经系统活动对于实现晚期非小细胞肺癌的持久反应和持久影响至关重要，开发具有中枢神经系统活动的药物，可以想象是我们所有早期阶段项目的一个原则。

And so this is the data then combining olomorasib with pembrolizumab. We reported at ASCO 64 patients combined pembrolizumab plus olomorasib but 2 drugs undergoing ongoing dose optimization development with pembro, 50 milligrams and 100 milligrams. This is efficacy data in the first line. You see a 77% response rate across a range of PD-L1 levels. You see a favorable median PFS. We acknowledge this is an early cohort, but nonetheless gives us enthusiasm that this is a regimen that can make a difference in first-line lung cancer.

因此，这是将 olomorasib 与 pembrolizumab 结合的数据。我们在 ASCO 报告了 64 名患者联合使用 pembrolizumab 和 olomorasib，但有 2 种药物正在进行持续的剂量优化开发，分别是 50 毫克和 100 毫克的 pembro。这是一线疗效数据。您可以看到在一系列 PD-L1 水平中有 77%的响应率。您可以看到有利的中位 PFS。我们承认这是一个早期队列，但仍然让我们对这种方案在一线肺癌中产生影响感到兴奋。

And here is the tolerability profile. We are pleased to see that discontinuation due to treatment-related adverse events are infrequent. Fundamentally, this is a tox profile we think is consistent with first-line development motivating the SUNRAY-01 trial that I'll tell you about now.

这是耐受性概况。我们很高兴看到因治疗相关不良事件而中止治疗的情况很少。基本上，我们认为这是与首选治疗一致的毒性概况，这激励了我现在要告诉你的 SUNRAY-01 试验的开展。

Jake alluded to this study earlier. This is a study that's been designed for fundamentally Phase III [indiscernible] across a wide range of Phase III sites. It is a master vertical. Sites love this, right? You start with a dose optimization experience. When that is completed, the trial seamlessly transitions then to 2 parallel Phase III trials. We expect that transition to Phase III later on this year. Those 2 trials are meant to represent real-world practice in KRAS-positive lung cancers. You get a local biomarker result that comes back. You could either put that patient on to an immunotherapy-based regimen or a chemoimmunotherapy-based regimen based on neuro clinical judgment and their biomarker results. As Jake mentioned, this allows enrollment after one cycle of standard of care therapy. To give time for that patient to get started urgently on treatment, get biomarker results. We've got enormous positive feedback from sites of how that enables them to enroll effectively. We really think this is designed for rapid enrollment. It's already active and across a wide range of global sites.

杰克早些时候提到了这项研究。这是一项专为广泛范围的第三阶段[不可辨识]设计的研究。这是一个主竖向研究。研究站点很喜欢这个，对吧？您从剂量优化经验开始。完成后，试验会顺利过渡到 2 个平行的第三阶段试验。我们预计这项研究将在今年晚些时候过渡到第三阶段。这两项试验旨在代表 KRAS 阳性肺癌的真实世界实践。您会得到一个本地生物标志物结果。根据神经临床判断和他们的生物标志物结果，您可以将患者放入基于免疫疗法的方案或基于化疗免疫疗法的方案。正如杰克所提到的，这允许在标准治疗周期后进行入组。为患者争取时间，紧急开始治疗，获取生物标志物结果。我们从各个站点获得了巨大的积极反馈，称赞这有助于他们有效招募。我们真的认为这是为快速招募而设计的。它已经在全球范围内活跃。

I'm going to move on to the 2 other drugs in the KRAS portfolio. First, KRAS G12D. KRAS G12D is the most common KRAS variant. It is more prevalent in GI cancers, especially colon cancer and pancreatic cancer. This is potential for a big impact. But the development of an orally bioavailable KRAS G12D inhibitor has been challenging. In our R&D unit, we have been able to learn from the development of olomorasib. And so through persistent iterative R&D, we have identified an orally bioavailable G12D inhibitor, a drug that has excellent PK properties so far as we can tell in our preclinical models and motivates us to get this quickly into patients. We think this can make a real impact, especially in GI cancers.

我将继续介绍 KRAS 组合中的另外两种药物。首先是 KRAS G12D。KRAS G12D 是最常见的 KRAS 变体。它在 GI 癌症中更为普遍，尤其是结肠癌和胰腺癌。这具有巨大的潜力。但是口服可用的 KRAS G12D 抑制剂的开发一直是具有挑战性的。在我们的研发部门，我们已经能够从 olomorasib 的开发中学到经验。因此，通过持续的迭代研发，我们已经确定了一种口服可用的 G12D 抑制剂，这种药物在我们的临床前模型中表现出优异的药代动力学特性，激励我们迅速将其应用于患者。我们认为这可能会在 GI 癌症中产生真正的影响。

Here, you see the selectivity for G12D compared to other KRAS targets. On the right, you see activity across a range of cell line models. This drug is potent. This drug, we expect to be highly selective and our hope getting into the clinic later this year, we will quickly get to effective and tolerable doses, thus allowing the kind of creative combination regimens that we've seen, and we've been trying with olomorasib. So again, we can make an impact quickly here into the clinic later this year.

这里，您可以看到相对于其他 KRAS 靶点，对 G12D 的选择性。在右侧，您可以看到在一系列细胞系模型中的活性。这种药物很有效。我们期望这种药物具有很高的选择性，希望能在今年晚些时候进入临床，我们将迅速确定有效且耐受的剂量，从而允许我们尝试过 olomorasib 的那种创造性的联合疗法。因此，我们可以在今年晚些时候迅速在临床中产生影响。

Finally, I'll end with the pan-KRAS inhibitor. We realized that this is more ambitious. At the same time, this is 1 in 7 cancers. So if we can develop a drug across all of KRAS, there's a potential for broad impact. There are a lot of ways to target KRAS. There is a unique thesis to this molecule, which is that we can target KRAS activating alterations, wild-type KRAS dependency, but spare a HRAS and NRAS. By sparing HRAS and NRAS, we believe we can get around the rash and other intolerance that other multi-KRAS inhibitors have exhibited. And we see this already in preclinical molecules, making us hopeful that this drug will be able to get to potent effective doses without the toxicity challenges.

最后，我将以泛 KRAS 抑制剂结束。我们意识到这更为雄心勃勃。同时，这是 7 种癌症中的 1 种。因此，如果我们能开发一种跨越所有 KRAS 的药物，就有广泛影响的潜力。有很多方法可以针对 KRAS。这种分子有一个独特的理论，即我们可以针对 KRAS 激活变异、野生型 KRAS 依赖性，但避免影响 HRAS 和 NRAS。通过避免影响 HRAS 和 NRAS，我们相信我们可以避开其他多 KRAS 抑制剂所表现出的皮疹和其他不耐受性。我们已经在临床前分子中看到了这一点，这让我们对这种药物能够达到有效剂量而不受毒性挑战感到希望。

Again, on the left, you see selectivity for a range of G12 and G13 mutations, activity in wild-type KRAS dependency, but sparing HRAS and NRAS motivating our thesis and on the right activity across a range of cell line models. Again, this is also going into the clinic later this year. Our expectation is this drug will have a slightly more measured dose escalation in a slightly more narrow therapeutic index as compared to the selective G12D inhibitor. But nonetheless, with this KRAS portfolio, we think we'll be positioned to make an impact across a wide range of cancers.

再次，在左侧，您可以看到对一系列 G12 和 G13 突变的选择性，对野生型 KRAS 的活性依赖，但避免 HRAS 和 NRAS，激发了我们的论点；而在右侧，对一系列细胞系模型的活性。同样，这也将在今年晚些时候进入临床。我们的期望是，与选择性 G12D 抑制剂相比，这种药物将有稍微更为谨慎的剂量递增，疗效指数也会稍微更窄。但尽管如此，凭借这种 KRAS 组合，我们认为我们将能够在广泛的癌症范围内产生影响。

And with that, I'm going to hand off to under to Dr. Arjun Balar.

随着这一点，我要把话题交给阿尔琼·巴拉博士。

Arjun Balar 阿尔琼·巴拉

Thanks so much, Geoff. So my name is Arjun Balar. I'm a medical oncologist by training, much like my colleagues. And after 10 years in the clinic at NY Langone Health leading the GU Cancers program there and also the clinical trials office. I was really thrilled to join Lilly about 2 years ago to lead development programs across a variety of different modalities.

非常感谢，杰夫。我叫阿尔琼·巴拉尔。我是一名医学肿瘤学家，和我的同事们一样。在纽约大学朗格尼健康中心临床工作了 10 年，领导泌尿系统癌症项目和临床试验办公室。大约两年前，我非常高兴加入了礼来公司，负责跨多种不同模式的开发项目。

I want to focus on 2 programs, LOXO-435 and also our Nectin-4 targeted ADCs which are really poised to change treatment options for patients with metastatic urothelial cancer and which is a personal area of research interest for me.

我想专注于 2 个项目，LOXO-435 以及我们的 Nectin-4 靶向 ADCs，这些项目真的有望改变转移性膀胱癌患者的治疗选择，这也是我个人研究兴趣的领域。

Let's jump right in. So LOXO-435, this is our isoform-selective FGFR3 inhibitor, A little bit of background. FGFR alterations are activating are present in about 15% to 20% of patients with advanced urothelial cancer. There is an approved available agent, sertofitinib, responses and also a survival benefit against single-agent chemotherapy. However, it comes with a little bit of baggage, a lot of toxicities. These include things like alopecia, fatigue, hand-foot syndrome, diarrhea, ocular toxicity. And these are due to the fact that it's essentially a pan inhibitor. There are other isoforms of FGFR that we need to know about, such as FGFR4 but in particular, FGFR2 and FGFR1. Targeting these off-targets is what drives these toxicities.

让我们开始吧。所以 LOXO-435，这是我们的同工型选择性 FGFR3 抑制剂，一点背景。FGFR 变异是激活的，在晚期膀胱癌患者中约占 15%至 20%。有一种已批准的药物，sertofitinib，对单药化疗也有反应和生存益处。然而，它带来了一些包袱，很多毒性反应。这些包括脱发、疲劳、手足综合征、腹泻、眼部毒性。这些是因为它本质上是一种泛抑制剂。我们需要了解其他 FGFR 同工型，比如 FGFR4，但尤其是 FGFR2 和 FGFR1。瞄准这些非靶点是导致这些毒性反应的原因。

So our core hypothesis here was that let's develop a truly isoform selective molecule, focuses on the target of interest, and avoid those other targets that we really don't like. That enables us to have a better safety profile but also captures the full benefit of patients receiving therapy, staying on therapy long enough and not needing dose reductions. These are some of the challenges that patients on erdafitinib have so that we can actually maximize the benefit.

因此，我们在这里的核心假设是，让我们开发一种真正的异构体选择性分子，专注于感兴趣的靶点，并避免那些我们真的不喜欢的其他靶点。这使我们能够拥有更好的安全性概况，同时也能够充分获得接受治疗的患者的全部益处，保持足够长时间的治疗并且不需要减少剂量。这些是接受厄达非尼治疗的患者面临的一些挑战，以便我们实际上最大化受益。

We've been in the clinic since '23, early 2023. But I want to share with you a little bit about the preclinical profile that gives us a sense of how this drug will perform in the clinic.

自 23 年初，我们一直在诊所。但我想和你分享一点关于临床前资料，让我们对这种药物在临床中的表现有所了解。

On the left is an enzyme innovation assay that measures IC50 and looking at nanomolar concentrations. The first 4 rows there, just to make things simple, are representative pan-inhibitors, erdafitinib, obviously at the top. The nanomolar concentration, they're essentially about the same, and that really defines what a pan-inhibitor is.

左侧是一种酶创新测定法，用于测量 IC50 并观察纳摩尔浓度。前 4 行代表性泛抑制剂，厄罗替尼显然位于顶部。纳摩尔浓度基本相同，这确实定义了泛抑制剂的特性。

At the far bottom, you'll see LOXO-435. At 0.3 nanomolar, you have exquisite potency against FGFR3, but then if you look at the other concentrations, we're obviously very much sparing those other targets that we don't like.

在最底部，您会看到 LOXO-435。在 0.3 纳摩尔时，您对 FGFR3 有绝佳的效力，但是如果您看其他浓度，我们显然非常节约那些我们不喜欢的其他靶点。

On the far right, you'll essentially see how we look at selectivity, which is basic arithmetic. Inhibitors are doing what they should be doing, which is really nonpreferentially targeting FGFR3 and the other isoforms, but we've shown exquisite sensitivity in these in vitro models -- I'm sorry, selectivity in these in vitro models for FGFR3, over FGFR1 and also FGFR3 and FGFR2.

在最右侧，您基本上会看到我们如何看待选择性，这是基本的算术。抑制剂正在做它们应该做的事情，即非优先靶向 FGFR3 和其他同工型，但我们已经在这些体外模型中展示了对 FGFR3 的精细敏感性，对 FGFR1 以及 FGFR3 和 FGFR2 的选择性。

The last thing I'll mention is that middle column, FGFR3 V55M. What is that? So this is an acquired gatekeeper resistance mutation. It develops in the context of progression on pan-inhibitors such as erdafitinib, and these drugs lose their effectiveness and best represented in the IC50s there. We maintain potency even against the gatekeeper resistance mutation.

我要提到的最后一件事是中间那一栏，FGFR3 V55M。那是什么？这是一种获得性的守门抵抗突变。它在使用诸如埃达替尼之类的泛抑制剂后发展，并且这些药物失去了效力，在 IC50 中最好地体现出来。我们甚至在面对守门抵抗突变时仍保持药效。

Pharmacodynamically, one of the things that we measure are things like hyperphosphatemia. That's actually specifically due to FGFR1 engagement, erdafitinib comparator causes hyperphosphatemia in preclinical models and all the dose ranges that we tested showed no hyperphosphatemia for LOXO-435. In the middle you've got representative examples of tumor growth inhibition, what we expect to see preclinically.

从药效动力学的角度来看，我们测量的一个指标是高磷血症等因素。这实际上是由于 FGFR1 的参与，厄达替尼比较试验在临床前模型中引起高磷血症，而我们测试的所有剂量范围均未显示 LOXO-435 引起高磷血症。在中间，您可以看到肿瘤生长抑制的代表性示例，这是我们在临床前期预期看到的。

I'm excited to report that after a little over a year in the clinic, we've hit therapeutic exposures, showing really nice responses and also a safety profile that's consistent with our thesis.

我很高兴地报告，在临床进行了一年多后，我们已经达到了治疗暴露水平，显示出非常好的反应，同时也符合我们的论点。

I'll continue on with our Nectin-4 program. Nectin-4 is a well-validated target in metastatic urothelial cancer, but also some other solid tumor types that we're learning about.

我将继续进行我们的 Nectin-4 项目。Nectin-4 是转移性膀胱癌中一个经过充分验证的靶点，但也是我们正在了解的一些其他实体肿瘤类型。

[indiscernible] demonstrated meaningful transformation in the metastatic urothelial cancer in particular, when combined with KEYTRUDA has displaced platinum-based chemotherapy in the first-line setting. But what we know is that treatment resistance will develop, so patients will need options in the post Padcev space. We've shown preclinically, and I'll talk about this in our 2 programs that the primary mechanism of resistance is actually the payload, primarily through drug efflux pumps. And Nectin-4 remains the most important target in urothelial cancer even after progression on Padcev.

[不可辨识] 尤其在转移性膀胱癌方面展示了有意义的转变，当与 KEYTRUDA 结合时，已经在一线治疗中取代了基于铂的化疗。但我们知道治疗耐药性会发展，因此患者将需要在 Padcev 后的空间中有选择。我们在临床前已经表明，并且我将在我们的两个项目中谈到这一点，耐药的主要机制实际上是药物载体，主要通过药物外流泵。即使在 Padcev 进展后，Nectin-4 仍然是膀胱癌中最重要的靶点。

We have 2 programs that are entering the clinic, and you'll see them on your bottom right, LY4101174 which I'll call 1174 for simplicity and then LY4052031. I'll call that 2031.

我们有 2 个项目进入诊所，您会在右下角看到它们，LY4101174，我会简单地称之为 1174，然后是 LY4052031，我会称之为 2031。

1174, we acquired last year as part of our acquisition of a Biotech in Western Europe called Emergence. They were developing antibody drug conjugates with technologies that we really liked. And internally, by coincidence, we happen to have an internal program that looked very similar, but add some unique differences that I'm going to walk you through.

我们在去年收购了一家名为 Emergence 的西欧生物技术公司，其中包括 1174。他们正在开发我们非常喜欢的技术的抗体药物结合物。而巧合的是，我们内部恰好有一个看起来非常相似的内部项目，但又有一些独特的差异，我将为您详细介绍。

Let's zoom in on these 2 programs. On the left, you have 1174. And on the right, you have 203. What's common? IgG1 antibody with an Fc gamma receptor silent structure here primarily to avoid things like drug antibodies. And let's talk about where things are different. And also actually, both are DAR8, highly homogeneous and in vitro studies, we've shown excellent linker palo stability.

让我们来看看这两个程序。在左边，你有 1174。在右边，你有 203。有什么共同点吗？这里主要是为了避免药物抗体等问题，IgG1 抗体与 Fcγ受体沉默结构相同。让我们谈谈它们的不同之处。实际上，两者都是 DAR8，高度均一且在体外研究中，我们展示了出色的连接子稳定性。

But what's different here? On the left, it's a novel [indiscernible] linker, cleaved by beta-glucuronidase. This helps us concentrate this drug more in tumors. The payload, however, is tried and true. It's exatecan well-known TOPO 1 class inhibitor.

但这里有什么不同？在左边，这是一种新型的[不可辨识]连接物，由β-葡聚糖酶切割。这有助于我们更集中地将这种药物用于肿瘤。然而，药物的有效成分是经过验证的。它是一种著名的拓扑异构酶 1 类抑制剂——依西替康。

And on the right, you have 2031, a conventional GGFG-linker, cathepsin mediated cleavage but a novel payload [CAMP-98]. It's not been tested in the clinic, but preclinically has shown higher CD and perhaps more potency. You can see, we like both assets. And this reflects our conviction in this target and putting this in the clinic.

在右侧，您有 2031，一个传统的 GGFG-连接物，由 cathepsin 介导的裂解，但携带了一种新型有效荷载[CAMP-98]。尚未在临床中进行测试，但在临床前阶段显示出更高的 CD 值，可能具有更强的效力。您可以看到，我们喜欢这两种资产。这反映了我们对这一靶点的信心，并将其投入临床试验。

I'm excited to report that 1174, we treated our first set of patients, and we're proceeding through escalation. And with 2031, we just received our safety proceed letter from the FDA, and we'll soon treat our very first patients later this month.

我很高兴地报告，在 1174 年，我们治疗了我们的第一组患者，并且我们正在进行逐步升级。而在 2031 年，我们刚刚收到了 FDA 的安全审批函，本月晚些时候我们将很快治疗我们的第一批患者。

So I'm going to hand it off to Barry, who's going to do his best Mariano Rivera and close this out.

所以我要把它交给巴里，他会尽力像马里亚诺·里维拉一样结束这一切。

Barry Taylor 巴里·泰勒

So all downhill from here with that introduction. Good evening, everyone. My name is Barry Taylor. I am the Scientific Officer of Oncology at Lilly. I joined Lilly in the summer of 2020, having served as an academic faculty member, running a translational cancer research laboratory first at UCSF and then for many years at Memorial Sloan Kettering Cancer Center in New York City. It's a pleasure to be here. I guess this is technically the anchor leg of our teams relay tonight. And I'm looking forward to walking you through a few additional clinical stage projects that are emerging from our portfolio this year.

所以从这里开始，一切都会顺利进行。晚上好，大家好。我叫巴里·泰勒。我是 Lilly 公司肿瘤学科学官。我于 2020 年夏季加入了 Lilly 公司，之前曾在 UCSF 担任学术教职成员，在纽约市的 Memorial Sloan Kettering 癌症中心领导转化癌症研究实验室多年。很高兴能在这里。我想这在技术上算是我们团队今晚的最后一棒。我期待着向您介绍我们今年从我们的项目组合中涌现的一些额外临床阶段项目。

The first of these is our selective SMARCA2 selective inhibitor program. This is actually a collaboration with a partner, Foghorn Therapeutics. The thesis of this program is to exploit the so-called synthetic dependency in cancer cells. So what do I mean when I say that, SMARCA2 and it's closely related partner SMARCA4 together comprise the catalytic engine that drives a large multiprotein complex called the BAF complex. And the BAF complex is what rearranges and remodels chromatin to facilitate gene expression in every cell of our body, but tumor-specific loss of that partner SMARCA4, which arises in 10% of lung cancer through loss of function and truncating mutations forces a lung cancer cell to then rely on SMARCA2 to meet the BAF complex function. And that creates a therapeutic opportunity for us, if we were to be able to engineer potent and selective SMARCA2 inhibitor, we could exploit a synthetic lethality created by SMARCA4 loss. And I say selective because the inhibition of both SMARCA2 and SMARCA4 is not particularly well tolerated normal cells, and we'll get back to the selectivity piece in the second, but this synthetic lethality is a debt to the pioneering work of PARP inhibitor therapy in patients with BRCA 1 and 2 mutations, a very similar concept. In fact, over the last, say, 10 years of academic research, cancer genomic profiling as well as functional genetics SMARCA2, SMARCA4 synthetic lethal relationship is among the strongest associations in all of [indiscernible]. So we're came to test this mechanism in patients.

这些项目中的第一个是我们的选择性 SMARCA2 选择性抑制剂项目。实际上，这是与合作伙伴 Foghorn Therapeutics 合作的。该项目的主题是利用癌细胞中所谓的合成依赖性。当我说到这一点时，我指的是，SMARCA2 及其密切相关的合作伙伴 SMARCA4 共同组成了驱动一个名为 BAF 复合物的大型多蛋白复合物的催化引擎。BAF 复合物是重新排列和重塑染色质以促进我们身体每个细胞基因表达的东西，但肿瘤特异性丧失该合作伙伴 SMARCA4，这在 10%的肺癌中通过功能丧失和截短突变产生，迫使肺癌细胞依赖 SMARCA2 来满足 BAF 复合物功能。这为我们创造了一个治疗机会，如果我们能够设计出有效和选择性的 SMARCA2 抑制剂，我们就可以利用由 SMARCA4 丧失造成的合成致死性。 我说选择性是因为抑制 SMARCA2 和 SMARCA4 对正常细胞的耐受性不是特别好，我们将在接下来的部分回到选择性问题，但这种合成致死性是 PARP 抑制剂治疗患有 BRCA 1 和 2 突变的患者的开创性工作的债务，这是一个非常相似的概念。事实上，在过去的，比如说，10 年的学术研究中，癌症基因组分析以及功能遗传学 SMARCA2、SMARCA4 合成致死关系是所有[不可辨识]中最强的关联之一。因此，我们来测试这种机制在患者身上。

As such, we developed a molecule called LY4050784, again with our colleagues at Foghorn Therapeutics. This is an oral SMARCA22 selective inhibitor. It has about a 30-fold margin over SMARCA4 in vitro. And so it demonstrates potent antiproliferative activity in SMARCA4 mutant, but not SMARCA4 wild-type lung cancer. Cell lines on the right, you're seeing just an example of that, we've now profiled this in vitro over a much larger panel of SMARCA4 mutant lines that really represent the mutational diversity of human lung cancers.

因此，我们与 Foghorn Therapeutics 的同事共同开发了一种名为 LY4050784 的分子。这是一种口服 SMARCA22 选择性抑制剂。它在体外对 SMARCA4 有大约 30 倍的边际。因此，它在 SMARCA4 突变体中表现出强大的抗增殖活性，但在 SMARCA4 野生型肺癌中没有。右侧的细胞系，您只是看到一个例子，我们现在已经在更大的 SMARCA4 突变系列中对其进行了体外分析，这些系列真正代表了人类肺癌的突变多样性。

And most exciting of all is that this result has translated in vivo. And I want to spend a moment on this slide to give you a historical perspective. These are 3 xenograft models of lung cancer, [indiscernible] models with lung cancer. And on the far right, we see something we actually saw a lot of is we were canvassing the academic literature and the work of our peer companies when we embarked on this project, which was tumor growth inhibition. But we really embarked on this journey not knowing if we could deliver on the kinds of [indiscernible] tumor regressions but suspected that if we were able to engineer the right molecule at the right properties, that would be on the table, which you see in the 2 in vivo models on the far left and in the middle, these are 2 SMARCA4 mutant lung cancer models where we can observe single-agent reverses at multiple dose levels. And actually, these are quite aggressive models of the human disease. Multiple of these models have co-mutations like p53, KRAS and actually maybe most notably, STK11 and KEAP1 mutations, which actually define a particularly poor prognosis set of lung cancers and one with particularly poor outcomes to immunotherapy containing regimens. So with these attributes and molecules excellent oral properties, we're excited to test this clinically starting later in the year.

最令人兴奋的是，这一结果已经在体内得到验证。我想花一点时间在这张幻灯片上，让您对历史有个全面的了解。这些是 3 个肺癌异种移植模型，[无法辨识] 肺癌模型。在最右边，我们看到了一些我们在调查学术文献和同行公司工作时实际看到的东西，即肿瘤生长抑制。但我们在着手这个项目时并不确定我们是否能够实现[无法辨识] 肿瘤的逆转，但我们怀疑如果我们能够在适当的属性上设计出正确的分子，这将是可能的，这也可以在最左边和中间的 2 个体内模型中看到，这是 2 个 SMARCA4 突变肺癌模型，我们可以观察到单药反转在多个剂量水平上。实际上，这些是人类疾病相当具侵略性的模型。 这些模型中有多个共同突变，如 p53、KRAS，实际上可能最显著的是 STK11 和 KEAP1 的突变，这些突变实际上定义了一组特别预后不良的肺癌，并且对含有免疫治疗方案的治疗效果尤为不佳。因此，凭借这些特性和分子的出色口服特性，我们很高兴能在年底开始临床测试。

And this was prior to place in our larger portfolio of mechanism-based therapies in lung cancer is typified by the mutant selective and isoform selective KRAS inhibitors that Geoff was a little bit earlier.

这是在我们更大的机制为基础的肺癌治疗组合中之前，由 Geoff 稍早提出的突变选择性和亚型选择性 KRAS 抑制剂所代表。

So switching gears slightly and entirely consistent with something Jake mentioned at the front, which was a very deliberate path toward therapeutic modality diversification in the oncology pipeline. We're incredibly excited to bring radiopharmaceuticals into the portfolio in oncology at Lilly.

所以稍微转变一下方向，完全符合杰克在前面提到的内容，即在肿瘤学管道中朝着治疗模式多样化的非常有意识的路径前进。我们非常兴奋地将放射性药物带入到礼来的肿瘤学组合中。

This began with in of POINT Biopharma, a little less than a year ago. This is a deeply experienced team with a current clinical presence of next-generation molecules, which I'll talk about in a second but also deep radiochemistry experience, a robust isotope supply chain as well as internal commercial scale manufacturing capabilities, and we supplemented that subsequently with our recently announced partnership with Aktis Oncology, which is to bring a novel targeting moiety to the development of RLTs, and we're excited about that as well.

这始于不到一年前的 POINT 生物制药公司。这是一个经验丰富的团队，目前拥有下一代分子的临床存在，我稍后会谈到，同时也具有深厚的放射化学经验、强大的同位素供应链以及内部商业规模的制造能力，我们随后通过与 Aktis Oncology 最近宣布的合作进一步补充了这一点，这将为 RLT 的开发带来一种新颖的靶向基团，我们对此也感到兴奋。

But we've also devoted a substantial effort internally in our own discovery labs for the development of RLTs. And this helps let us take advantage of the deep experience we have in structure-guided small molecule design as well as to tap into the broader Lilly capabilities, be therapeutic peptides or otherwise.

但我们也在我们自己的发现实验室内投入了大量的努力，用于 RLT 的开发。这有助于我们利用我们在结构引导小分子设计方面的丰富经验，并利用更广泛的 Lilly 能力，无论是治疗性肽还是其他方面。

Of course, the thesis with radioligand therapy is highly tumor-specific targeting of radionuclides. And the beauty of the thisteronostic approach, which payers an imaging agent with a therapeutic agent, is if you can see it, and you can deliver high-dose financing radiation locally, those cancer cells will die. And that's because this is fundamentally not indexed on the often intractable nuanced and heterogeneous biology of individual cancer cells.

当然，放射配体疗法的论点是对放射性核素的高度肿瘤特异性靶向。而治疗性与诊断性相结合的方法之美在于，如果您能看到它，并且能够将高剂量的放射线局部传递，那些癌细胞将会死亡。这是因为这基本上不是基于个体癌细胞的常常难以处理的微妙和异质生物学。

And so this process is schematized here on the slide. On the far left is a patient with advanced metastatic prostate cancer whose tumor expresses PSMA. If you take a PSMA ligand and through a linker and a chelator deliver an imaging agent, be it gallium or otherwise, you can do PET imaging baseline and identify, in this case, widespread metastatic disease.

因此，这个过程在幻灯片上被概括出来。在最左边是一个患有晚期转移性前列腺癌且肿瘤表达 PSMA 的患者。如果你使用 PSMA 配体，并通过连接剂和螯合剂传递成像剂，无论是镓或其他物质，你可以进行 PET 成像基线，并识别，在这种情况下，广泛的转移性疾病。

But now if you replace that imaging agent with a therapeutic isotope, leveraging the exact same PSMA ligand as you're targeting agent, you can deliver potentially transformative antitumor activity in the patient as indicated on the far right, while really sparing normal healthy organs. It's this kind of result that got us excited and really built our conviction in the therapeutic modality, and we're keen to work as part of a community to really develop radiopharmaceuticals as a pillar of cancer care across therapeutic indications in the future.

但是现在，如果您用治疗性同位素替换成像剂，利用与您的靶向剂相同的 PSMA 配体，您可以在病人身上提供潜在的转变性抗肿瘤活性，如最右侧所示，同时真正地保护正常健康器官。正是这种结果让我们感到兴奋，并真正坚定了我们对治疗模式的信念，我们渴望作为社区的一部分努力发展放射性药物作为未来治疗癌症的支柱。

And so I was mentioning about a current clinical presence. This is our active Phase I program called Excel. This is currently enrolling in Canada, though we hope to bring it to the U.S. quite soon. This is testing a novel PSMA ligand to deliver an alpha-emitting actinium isotope. So this is a shorter range but higher energy isotope.

所以我提到了一个当前的临床项目。这是我们正在进行的活跃 I 期项目，名为 Excel。目前在加拿大招募中，尽管我们希望很快将其引入美国。这是在测试一种新型 PSMA 配体，用于释放α放射性锕同位素。因此，这是一个射程较短但能量较高的同位素。

The fundamental thesis with this program is really one of biodistribution because in prostate cancer, unfortunately, these aren't the only cells in the body that express PSMA. In fact, PSMA as expressed in the salivary gland. And what we and others in the community have seen is significant off-target uptake in the salivary gland of first-generation PSMA targeting radioligands. And so the question here was, can we develop a PSMA ligand that not just improves its affinity and leads to increased internalization, but fundamentally increase the tumor uptake of the radioisotope, thereby sparing salivary and renal toxicities.

该程序的基本论点实际上是生物分布的一个问题，因为在前列腺癌中，不幸的是，这些并不是身体中唯一表达 PSMA 的细胞。事实上，唾液腺中也表达 PSMA。我们和社区中的其他人看到的是第一代 PSMA 靶向放射配体在唾液腺中存在显著的非靶向摄取。因此，这里的问题是，我们能否开发一种 PSMA 配体，不仅提高其亲和力并导致内化增加，而且从根本上增加放射性同位素的肿瘤摄取，从而避免唾液腺和肾脏毒性。

And so here is just a summary of those key characteristics. PSMA2 is at novel ligand juxtaposed here to 2 additional first-generation PSMA ligands, both I&T, which is part of the lutetium-based .2002 product as well as PSMA-617, which is the ligand in [indiscernible]. And here, this just encapsulates what I was mentioning before of improved affinity, greater degree of internalization leading to a significant increase in tumor uptake in what we hope will be reduced normal organ uptake. And so we're incredibly excited that this study is enrolling metastatic castrate-resistant prostate cancer is now though after initial safety data, we hope to expand enrollment to even earlier stage hormone-sensitive prostate cancers in the not-too-distant future.

因此，这里只是对这些关键特征的简要总结。PSMA2 是一种新型配体，与另外两种第一代 PSMA 配体相邻，分别是 I＆T，它是基于镥的 2002 产品的一部分，以及 PSMA-617，它是[indiscernible]中的配体。在这里，这只是概括了我之前提到的改善亲和力，更大程度的内化导致肿瘤摄取量显著增加，我们希望能减少正常器官的摄取。因此，我们非常激动地看到这项研究正在招募转移性去势抵抗性前列腺癌患者，尽管在初步安全数据之后，我们希望不久的将来将扩大招募范围，甚至包括早期激素敏感性前列腺癌患者。

But hopefully, this reflects an effort on our part to really build out a rich portfolio of RLTs at Lilly and really established this as a mainstay of oncology care for patients in need of transformative therapies.

但希望这反映了我们在努力构建艾利公司丰富的 RLT 组合的努力，并真正将其确立为需要转化疗法的患者的肿瘤治疗的支柱。

So I just wanted to end and this settles back to something that Jake was describing at the beginning. We are enormously excited by the large number of clinical starts that we're embarking on this year. But I think when you combine that with our advanced assets, we hope this reflects, and we believe it does a significant expansion in our R&D capabilities. Again, through the deliberate diversification of our therapeutic modalities and new technologies, it allows us to remain focused on the highest conviction areas of cancer biology, in disease indications in need of real fundamental transformative medicines.

所以我只是想结束，这回到了杰克在一开始描述的事情。我们对我们今年开始的大量临床试验感到非常兴奋。但我认为，当您将这与我们的先进资产结合起来时，我们希望这反映出，我们相信这确实是我们研发能力的显著扩展。再次，通过有意识地多样化我们的治疗模式和新技术，这使我们能够继续专注于癌症生物学的最有信念领域，以及需要真正基础性转化药物的疾病指标。

And so to bring us back to something that Jake said, this big bet we took 4 years ago to refactor the oncology pipeline at Lilly. We hope this is at least an initial down payment on the output of that process, though we're keen to continue that work with a rich discovery engine for years to come. So with that, I'll give it back to Jake.

所以让我们回到杰克说的话题，4 年前我们在礼来公司对肿瘤学管道进行重构所做的重大赌注。我们希望这至少是对该过程产出的一个初始首付，尽管我们渴望继续利用丰富的发现引擎继续这项工作多年。因此，我将把话题交回给杰克。

Jake Van Naarden 杰克·范纳登

Thank you, Barry and team. Before we go into Q&A, I think when you look at this slide, you look at particularly the new clinical starts. In addition to, hopefully, we've convinced you about our conviction in the biology ideas here, but really, the theme that connects a lot of these that I think actually connects back to some of our initial successes with -- that are now approved medicines is the idea of bringing what I think we were used to calling precision medicine to larger populations.

谢谢，巴里和团队。在我们进行问答环节之前，我认为当您看这张幻灯片时，您特别要关注新的临床启动。除此之外，希望我们已经说服您对这里的生物学理念有信心，但实际上，连接许多这些想法的主题，我认为实际上与我们最初成功的一些 -- 现在已经获批准的药物有关的是，将我认为我们习惯称之为精准医学带给更广泛的人群的想法。

I think when we think about these great precision medicines in oncology, drugs like larotrectinib Vitrakvi from the original Loxo experiment, drugs like selpercatinib Retevmo, drugs like alectinib and at this meeting, even lorlatinib, these are medicines that have huge effect sizes for the patient populations that they deliver for. But unfortunately, for like the universe those patient populations are not large relative to the global impact that cancer diagnoses have.

我认为当我们考虑肿瘤学中这些精准药物时，像拉罗曲替尼 Vitrakvi 这样的药物来自原始 Loxo 实验，像塞帕曲替尼 Retevmo 这样的药物，像阿雷替尼这样的药物，甚至在这次会议上还有洛拉替尼，这些药物对于其服务对象的患者群体有巨大的效果大小。但不幸的是，对于像宇宙那样的患者群体来说，相对于癌症诊断所产生的全球影响，这些患者群体并不大。

And so we tried to learn from those efforts and say, how can we choose targets, how can we make medicines that can deliver that kind of benefit risk, but for larger populations and make a much bigger impact on cancer care.

因此，我们尝试从这些努力中学习，并思考，我们如何选择目标，如何制造可以提供那种利益风险的药物，但是针对更大的人群，并对癌症护理产生更大的影响。

So thanks, everyone, for joining tonight. I think we'll now take some questions, and I'll ask my colleagues to come back on stage. I think the Lilly IR team is sitting around with some microphones. And we'll answer your questions. Thank you.

感谢大家今晚的参与。我想现在我们会接受一些问题，我会请我的同事们回到舞台上。我想 Lilly IR 团队正坐在那里，手里拿着一些麦克风。我们会回答你们的问题。谢谢。

Question-and-Answer Session

问答环节

Q - Evan Seigerman  Q - 埃文·西格曼

Evan Seigerman from BMO Capital Markets. Thank you for the fantastic presentation today. I wanted to touch on KRAS G12C, really kind of diving into a little bit on not the commercial challenges of sotorasib and adagrasib, but mainly, what really gives you excitement about the profile of olomorasib, especially given the challenges we've seen in developing these 2 assets and really getting them to the front line, what's differentiated about the profile? And how can you accelerate that development to get this to patients more quickly.

来自 BMO Capital Markets 的 Evan Seigerman。感谢您今天的精彩演讲。我想谈谈 KRAS G12C，真的是深入探讨一下，不是 sotorasib 和 adagrasib 的商业挑战，而是，您对 olomorasib 的特点感到兴奋的原因，特别是考虑到我们在开发这两个资产方面所面临的挑战，以及如何使其区别于其他资产的特点是什么？您如何加速开发，以更快地将其提供给患者。

Jake Van Naarden 杰克·范纳登

Geoff, do you want to take that?

吉夫，你想拿那个吗？

Geoff Oxnard

Sure. I mean, we're aware that there are a lot of these KRAS inhibitors, right? And so there are needs that are adequately addressed perhaps by some of the drugs. But there was a need every lung cancer don't acknowledge is that first line, we give these treatments and they're just unreliable, like sometimes the IO works and sometimes it doesn't work. And sometimes chemo works 2 cycles and the patient progresses. And so I think in breast cancer, we've learned to like build and do more. And in lung cancer, that we're starting to do it. So I think we, as lung cancer docs are ready to build and do more. And so these combinations are built to make the impact upfront, make that impact durable and fundamental bent the curves and get more patients on to the flat part of the curve where the durable from these drugs.

当然。我的意思是，我们知道有很多这些 KRAS 抑制剂，对吧？因此，也许一些药物已经充分满足了某些需求。但是肺癌患者普遍没有意识到的需求是，第一线治疗时，我们给予这些治疗是不可靠的，有时 IO 疗法有效，有时无效。有时化疗有效 2 个疗程，患者却出现进展。因此，我认为在乳腺癌领域，我们已经学会了更多的建设和实践。在肺癌领域，我们正在开始这样做。因此，我认为我们作为肺癌医生已经准备好进行更多的建设和实践。因此，这些组合治疗旨在产生前期影响，使这种影响持久并基本上改变曲线，并使更多患者进入曲线的平坦部分，从而使这些药物的效果持久。

I think the trial is designed to enroll. I won't deny that tolerability is the key barrier. And we've heard very clearly, this drug has overcome that barrier. We've identified efficacy, CNS activity, activity in previously treated patients and now tolerability that together allow us to combine with immunotherapy. We see them in our day, and that's what motivates the first-line trial. I think it's going to be -- I mean, it's a worthy experiment. We can enroll this trial, and I'm hopeful it will play out.

我认为试验的设计是为了招募。我不会否认耐受性是关键障碍。我们听到非常清楚，这种药物已经克服了这一障碍。我们已经确定了疗效、中枢神经系统活性、先前接受治疗患者的活性，现在包括耐受性，这使我们能够与免疫疗法结合。我们在日常工作中看到它们，这就是激励我们进行一线试验的原因。我认为这将是一个有价值的实验。我们可以招募这个试验，我对它能够成功进行抱有希望。

Seamus Fernandez 西莫斯·费尔南德斯

Seamus Fernandez from Guggenheim Securities. So just a couple of questions. Jake, when you think about partibrutinib and the sort of magnitude of the opportunity for that product, can you just give us a sense of kind of your vision and Lilly's vision for how far that product can go and relative to some of the sales that we've seen in ibrutinib, Calquence, et cetera, where do you really see that product positioned?

Seamus Fernandez 来自高盛证券。所以只有几个问题。Jake，当你考虑到 partibrutinib 以及该产品的机会规模时，你能否给我们一些关于你的愿景和 Lilly 的愿景，以及该产品可以达到的程度的感觉，相对于我们在 ibrutinib、Calquence 等产品中看到的一些销售额，你真正认为该产品定位在哪里？

And then just the second question is on the folate targeted ADC. I think we had the [indiscernible] fully targeted ADC, and it saw some fairly meaningful toxicity following a partnership with Bristol. Is there toxicity risk associated with full ADCs in general that you guys are trying to avoid? Or have you studied some of those molecules to really see what those issues potentially were? And so they really view that as a well-targeted therapies.

然后第二个问题是关于叶酸靶向的 ADC。我认为我们已经有了完全靶向的 ADC，并且在与 Bristol 合作后，它出现了一些相当有意义的毒性。您是否担心全 ADC 普遍存在毒性风险，您是否正在尝试避免这种情况？或者您是否已经研究了一些分子，以真正了解这些潜在问题是什么？因此，他们真的认为这是一种良好的靶向疗法。

Jake Van Naarden 杰克·范纳登

So yes, I can start with the Jaypirca commercial question. It's interesting. We folks who follow that program have probably seen. We've been on a journey with this medicine that when we started thinking it was sort of a niche product in previously treated patients, maybe those only with C481S resistance mutations. And over time, just as we've grown -- I would say, as we've gathered more clinical data, we've seen the medicine can be a lot bigger than that.

是的，我可以从 Jaypirca 商业问题开始。这很有趣。我们这些关注该项目的人可能已经看到了。我们一直在与这种药物一起进行旅程，当我们开始思考时，它似乎是一种在先前接受治疗的患者中的利基产品，也许只有 C481S 耐药突变的患者。随着时间的推移，就像我们成长一样——我会说，随着我们收集更多临床数据，我们发现这种药物的潜力远不止于此。

And so I think in our space, it's probably true for like all drug development, but it's definitely true in oncology. It's pretty hard to project out to I think what will be the ultimate peak opportunity for any medicine in its early innings, and that's really what this one is.

所以我认为在我们的领域，对于所有药物开发来说可能都是真的，但在肿瘤学领域肯定是真的。很难预测我认为在早期阶段任何药物的最终峰值机会会是什么，这确实是这个的情况。

In this class, in particular, we've seen sort of early winners and later winners, and I think it's still an evolving class actually with some of the recent data that's emerged. So where does that put us? Well, as John talked about, we're just trying to develop the medicine in all the right places with all the right combination partners to result in positive data readouts that are label-enabling so that physicians can use the medicine however they want. And that actually is increasingly a theme we hear from physicians when we talk to them about the medicine, especially now that they've had the chance to use it commercially, they just say, "Oh, I want to use it continuous dosing in the first line. I want to use it post BTK in the second line. I want to use it after BTK and BCL2."

在这个班级中，特别是，我们看到了早期获胜者和后来的获胜者，我认为实际上这仍然是一个不断发展的班级，尤其是最近出现的一些数据。那么，这将把我们带到哪里？嗯，正如约翰所谈到的，我们只是试图在所有正确的地方开发药物，与所有正确的组合伙伴合作，以产生积极的数据结果，这些数据结果是标签启用的，以便医生可以根据需要使用药物。实际上，这实际上是我们在与医生谈论药物时经常听到的一个主题，特别是现在他们有机会商业化使用后，他们只是说，“哦，我想在一线持续使用它。我想在第二线使用它在 BTK 之后。我想在 BTK 和 BCL2 之后使用它。”

I think there are a lot of different potential ways this medicine can benefit patients. And there's a lot of variety, frankly, in how physicians both in the United States and elsewhere may want to use it.

我认为这种药物可以在很多不同的方面造福患者。坦率地说，无论是在美国还是其他地方，医生们可能会有很多不同的想法来使用它。

Our job is just to enable that use. And I think if we can do that, this medicine to make a big impact for patients and probably be a meaningfully large product for the business.

我们的工作就是让这种用法成为可能。我认为如果我们能做到这一点，这种药物将对患者产生重大影响，并可能成为业务上有意义的大产品。

On the full it ADC question, I may actually have Barry answer that because it sort of has a lot to do with linker payload design as much as anything else.

在完整的 ADC 问题上，我可能会让 Barry 回答，因为这与链接载荷设计有很大关系，几乎比其他任何事情都重要。

Barry Taylor 巴里·泰勒

Yes, thank you for the question. I think what we're learning and even as evident from today in the last several days at ASCO is that the devils in the details with ADCs. It's really a 3-component system. And so is your question, is this really a fundamental attribute of the target? Is this toxicities associated with the release of the payload in circulation, not necessarily in an antigen-mediated way? Is this pharmacology related to the linker? I think all of those things for different products have sort of reared their heads, I think in many ways. And we're integrating all of those lessons, not just studying molecules preclinically but even sort of the first principles by which we design our own medicines, really have to solve the ternary problem of those 3 pieces simultaneously. And so I think these different medicines are reading out the answer to your question in different ways, actually.

是的，谢谢您的提问。我认为我们正在学习的，甚至从今天在 ASCO 过去几天所看到的，ADC 中的魔鬼在于细节。这实际上是一个由 3 个组成部分组成的系统。所以您的问题是，这真的是目标的基本属性吗？这与有效荷物在循环中释放相关的毒性，不一定是通过抗原介导的方式？这与连接物相关的药理学？我认为，对于不同的产品，所有这些事情在很多方面都已经显现出来。我们正在整合所有这些教训，不仅仅是在临床前研究分子，甚至是我们设计自己药物的第一原则，真的必须同时解决这 3 个部分的三元问题。因此，我认为这些不同的药物实际上正在以不同的方式回答您的问题。

John Pagel 约翰·佩格尔

If you don't mind, Jake, let me jump at too.

如果你不介意，杰克，让我也来试试。

Jake Van Naarden 杰克·范纳登

Yes, please. 好的，请。

John Pagel 约翰·佩格尔

We actually do think based on our preclinical data, of course, as well that this drug we have in development will differentiate itself from, I only hear from an ocular toxicity standpoint. It's probably not because of folate receptor involving the eye, it's really the payload. And I say that here, we're differentiated with the tube summaries payload. But if you look at the MMA, payloads that are typically associated with ocular toxicity. And I think that will be probably the biggest differentiating factor. And as I said, our nonhuman primates, and we don't see that type of toxicity. Of course, it's not the same experiment as we see in humans. We'll see, but we're pretty confident that we'll have a differentiated product there.

根据我们的临床前数据，我们实际上认为，当然，我们正在开发的这种药物将在某种程度上与眼毒性有所区别。这可能不是因为叶酸受体涉及眼部，而是因为药物的有效成分。我在这里说，我们与管总结有效成分有所区别。但是，如果您看一下通常与眼部毒性相关联的 MMA 有效成分。我认为这可能是最大的区别因素。正如我所说，我们的非人灵长类动物，我们并没有看到那种类型的毒性。当然，这与我们在人类中看到的实验不同。我们将看到，但我们相当有信心我们将在那里拥有一种有差异的产品。

Geoff Meacham

Geoff Meacham of Bank of America. I had a couple for you, Jake. In the spirit of tonight, I wanted to ask you maybe a higher level, you have a lot of newer technologies, newer assets. You're developing clinical trials in a novel way, right, in oncology. I guess the question is, what is the appetite for taking target risk to do through basic discovery and to go after novel targets at Lilly? Is that something that you would say as a priority or not?

美国银行的 Geoff Meacham。我有几个问题要问你，Jake。顺着今晚的精神，我想问你可能更高层次的问题，你有很多新技术，新资产。你正在以一种新颖的方式开展临床试验，对吧，在肿瘤学方面。我想问的是，对于通过基础发现来承担目标风险，并追求 Lilly 的新颖目标，你们的兴趣是什么？这是你们会把它视为优先事项还是不是？

And the second question is when you look at life cycle management for Verzenio down the road, I know you're studying the SERD in combination, but what's the appetite for looking at other CDKs like some of your other competitors are?

第二个问题是，当您展望未来的 Verzenio 生命周期管理时，我知道您正在研究 SERD 的组合，但您对研究其他 CDKs 的兴趣如何，就像您的其他竞争对手一样？

Jake Van Naarden 杰克·范纳登

Yes. Sure. I'm going to start on that on the first one and then have Barry chime in, too. When we started a couple of years ago revitalizing the pipeline, I think one of the things we wanted to make sure is that the early wave of medicines had a higher probability than that which we inherited. And so part of the way to do that is to work a little bit more geared towards validated targets with what we think are better medicines. Coming from behind the things we didn't talk about tonight are way less validated ideas.

是的。当然。我将从第一个开始，然后让巴里也加入讨论。几年前我们开始重振管线时，我认为我们想要确保早期药物的成功概率高于我们继承的那些。因此，为了实现这一点，我们的工作方式更偏向于验证目标，以及我们认为更好的药物。我们没有在今晚讨论的内容中，有很多尚未经过验证的想法。

The other interesting thing that we didn't touch on tonight in the prepared section is the opportunity for novel targets, particularly in the context of radioligand therapies because those are not targets that you need to have any biologic role in the cancer cell. And that's sort of a truism for ADC targets, too except for RLT, you can actually target interest out of their proteins. So there's a whole suite of interesting ideas for targets that are overexpressed in cancer but actually have nothing to do with the cancer itself that if you can bring high-energy radiation locally to, you can actually kill the cancer cells. So the RLT portfolio actually is going to probably over time end up being very geared towards targets and ideas that like you don't see walking around the halls of ASCO or AACR at all. But Barry, why don't you should chime in further on the topic?

我们今晚在准备部分没有涉及到的另一个有趣的事情是在新型靶点方面的机会，特别是在放射配体疗法的背景下，因为这些并不是您需要在癌细胞中具有任何生物学作用的靶点。这对于 ADC 靶点来说也是一个真理，除了 RLT，您实际上可以瞄准他们蛋白质中的兴趣点。因此，有一整套有趣的靶点想法，这些靶点在癌症中过度表达，但实际上与癌症本身无关，如果您可以将高能辐射局部引入，实际上可以杀死癌细胞。因此，RLT 组合实际上可能会随着时间的推移最终变得非常偏向于那些您在 ASCO 或 AACR 走廊上根本看不到的靶点和想法。但是，Barry，为什么不让您进一步发表意见呢？

Barry Taylor 巴里·泰勒

Yes. No. I mean, exceptionally well said. I think outside of the radio pharmaceutical target base, the pillars of cancer biology are unchanged. They've lasted for 25, 30, 35 years of cancer research experience, and that's like partly why we see a lot of clustering around core target ideas. We are in our earliest phased projects taking on a little bit more target risk, but staying central to the sort of fundamental tenants of cancer biology for the non-radiopharmaceutical products in our portfolio.

是的。不是。我的意思是，说得非常好。我认为在放射性药物的靶向基础之外，癌症生物学的支柱没有改变。它们已经持续了 25、30、35 年的癌症研究经验，这部分是我们看到很多围绕核心靶点思想聚集的原因。在我们最早期的项目中，我们承担了更多的靶点风险，但仍然保持对我们投资组合中非放射性药物产品的癌症生物学基本原则的核心。

Cancer is a little bit different, I think, than many other indications, even both at Lilly and elsewhere in this regard and there's quite a bit of clustering around core tenants that we're really planning the vast majority of our target work around.

癌症在某种程度上与其他很多疾病不太一样，即使在礼来以及其他地方也是如此，围绕核心原则有相当多的聚集，我们真的计划将绝大多数的目标工作围绕在这些原则周围。

John Pagel 约翰·佩格尔

And then on the CDK work, Lillian, you should probably chime in here because we've thought about this idea and looked at a lot of these programs.

然后在 CDK 工作上，莉莲，你可能应该在这里插话，因为我们已经考虑过这个想法，并查看了许多这些程序。

Lillian Smyth 莉莲·斯密斯

Yes. I mean I think that the post-MONARCH data, at least reinforce to us, right, the importance of CYCLONEs in HER2-negative breast cancer. I mean, I think, obviously, there's a couple of others looking at CDK2, and CDK4 inhibitors. I think as I think about the development of those kind of molecules, there probably is potential to build upon what we're seeing in post-MONARCH with CDK4/6 inhibition, there's, by adding on some synergistic mechanism of action agents. However, the CDK4 piece is a little trickier in terms of development, right? Because you're looking at potentially head-to-head studies against very potent CDK4/6 inhibitors like abemaciclib, which we already know is very CDK4 selective. So I think that really, it's about integrating what the development path looks like for those molecules into decisions there.

是的。我的意思是，我认为后 MONARCH 数据，至少向我们强调了 CYCLONEs 在 HER2 阴性乳腺癌中的重要性。我认为，显然还有一些其他人在研究 CDK2 和 CDK4 抑制剂。我认为，当我考虑这些分子的发展时，可能有潜力在后 MONARCH 中建立在 CDK4/6 抑制上所看到的基础上，通过添加一些协同作用机制的药物。然而，从发展的角度来看，CDK4 部分有点棘手，对吧？因为你可能需要进行针对非常有效的 CDK4/6 抑制剂如阿贝曲单抗的头对头研究，我们已经知道它非常选择性地作用于 CDK4。所以我认为，真正关键的是将这些分子的发展路径整合到决策中。

Steve Scala 史蒂夫·斯卡拉

Steve Scala from TD Cowen. Jake, I believe consensus suggests Lilly Oncology will contribute a high teens percent of Lilly 2024 revenue, and that likely will be a single-digit percentage in about a decade. So a relatively small contributor to the overall company. You sit on the Lilly Executive Committee, so you're privy to the 10-year plan. Is that likely how it plays out? Or are we underestimating Lilly Oncology or overestimating something else?

来自 TD Cowen 的 Steve Scala。Jake，我相信共识认为，到 2024 年，Lilly 肿瘤学将贡献 Lilly 总收入的高十几个百分点，大约十年后可能会降至个位数百分比。因此，在整个公司中算是相对较小的贡献者。你是 Lilly 执行委员会的成员，所以你知晓这个 10 年计划。事情可能会按照这种方式发展吗？或者我们是在低估 Lilly 肿瘤学，或者高估了其他什么？

And secondly, Dr. Smyth, you might not have intended it this way, but you basically referred to the Novartis Kisqali NATALEE data as noise. Novartis has a pretty formidable data package. So what's the weaknesses in it?

其次，Smyth 博士，您可能并非有意这样，但您基本上将诺华 Kisqali NATALEE 数据称为噪音。诺华拥有一个相当强大的数据包。那么它的弱点是什么？

Jake Van Naarden 杰克·范纳登

Why don't you take NATALEE first?

为什么不先给她 NATALEE 呢？

Lillian Smyth 莉莲·斯密斯

Yes. Okay. So NATALEE, obviously, it's great for patients to generate more data with more molecules, even in broader population. So it's a positive study and it's great to see that data. When you sort of talk about, okay, what are the weakness as well, I mean, first of all, follow-up and maturity of data sets is crucially important in natural breast cancer. You're talking about cure, which is clearly paramount, but you're also talking about toxicities, of these therapies which are not insignificant. And so that benefit risk assessment is crucially important in the adjuvant setting. So maturity of data set, degree of follow-up crucially important. Clearly, there are differences between the monarchE study and naturally relative to that point of maturity of data sets. So that's number one.

是的。好的。所以 NATALEE，显然，对于患者来说，生成更多分子的数据，甚至在更广泛的人群中，都是很好的。因此，这是一项积极的研究，很高兴看到这些数据。当你谈论，好的，还有哪些弱点时，首先，随访和数据集的成熟度在自然乳腺癌中至关重要。你在谈论治愈，这显然是至关重要的，但你也在谈论这些治疗的毒副作用，这些毒副作用并不可忽视。因此，在辅助治疗中，效益风险评估至关重要。因此，数据集的成熟度和随访程度至关重要。显然，单个数据集的成熟度和随访程度在 monarchE 研究和自然乳腺癌之间存在差异。这是第一点。

Number two, we need to evaluate the duration of the therapy, right? We know that 3 years of therapy is what was evaluated in NATALEE. The question is, is that needed is the additional year be, particularly for that high-risk patient population for which you already have abemaciclib available to you, is that additional year of therapy justified in that context. We need to see with more maturity of data, those curves are looking in that off-treatment period. We know that there are patients still on that therapy still on the study. So that's important to see patients off-therapy and see how those curves are behaving.

第二，我们需要评估治疗的持续时间，对吧？我们知道在 NATALEE 中评估了 3 年的治疗。问题是，是否需要额外的一年，特别是对于那些已经有阿贝曲唑可用的高风险患者群体，这一年的额外治疗在这种情况下是否合理。我们需要看到更成熟的数据，看看那些曲线在停药期间的情况。我们知道仍在接受治疗的患者仍在研究中。因此，看到停药的患者以及观察这些曲线的行为是很重要的。

The no negative group that was presented at ASCO represents a relatively small group that was enrolled to the NATALEE study. Clearly, they had high-risk features, but I think, particularly for that group, when you're considering 3 years of deal adjuvant therapy, it will be very important to see a mature data set and how those curves look because we know there's node negative, although they're high-risk node negative patients, they do need longer follow-up to see how those events come in.

在 ASCO 展示的无阴性组代表了 NATALEE 研究中招募的一个相对较小的组。显然，他们具有高风险特征，但我认为，特别是对于那个组，当您考虑 3 年的辅助治疗时，看到成熟的数据集以及这些曲线的样子将非常重要，因为我们知道有无淋巴结受累，尽管他们是高风险的无淋巴结受累患者，但他们需要更长时间的随访来观察这些事件的发生。

Kara Clinton 卡拉·克林顿

I would just add one other comment, which is I think that there is still a number of patients with high-risk breast cancer who are not receiving treatment today, and so in some ways, we welcome having another organization, we're talking about those patients in the need therapy.

我只想再补充一点，我认为仍然有许多患有高危乳腺癌的患者今天没有接受治疗，因此在某种程度上，我们欢迎另一个组织，我们正在谈论那些需要治疗的患者。

I think if you want to also look at the ASCO guidelines that were recently released, I think they were pretty clear about how they view all of the issues that Lillian just talked about but also the importance of the separation and deepening of the benefit over the course of time.

我认为如果您想看一下最近发布的 ASCO 指南，我认为他们对 Lillian 刚刚谈到的所有问题的看法非常明确，同时也强调了随着时间推移利益的分离和加深的重要性。

Jake Van Naarden 杰克·范纳登

Your first question, Steve. Look, Lilly is at an incredibly interesting moment in time right now. I think we all appreciate that, and the health care benefit in portfolio are delivering for patients is extremely significant and position the broader company, I hope, for a lot of success over the next decade.

史蒂夫，你的第一个问题。看，莉莉目前正处于一个非常有趣的时刻。我认为我们都很欣赏这一点，组合中的医疗保健福利对患者的贡献非常重要，并且为更广泛的公司带来了极大的成功希望，希望在未来十年取得很多成功。

One of the knock-on effects of that is the financial strength of the company allows us to invest significant capital in the other disease areas that we focus in, including in oncology. And so when I sit around that table that you referenced,, the success that we're having with the incretin portfolio makes me not just, of course, excited for what it can do for society and for patients, but it really affords us, I think, a unique opportunity sort of among our peer set to invest in oncology, in addition to neuroscience, in addition to chronic immunologic diseases. So I think as we think about accelerating clinical trials, doing things differently, taking more risk, putting lots more medicines into the patient into clinic all at once, a lot of the reason we're able to do that actually is because of the success that the rest of the business is having. So I don't know if consensus 10 years from now is right or wrong, but I think the success the company is having right now really is a sort of rising tide that list the boat of all the other therapeutic areas we invested in, including oncology.

其中一个连锁效应是公司的财务实力使我们能够在我们关注的其他疾病领域，包括肿瘤学，投入大量资金。所以当我坐在你提到的那张桌子旁时，我们在胰岛素素组合产品组合方面取得的成功不仅让我感到兴奋，当然，我对它对社会和患者的贡献感到兴奋，但我认为这确实为我们提供了一个独特的机会，可以在我们的同行中投资肿瘤学，除了神经科学，还有慢性免疫疾病。因此，我认为当我们考虑加速临床试验，采取不同的做法，承担更多风险，一次性将更多药物投入患者临床试验中时，我们能够做到这一点的原因实际上很大程度上是因为公司其他部门取得的成功。所以我不知道 10 年后的共识是对还是错，但我认为公司目前取得的成功确实是一种上升潮，提振了我们投资的所有其他治疗领域的船只，包括肿瘤学。

Chris Schott 克里斯·施特

Chris Schott at JPMorgan. Just two questions for me. Maybe coming back to the POINT acquisition. How quickly can you move those additional targets forward as you think about kind of building out a suite of these opportunities? And at this point, do you have all those capabilities in-house? Or do we have to think about additional acquisitions to really get to the POINT you want it to be there?

JPMorgan 的 Chris Schott。对我来说只有两个问题。也许回到 POINT 收购。在您考虑构建这些机会套件时，您可以多快推进这些额外目标？目前，您是否拥有所有这些能力？还是我们需要考虑额外的收购来真正达到您想要的程度？

The second one is just a bigger picture question, more commercial. There's been a number of questions around the Part D redesign and some of the changing payer landscape. When I think about a drug like Verzenio or any oral kind of Part D potential medication, do you anticipate there'll be greater efforts from the payer universe to manage formularies in oncology differently than the past? Or do you think this will still be a category where that's less frequently occurring.

第二个问题只是一个更大的问题，更商业化。关于第 D 部分的重新设计以及一些不断变化的付款人格局已经有了许多问题。当我考虑像 Verzenio 这样的药物或任何口服的第 D 潜在药物时，您是否预计付款人宇宙将会采取更大的努力来管理肿瘤学处方清单，与过去不同？或者您认为这仍然是一个发生频率较低的类别。

Jake Van Naarden 杰克·范纳登

Barry, do you want to take the RLT question and then I'm going to have Winselow Tucker, who leads commercial for us in oncology, take your second question.

Barry，你想回答 RLT 问题吗？然后我会让 Winselow Tucker，负责我们肿瘤学领域的商业业务，回答你的第二个问题。

Barry Taylor 巴里·泰勒

I think with regard to how quickly we can continue to move forward, RLT programs that are in the discovery phase of our pipeline, the intense focus we bring to all of the other therapeutic modalities to get them to patients in a competitive time frame, we apply to the RLT and several of those programs, depending on the specific question and feature of the molecule we're optimizing for can be moved along quite quickly, actually. But I think it also gives us the opportunity to do something that perhaps radioligand therapy hasn't enjoyed per se to date and historically, which is to bring real professional molecule creation to radiopharmaceuticals. We obviously have cut our teeth for many years, engineering medicines against really tough complex and nuanced TPPs to bind and inhibit targets to avoid off targets to solve challenging ADME and oral pharmacology, and we are really looking forward to bringing the kind of die in the wall professional drug development to RLTs but do it at a cadence that's competitive. And to move these programs along, we I think, have every expectation we can deliver on exactly that.

我认为关于我们能够继续快速前进的方式，我们在管道发现阶段的 RLT 项目，我们对所有其他治疗模式的强烈关注，以在竞争时间框架内将它们提供给患者，我们将应用于 RLT 和其中几个项目，取决于我们正在优化的分子的具体问题和特征，实际上可以相当快地推进。但我认为这也给了我们一个机会，做一些也许放射配体疗法迄今为止并且历史上没有享受过的事情，那就是将真正专业的分子创造带到放射制药领域。显然，多年来，我们一直在针对非常棘手、复杂和微妙的 TPP 工程化药物，以结合和抑制目标，避免非靶点，解决具有挑战性的 ADME 和口服药理学，我们真的很期待将这种专业的药物开发带到 RLT，但要以竞争的节奏进行。我认为，为了推动这些项目，我们确实对能够准确交付有着每一个期望。

And we do have the vast majority of the capabilities necessary in-house. I don't think that necessarily precludes additional external innovation, which, as Jake put it at the very beginning, we're constantly looking for typified by the recent Aktis Oncology partnership. Thank you for your question.

我们确实拥有绝大部分必要的内部能力。我认为这并不一定排除了额外的外部创新，正如杰克在一开始所说的，我们一直在寻找，正如最近的 Aktis Oncology 合作所体现的那样。谢谢你的问题。

Winselow Tucker 温斯洛·塔克

Thank you for your question. I think when it comes to the Part D benefit redesign, there may be a desire to pay to more and do more managing. But oncology has been had a bit of a protected class in some ways. And so we see that continuing over some time, like there may be some effort, but I do think it's still going to be one that's going to be hard fought for a major change in that space.

感谢您的提问。我认为在涉及 D 部分福利重新设计时，可能会有一种愿望，即支付更多并进行更多管理。但在某种程度上，肿瘤学一直是一种受保护的类别。因此，我们看到这种情况会持续一段时间，可能会有一些努力，但我认为这仍然是一个将会艰难争取在这一领域进行重大变革的问题。

Akash Tewari 阿卡什·特瓦里

Akash for Jefferies. All right. So I have a couple. In your earlier studies for your SERD, you had a 6-month ET cutoff you remove that in your Phase III study. I think if you look at some of the emerging SERD data sets, it's clear that having patients on a CDK4/6 enriches for ESR expression. And then number two, you're kind of kicking out some of these ETFs progressors. How much of that is a risk with your upcoming EMERALD study? And what's your confidence that you're going to be able to get both a wild type and ESR1 label?

阿卡什给杰弗里斯。好的。所以我有几个问题。在您早期的选择性雌激素受体降解剂（SERD）研究中，您设定了一个 6 个月的内分泌治疗（ET）截止时间，而在您的第三期研究中取消了这一设定。我认为，如果您查看一些新兴的 SERD 数据集，很明显，让患者接受 CDK4/6 治疗会丰富雌激素受体（ESR）的表达。其次，您似乎正在排除一些 ET 进展者。这在您即将进行的 EMERALD 研究中存在多大风险？您对能否同时获得野生型和 ESR1 标记有多大信心？

Number two, when we look at the DESTINY-06 data, there's this kind of question, well, what's going to happen with HR positive going forward? I mean you're showing a 13.2 benefit in HER2 low. There's a 75% overlap between HER2 low and HR positive, do you feel like that's going to be kind of a changing for your franchise?

当我们看 DESTINY-06 数据时，有这样一个问题，那么 HR 阳性的未来会发生什么？我的意思是，您在 HER2 低中显示了 13.2 的益处。HER2 低和 HR 阳性之间有 75%的重叠，您觉得这会对您的特许经营产生一种改变吗？

Jake Van Naarden 杰克·范纳登

Lillian, do you want to take a stab at both of those?

莉莲，你想试试这两个吗？

Lillian Smyth 莉莲·斯密斯

Yes. I want to make sure I remember all of them. Okay. So first of all, with respect to minimum duration of prior therapy, yes, you're right, we have a requirement in there in terms of number of months on prior endocrine or CDK4/6 inhibitor nor did the EMERALD study. So I think that we are in a position still, particularly given the sample size that we've designed here, 860 patients enrolled, I think we will be in a position to be able to appreciate that benefit robustly.

是的。我想确保我记住了所有的内容。好的。首先，关于先前治疗的最短持续时间，是的，您是对的，我们在这方面有一个要求，即在先前内分泌治疗或 CDK4/6 抑制剂上的月份数，EMERALD 研究也没有。所以我认为我们仍然处于一个位置，特别是考虑到我们在这里设计的样本量，已有 860 名患者入组，我认为我们将能够充分地意识到这种益处。

And to your point about ESR1 mutation acquisition, I think we expect that it should be in that range of around 30%. And as I mentioned, that end point is one of our primary end points. So I think that positions us well in terms of our statistical design to be able to see a positive study. The next question versus about...

关于您提到的关于 ESR1 突变获取的观点，我认为我们预计它应该在大约 30%的范围内。正如我提到的，这个终点是我们的主要终点之一。所以我认为在统计设计方面，这使我们处于一个良好的位置，能够看到一项积极的研究。下一个问题是关于...

Jake Van Naarden 杰克·范纳登

[indiscernible] versus ITT.

[不可辨识] 对比 ITT。

Lillian Smyth 莉莲·斯密斯

Yes. Okay. So I mean, we -- I think it's, obviously, we have to look at the data sets that have been generated thus far and across other programs, including the approved agent. There does appear to be an enrichment to benefit in the ESR1 mutants. Having said that, we would also hope that we can demonstrate at least that this agent is also equally efficacious without added tolerability issues in the wild-type patient population. We appreciate that, that was not the case in EMERALD and that restricted label occurred for the ESR1 mutants. However, we feel and having spoken to a lot of physicians and patients about this, that, that alternative route of administration is crucial for patients. We know that they want to be able to take medicines at home. So I think, obviously, we need to see the data to enable that risk-benefit argument with the regulators, but certainly, that is, I think, an important attribute.

是的。好的。所以我的意思是，我们--我认为，显然，我们必须查看迄今为止已生成的数据集以及其他项目，包括已批准的药物。在 ESR1 突变体中似乎存在受益的丰富性。话虽如此，我们也希望至少能证明这种药物在野生型患者群体中同样有效，而且没有额外的耐受性问题。我们感谢，EMERALD 中并非如此，ESR1 突变体发生了限制性标签。然而，我们认为并且已经与许多医生和患者讨论过，这种替代的给药途径对患者至关重要。我们知道他们希望能够在家中服用药物。因此，我认为，显然，我们需要查看数据以使监管机构能够进行风险-益处论证，但肯定，我认为，这是一个重要的特征。

With respect to then, I think you had a third, DESTINY.

就那时而言，我认为你有第三个，命运。

Jake Van Naarden 杰克·范纳登

Let me I just want to chime in on EMBER for a second. Look, I think there's no question that seeing benefit over fulvestrant in the ESR1 wild types is a riskier proposition. I think we know that from all the other studies that we've seen. But over the past couple of years, in particular, we've had a lot of conversations with society about like access to medicine, access to care equity in the context of that. And yet we're demanding superior efficacy for an oral agent that patients can take at home versus a painful intramuscular injection that requires extra visits to the health care office, hours of lost time, lost wages, et cetera. I don't think that we, frankly, as a society should be looking at this through conventional lenses of superiority on PFS end points for methods of administration that are so radically different. So we'll see what the data show, but we hear consistently from physicians that the oral route of administration is valuable even in the event of the same PFS, and I don't think that's what we're going to show either, but it just gives you a sense for sort of how the treating world is thinking about this.

让我简单谈谈关于 EMBER 的问题。看，我认为毫无疑问，在 ESR1 野生型患者中看到比富维司汀更有益处是一个更具风险的主张。我认为我们从我们看到的所有其他研究中都知道这一点。但特别是在过去几年里，我们与社会进行了许多关于药物获取、医疗保健公平性的对话。然而，我们要求口服药物具有更优越的疗效，患者可以在家中服用，而不是需要额外到医疗机构注射疼痛的肌肉注射，耗费额外时间、工资等。坦率地说，我认为我们作为一个社会不应该用传统的优越性视角来看待这个问题，即对于如此根本不同的管理方法，我们应该以 PFS 终点为优势。因此，我们将看到数据显示什么，但我们一直从医生那里听到的是，口服给药途径即使在相同的 PFS 情况下也是有价值的，我认为我们也不会展示出这一点，但这只是让你了解治疗世界对此问题的思考方式。

And Lillian, you want to take the D-B06 Yes. I mean it was great to see the D-B06 data. Obviously, collectively, for T-DXd, the D-B06 and D-B04 data tell you that you can offer this therapy for patients in that first- or second-line chemo appropriate. And I think that's the point. I don't think that the community will swing from maximizing and optimizing endocrine and oral therapy options for patients. We know it's important that they don't want to jump immediately to infusional therapy nor in fact, do the data tells that they need to do that. I think that we're seeing in that first-line chemo appropriate setting, obviously, the patient population that was enrolled to D-B06 had a median number of 2 prior therapies. So most of these patients had obviously received, all of them have received a CDK4/6 inhibitor and in fact, more had received a second line of endocrine therapy.

莉莲，您想要接受 D-B06 是的。我的意思是看到 D-B06 数据真是太棒了。显然，总体而言，对于 T-DXd，D-B06 和 D-B04 数据告诉您可以为那些需要第一线或第二线化疗的患者提供这种疗法。我认为这是关键。我不认为医学界会从最大化和优化内分泌和口服治疗选择转向这种疗法。我们知道重要的是他们不想立即转向输注疗法，事实上，数据也表明他们不需要这样做。我认为在适当的第一线化疗环境中，显然，参与 D-B06 试验的患者人群中，中位数为 2 种先前治疗方案。因此，这些患者中大多数显然已接受了 CDK4/6 抑制剂，事实上，更多人已接受了第二线内分泌治疗。

So I do think there's opportunity for us to build in that second-line post CDK setting, post-MONARCH is the start. Hopefully, EMBER-3 builds upon that. We see nice data with imlunestrant in combination with abemaciclib. And I think that, that second-line setting is really where we need to intensify for patients to delay the need for infusional therapy.

所以我认为我们有机会在 CDK 治疗后的第二线治疗中建立起来，MONARCH 之后是一个开始。希望 EMBER-3 能够在此基础上发展。我们看到 imlunestrant 与 abemaciclib 联合应用的数据很好。我认为，第二线治疗是我们需要加强的地方，以延缓患者需要输液治疗的时间。

Unidentified Analyst 未知分析师

Maybe just a follow-up on EMBER-3, I guess, at ESMO last year, we heard about the diarrhea profile overlapping with Verzenio. So maybe just confidence in the tolerability profile as you think about EMBER-3 and then the adjuvant setting.

也许只是对 EMBER-3 的跟进，我猜，在去年的 ESMO 大会上，我们听说腹泻剖面与 Verzenio 重叠。所以在考虑 EMBER-3 和辅助设置时，也许只是对耐受性剖面的信心。

And then the second question is just if EMBER-3 only shows a benefit in the ESR1 population, what does that imply for EMBER-4 in terms of your confidence level?

然后第二个问题就是，如果 EMBER-3 只在 ESR1 人群中显示出益处，那么对于您的置信水平来说，这对 EMBER-4 意味着什么？

Lillian Smyth 莉莲·斯密斯

Thanks for the question. So with respect to the tolerability profile of imlunestrant in combination with abemaciclib, we're pretty confident. We've generated a relatively robust Phase I data set with at least 80 patients that have received the combination. And when we looked at the comparative adverse events in those patients compared to the MONARCH 2 population, it certainly appeared no worse. So our expectation is that imlunestrant will not have additional significant toxicity over what we see with fulvestrant abemaciclib. So from a tolerability perspective, we're confident that, that will play out well in the Phase III setting.

感谢提问。关于 imlunestrant 与 abemaciclib 联合应用的耐受性概况，我们非常有信心。我们已经产生了一个相对强大的至少 80 名接受该联合应用的患者的 I 期数据集。当我们比较这些患者与 MONARCH 2 人群的不良事件时，结果显示并没有更糟。因此，我们的期望是 imlunestrant 不会比 fulvestrant abemaciclib 引起更多重要的毒性反应。因此，从耐受性的角度来看，我们相信在 III 期研究中会表现良好。

With respect to your question about ESR1-mutant restriction. So I mean, I think that it's important to recognize that early breast cancer and advanced breast cancer do have meaningful biological differences. Obviously, ESR1 mutations are not seen in the early breast cancer setting, but ESR1 mutations are surrogates for EOR dependency. And we know that most year positive breast cancer is EOR dependent. So I think that the question still remains relevant regardless if the label or study is confined to an ESR1-mutant benefit. I still think that, that has important and relevant read-through to the adjuvant EMBER-4 setting.

关于您关于 ESR1 突变限制的问题。我认为，重要的是要认识到早期乳腺癌和晚期乳腺癌确实存在着有意义的生物学差异。显然，在早期乳腺癌情境中并不会出现 ESR1 突变，但 ESR1 突变是 EOR 依赖的替代指标。我们知道大多数雌激素受体阳性乳腺癌是 EOR 依赖的。所以我认为，无论标签或研究是否局限于 ESR1 突变的益处，这个问题仍然是相关的。我仍然认为，这对于辅助 EMBER-4 情境具有重要和相关的指导意义。

And remember, in December 4 study, we're evaluating patients that have already demonstrated a degree of endocrine sensitivity by definition, they've gotten past that 2 years of therapy initial adjuvant therapy. So I think the question still remains relevant and important. And also recognize that the EMBER-4 study is a different comparator arm to EMBER-3. The hurdle is to be improving upon standard of care adjuvant endocrine therapy, not fulvestrant, which is obviously at the comparator EMBER-3.

请记住，在 12 月 4 日的研究中，我们正在评估那些已经通过定义表现出一定程度内分泌敏感性的患者，他们已经度过了最初的辅助治疗 2 年。所以我认为这个问题仍然是相关和重要的。同时也要认识到 EMBER-4 研究是 EMBER-3 的一个不同的比较组。障碍在于要改进标准护理的辅助内分泌治疗，而不是富马酸铁曲松，显然这是 EMBER-3 的比较组。

Dave Risinger 戴夫·赖辛格

Dave Risinger from Leerink Partners. So Jake, I was hoping that you could talk a little bit about post-MONARCH in terms of the commercial opportunity, when you think guidelines might change and when we might see that added to the labels globally?

来自 Leerink Partners 的 Dave Risinger。所以 Jake，我希望你能谈谈关于 MONARCH 后市场机会方面的一点，你认为指南可能何时改变，我们何时可能看到这一点被全球标签添加？

Jake Van Naarden 杰克·范纳登

Yes. So I could start and then Kara and Winselow should really chime in. The idea behind the study was not really motivated by commercial forces, so to speak. The medicine is already labeled in this population. And a lot of physicians have actually already been using the medicine for years now sort of in this way, and they can because it is labeled here.

是的。所以我可以开始，然后 Kara 和 Winselow 应该真正参与进来。研究背后的想法并不是真正由商业力量驱动的，可以这么说。这种药物已经在这个人群中标记了。实际上，很多医生多年来已经在这种方式下使用这种药物，他们可以这样做是因为这里已经标记了。

This was really an evidence generation question that we just had been hearing for years that physicians wanted an actual robust Phase III trial. And of course, now within imlunestrant, it complements that program as well. So it's just -- it's not, it's not been a main motivation. I think the feedback we hear at this meeting is that the results in many ways are what docs expected to see from this regimen. And so for those who are already doing it, they sort of feel validated in that approach. And for those who maybe weren't doing it, maybe they feel like they can have more comfort doing it now that there's Phase III randomized data. But I mean, Kara, you should talk about guidelines.

这实际上是一个证据生成的问题，多年来我们一直听到医生们希望有一个真正强大的三期临床试验。当然，现在在伊姆鲁那替这个项目中也有所补充。所以这只是——这不是主要动机。我认为我们在这次会议上听到的反馈是，从许多方面来看，结果与医生们预期从这个方案中看到的结果相符。因此，对于那些已经在实施的人来说，他们在这种方法上感到得到了验证。对于那些可能没有在实施的人来说，也许他们现在会觉得更有信心，因为有了三期随机数据。但是，我是说，Kara，你应该谈谈指南。

Kara Clinton 卡拉·克林顿

Yes, I think a couple of things. One is, I think that people still are largely unsatisfied for patients that don't have a biology-driven cancer and second-line metastatic breast cancer. So I think the enthusiasm has been relatively high, and people were really interested in answering this question in a randomized Phase III setting.

是的，我认为有几件事情。一是，我认为人们对于没有生物驱动的癌症和二线转移性乳腺癌的患者仍然不太满意。所以我认为热情相对较高，人们对在随机的三期临床试验中回答这个问题非常感兴趣。

I think overall, we haven't -- overall, we would anticipate that this information will be submitted to appropriate guidelines, and I would expect because it's a positive study with a PFS benefit of 27%. So that will be included in the guidelines and then we'll go through the categorization process for NCCN and others, right? What Jacob said, I think currently today in most markets, not only in the U.S. but in the world, if people are choosing to do this, it's within a labeled indication. So we -- I wouldn't say there's a significant amount of commercial upside.

我认为总体来说，我们还没有——总的来说，我们预计这些信息将被提交给适当的指南，我期望因为这是一项 PFS 受益率为 27%的积极研究。因此，这将被纳入指南中，然后我们将进行 NCCN 和其他机构的分类过程，对吧？Jacob 说的，我认为目前在大多数市场，不仅在美国，而且在全球范围内，如果人们选择这样做，那就是在标签指示范围内。所以我们——我不会说有很大的商业上涨空间。

Jake Van Naarden 杰克·范纳登

We're at time. All right. All right. Thanks, everyone, for coming tonight. Hopefully, we gave you a flavor of what we've been up to over the past couple of years. And as you can tell, like we still have a lot more work to do. We want to see these medicines start working against the profiles that we expect for these specific patient populations. And hopefully, we'll be doing one of these events in the near future. We can show you some of those emerging clinical data. So thanks, everyone, for coming.

我们准时了。好的。好的。谢谢大家今晚的到来。希望我们让您对我们过去几年的工作有所了解。正如您所看到的，我们还有很多工作要做。我们希望看到这些药物开始对我们期望的特定患者群体产生作用。希望我们将在不久的将来举办类似的活动。届时我们可以向您展示一些新兴的临床数据。所以感谢大家今晚的到来。