AMG510更新

首先是在Q2的presentation中更新了AMG510的情况(社会我安王，人狠话不多)：

• 肺癌的FIH数据将在今年WCLC上进一步更新

• 首次在结直肠癌和阑尾癌中观察到缓解

• 单药的剂量扩张研究入组完成(960mg QD，后文有提及，另外这个可以再回去看ASCO上的数据推测)

• 正在入组联合PD-1治疗的剂量扩张研究(NSCLC)

• 在2019年启动可能注册单药的Phase2研究(NSCLC)

有条不紊

随后的Earnings Call Transcript里面高管对AMG510做了如下诠释：

Bob Bradway(Chairman & Chief Executive Officer)

We'll be staying closely focused on execution and productivity, as we seek to invest in the long-term opportunities that will enable us to reestablish our long-term track record and growth. Our long-term opportunities include many novel first-in-class therapies across all phases of our pipeline.One of these of course is AMG 510 our KRAS G12C inhibitor, which has generated significant interest and continues to move very rapidly through the clinic.

David Reese( Chief Financial Officer)

在对KRAS抑制剂的探索40年之后，我们在ASCO上公布的FIH数据引起了业界强烈反响，NSCLC中ORR 50%而CRC中也基本是SD令人鼓舞，同时不良事件耐受很好。

Turning to oncology. I'll begin with AMG 510, our KRAS G12C inhibitor. After nearly four decades of research in the pursuit of a KRAS inhibitor, the response from the medical community to our first-in-human data at ASCO was simply overwhelming. We reported a 50% response rate in non-small cell lung cancer and very encouraging stable disease data in colorectal cancer with a tolerable adverse event profile.

今天也欣然报道在结直肠癌和阑尾癌中也观察到正式的缓解，整个研究计划快速推进，已经完成入组了单药扩张队列，并且正在入组接受联合PD-1治疗的NSCLC患者。

Today I am pleased to report that we now have formal tumor responses in colorectal and appendiceal cancer patients and the program is moving forward rapidly. We have completed enrollment in our monotherapy expansion cohort and are also now enrolling non-small cell lung cancer patients in the PD-1 combination arm.

同样也会在不久将来开始入组NSCLC患者启动可能注册单药的Phase2，并且将在9月份早期的WCLC上更新肺癌的进展。

We will also begin enrollment of lung cancer patients in the coming days in the potential registration enabling Phase 2 monotherapy portion of the program and we'll provide an update of our progress in lung cancer at the 2019 World Conference on Lung Cancer in early September.

Q&A

1 这里的缓解就是正式的肿瘤缓解(RECIST v1.1)，包括1名结直肠癌和1名阑尾癌，还需要继续影像学检查，期待未来有更多的结果数据，另外AMG 510的安全性和耐受性很好并对此留下了深刻印象。后续的研究都会采用960mg的剂量。

Operator

And our next question is from the line of Umer Raffat from Evercore ISI. Umer?

Umer Raffat

Hi. Thanks so much taking my questions. I had one question with three parts. It's all just a clarification. So thank you for that update on KRAS and you've mentioned formal tumor responses. I wanted to ask just to clarify;a, are these Reese's responses? Number one. Number two, can you confirm if it's more than one response in colorectal or you can only have one colorectal and one appendiceal? And finally also at what dose level? Thank you very much.

Bob Bradway

Yes. So taking those three parts in turn. Yes these are resist responses, which is what I alluded to by saying formal tumor responses. It is a patient niche in colorectal cancer and appendiceal cancer. These many of the patients dosed have yet to have repeat scans done so we expect in the coming few months to have a large amount of additional data at the target dose. Recall that we just opened the expansion cohort not long ago and have had a flood of patients enrolling on that. We are continuing to see very good tolerability. I've been involved in Phase I drug development for a long time now, and I can say I'm only very impressed with the emerging safety profile that we are seeing with AMG 510.

David Meline

Dose levels?

Bob Bradway

Dose levels. Going forward it's all at the 960 milligrams.

2 (肺癌部分)我们将在WCLC上对单药持久性的做更新，目前来说我们对持久性印象深刻，还没有出现快速耐药的情况。

(联合PD-1)临床前结果发现KRAS抑制和检查点抑制有着很强的协同效应，可能增强了免疫浸润和上调了肿瘤细胞上MHC I的表达，期待这类联合能引起持久的消除肿瘤细胞。

Michael Yee

Hey, great. Thanks for the question. David Reese on KRAS you talked about responses in colorectal et cetera. Maybe just going back to lung, can you comment on confidence around longer-term durability in monotherapy? And then to the comments around enrollment with the combination PD-1 talk about what you would expect to see there and when we could get first data as I – obviously, I would assume that's an exciting opportunity? Thanks.

David Reese

Yeah, thanks Mike. Yeah, in terms of durability as I mentioned, we will be presenting a clinical update at the World Lung Conference in September. But I would say that to-date we've been favorably impressed with potential durability. We have to all recall that it's early days and many of these patients have been recently enrolled on trials, so we'll gain further insight into durability as time goes on. But at least, to-date we are not seeing for example the rapid emergence of resistance.

In the PD-1 combinations, we have what I think are very strong preclinical data suggesting potential synergistic interactions between KRAS inhibition and checkpoint inhibition, probably due to enhanced immune infiltration and up-regulation of Class I MHC on tumor cells. And our goal with that kind of combination would of course be very long-lasting durable remissions.

3 (结直肠癌) 绝大多数继续接受治疗的患者都是960mg，ASCO披露的数据中CRC组好像只有1例是那个剂量，年底或者明年上半年积累足够多的数据能证明该剂量带来的临床活性后我们会提供相应的适应症的更新。

(注册) 肺癌可能是首个向前推的适应症，不久将来会开展Phase2，会很快。

Chris Raymond(Piper Jaffray)

Hey, thanks for taking the question. Just on AMG 510. So kind of keen on your commentary on the tumor responses in CRC. So I wonder if you could maybe give some clarity here. Are these new patients that were enrolled and got maybe the 960-milligram dose, or were these -- I know you have had an option for patients to have intrapatient up-dosing. So any color there in terms of who responded would be great. And then maybe a second part of that question also on the registration trial starting this year. I know you said it's in lung, but just kind of wondering if you could give some color on the design in the setting and what constitutes maybe a control in third-line lung would be great. Thanks.

Bob Bradway

Yes. Sure. With regard to colorectal, the majority of patients that we're reporting going forward will have been treated at 960 milligrams. As you may recall at ASCO, we only had I think one patient at that point who was on that dose level. And so we'll provide updates in that particular indication as we accumulate data towards the end of the year and the first part of next year when we have enough patients at the target dose to get a real sense of the clinical activity.

In terms of potential registration plans, we would assume that lung cancer will be the lead indication going forward. As I mentioned in the coming days, we will be enrolling in the Phase II portion of that program. We're moving very, very rapidly and we'll provide updates on that particular pathway as we go forward. But I would say, we've had productive discussions with regulatory authorities and have a good sense of the pathways moving forward.

4 (溶解度？)只能说PK、PD都很好，另外提醒大家对于一个共价抑制剂来说，关键是在靶点水平以上暴露一定时间以便在给药间隔占据靶点，基于目前临床数据，我们看到的很有吸引力的PK谱给我们很大的信心。

(联合的选择？)对于肠癌来说，可能就是联合免疫或靶向，更多指引会在今年晚些时候或明年早期更新。

Yaron Werber(Cowen)

Great. Thank you. And David I have a follow-up there also on 510 a little bit in two parts. Maybe the first one the -- what can you share with us on solubility or formulation of the compound? We understand that solubility is better and the gastric acidity a little bit lower than the intestinal. So what you see there on your journey especially on the formulation? And then on the CLC side, as you contemplate combo as the next stage now that you're seeing single-agent activity are you thinking a PD-1 combo or is that going to be a TKI combo next? Thank you.

David Reese

Sure. So let me take both of those questions in turn Yaron. In terms of solubility, I would say broadly we've been very happy with the pharmacokinetic and pharmacodynamic profile of the drug. And again to remind everyone with a covalent inhibitor, the key is really to maintain exposures above a target level for a period of time that is adequate to poison the target through a dosing interval. And based on what we've seen in the clinic to date now across several dozen patients gives us the confidence that we've got a very attractive pharmacokinetic profile.

In terms of colorectal cancer, obviously, combinations will be of great interest going forward, I would say potentially both with immunotherapeutic agents and additional targeted therapies. And as that program moves forward, we'll provide additional guidance a little later in the year and early into next year.