More NKTR

[HeartMD]

Cosmid,

Great post. I think most of what you have laid out has been hashed to some degree in many places already but it’s nice to see the summary of contrary points all in one place.

However, I would mention you shouldn’t underestimate what Bristol knows either. Don’t for one second think we have all the data. I’ve been on that side of the research world, you don’t show all your cards on the flop… we haven’t seen the river card just yet. However, I’m not foolish enough to believe that what we don’t know can’t be bad just as much as it could be good. Like you, I and many others have said, there is a lot of risk in NKTR.

Who said it was the largest deal ever for a drug? I must have missed that. I was never under that illusion. As for the abscopal effects… yes that’s been observed before. It was just an aside mention (and a deserved one) in my post and not a big part of my investment thesis.

Also, you said: Be careful, this can be very seductive. To my knowledge, 214 has yet to be tested with a control arm, so the appearance of increased efficacy is derived by comparison to historical trials. If I had a dime for every time that something performed better with each subsequent trial, I wouldn’t be investing, because I would be fully vested. In fact, I would interpret these findings to be a signal that they are getting better at selection against non-responders. This is good, right? Well, yes and no. An alternate interpretation (and my hunch) would be that there are more non-responders than anticipated, and they are getting better at NOT enrolling them. Not very holy grail-like.

I have some issues with this part of your post because some things need to be corrected and clarified. I think you may be misunderstanding what Saul, Chris and I summarized. Maybe that is my fault and I’ll try to do a better job this time. These are not “subsequent trials” or new enrollees in the trial. These are the same patients in the original trials who were not deemed responders after the initial follow up period but have become responders with a longer period of time on 214. That is not the same as the scenario you suggested where they pick better patient’s for 214 in later trials or subsequent phases to get better results. So the increasing efficacy has nothing to do with historical controls or lack of a control arm nor does it have anything to do with picking better patients for the trials or subsequent enrollees in a later phase of the trial.

Just so it’s clear, these are NOT new patients that NKTR selected because they felt there would be a higher percentage of responders in a more “selected" group nor is it because they are changing the divisor. These are the originally enrolled patients who remained on NKTR-214 despite not being a responder at initial follow up who then later became responders after a longer period of time taking the drug(i.e., patient 5 at 3 months follow up was not a responder but at 6 months of follow up patient 5 is now responding with much less cancer burden on imaging). That was almost unheard of in oncology until the PDL1 therapies. If it was just better patient selection I wouldn’t have even mentioned it in my post but it is the most impressive thing to me about 214 thus far. Many of them have become complete responders with no evidence of cancer remaining. What is the durability of the response? That’s the question now isn’t it? To be determined…

This is Phase 2 data, almost never compared with a control or placebo arm. It is observational data with endpoints/targets defined by the investigators that will be predominantly safety based followed by efficacy. Yes, historical comparisons will be made but that is NOT the aim of the study. The aim is two-fold, is it safe and does it work like the Phase 1 data suggested it would but on a larger scale? Did we miss something in the small scale that is now apparent on a larger scale? That’s what Phase 2 trials are intended to determine. The other point to be made here is that the patient’s being studied are in advanced stages of their disease for the most part. That’s the main reason there isn’t a control arm… what are you gonna do to the control? Watch them slowly waste away while offering them hospice? No. They are going to see how long 214 patients live and compare that to what we know already–> how long does a Stage 3/4 lung/breast/colon/melanoma cancer patient live on average? That’s the control and it’s the only one you need.

MC

[volfan84]

The other point to be made here is that the patient’s being studied are in advanced stages of their disease for the most part. That’s the main reason there isn’t a control arm… what are you gonna do to the control? Watch them slowly waste away while offering them hospice? No. They are going to see how long 214 patients live and compare that to what we know already–> how long does a Stage 3/4 lung/breast/colon/melanoma cancer patient live on average? That’s the control and it’s the only one you need.

Excellent point, HeartMD.
Seems that these are some of the worst cancers out there when already at Stage 3 or 4. It would definitely be cruel and heartless to give them a placebo.

[GauchoRico]

I am talking about investing now, at the current level, since that is what Saul brought up.

Hit reply later and circle back when you get your next 400% on this one. I will gladly eat crow if you do, as it will mean they came up with something pretty special.

Of course you made the valid point that a decision to buy, sell, or hold should be based on the price compared to the prospects compared to other investing alternatives. That decision should be on the table every day.

Personally, I think holding is the right decision for me. If you end up eating crow that would mean that NKTR will have become an $80B company without any further dilution (would also means a 20-bagger from my purchase but that it mostly irrelevant). Getting to $80B would mean NKTR would probably need more than 1 blockbuster including a few cancer cures. I think NKTR-181 and NKTR-214 have a very high chance of becoming blockbusters. Some cancer cures also seem likely based on the clinical data to date. The 214/262 combo is still too early to make any prediction with much confidence.

I like the odds with NKTR, but it’s still my smallest position at 4.3%, and I haven’y added any since September.

Chris

[qazulight]

Personally, I think holding is the right decision for me. If you end up eating crow that would mean that NKTR will have become an $80B company without any further dilution (would also means a 20-bagger from my purchase but that it mostly irrelevant). Getting to $80B would mean NKTR would probably need more than 1 blockbuster including a few cancer cures. I think NKTR-181 and NKTR-214 have a very high chance of becoming blockbusters. Some cancer cures also seem likely based on the clinical data to date. The 214/262 combo is still too early to make any prediction with much confidence.

Chris,

This may be poor off in the weeds question. Tell me if that is the case.

If Nektar has comw up with this drug, it would seem that they have assembled the talent and built an enviroment that can innovate in this area. I know in my simple job, when I solve on problem it often leads the way to solving another.

If this is the case here, then wouldn’t this team be valuable in and of itself?

Qazulight

[XMFfuma102]

If Nektar has come up with this drug, it would seem that they have assembled the talent and built an environment that can innovate in this area. I know in my simple job, when I solve on problem it often leads the way to solving another.

It is really difficult to make a successful mAb. Consider that, since 1986, when the first mAb was approved, there are currently only 47 on the market- across all spectrums of disease. There were 58, but 11 were removed from market for various reasons.

https://www.ncbi.nlm.nih.gov/pubmed/25529996

These are highly complex molecules with multiple bumps in the road… What makes sense doesnt play out in a test tube. What happens in a test tube doesnt play out in animal studies. What happens in animal studies doesnt play out in human safety data. What plays out in human safety data doesnt play out in blinded trials. What plays out in blinded trials doesnt necessarily play out in post-market studies (rare ADRs, efficacy not there, poor sales, etc).

For instance, PD1 inhibitors, when combined with other drugs - seem to work great even in classes of patients in whom giving a PD1 inhibitor doesnt make sense… simplifying a good bit, this means patients who were not overexpressing PD1, (who thus would not have been considered a candidate for PD1 inhibition) - when given PD1 inhibitors with other chemo agents, benefited more than either drug regimen separately. Made no sense, but seems to work out clinically, and really, thats the important part!

… add in that only 30% of phase 2 drugs make it to phase 3, and well, there are only a handful of players with successful mAbs. Its incredibly difficult and costly to just pump them out- plus your basically starting from scratch again. NKTR’s would be better served continuing to expand the label of 214, hoarding cash and buying / partnering with other promising fledgling biotechs.

[Cosmid]

Doc, I apologize in advance for not being able to respond in a point by point format, so this might be difficult for others to get context. I’m an old fart, and I don’t know how to cut, paste, and italicize on my kids iPad…

First up, my intention was never to personalize this. I’m not keeping score of who said what. My mention of you, Saul, and Chris was to acknowledge your level of sophistication for the purpose of providing contrast to those who are not at your level.

Regarding my underestimating BMS’ hand, I don’t think I did that. I said pretty clearly, I think, that there is a risk of underestimating others. Overestimating one and underestimating the other are not mutually exclusive. I just think there is danger in assuming that there is a “river card” in the first place, and that BMS bought it because they know more than us. That they did buy in shouldn’t be accepted as evidence that such a card exists. It’s easy for us to be influenced by this kind of qualifier. It’s like name-dropping. I don’t know how many times I hear people start a sentence with: well, at Harvard, blah, blah, blah. Well all that knowledge didn’t help much with their investments, did it? (Sorry if I offend anybody from Harvard…maybe I should have said Yale).

Who said that it was the largest drug deal? I don’t know, again, not keeping score. I am quite certain that the biotech writers on MF did, and I vaguely recall it being mentioned on this board, although quite possibly on NPI. I didn’t come up with these points based on what you said, they were just things that stuck with me in my own ruminations of the NKTR story. Several people not named Doc, Saul, or Chris have repeated these types of statements.

The increasing efficacy issue? You are right, I did misinterpret what was said. Nonetheless, I fail to see the the value in it even with my now corrected understanding. The increasing response rates in individual patients followed serially would be expected for most immunologicals. If you give a group of patients a flu vaccination and monitor them weekly for responsiveness, you are going to see an increased rate of response each week. The first week only a few, and each week thereafter a higher percentage of responders. An expectation that the response fraction should be fixed at a given time is misguided, I think, so I have trouble adding value to their observation.

Why would we expect 214 to act any differently? Individual patients have different levels of tumor reactive (although dysfunctional) T cells when they enter the study, they have different tumor burdens, in sites with different levels of vascularity. The drug has different distribution kinetics in different patients. Tumor rejection requires the accumulation of a critical mass of cytotoxic T cells to mediate tumor regression. Given this, why would we not expect “delayed” responses? The Rosenberg lab has observed this repeatedly in TIL studies, and it has also been observed with Ipi. I have first hand knowledge of this, although admittedly anecdotal. I don’t follow the Opdivo literature, so I wouldn’t know whether they see such a response. If they don’t, maybe they are the immunological outlier.

I made no criticism for them not doing a controlled study, because I am fully aware that these are phase I and II studies. I understand the difference. And to be honest, I don’t know what an appropriate control arm would be. Low dose IL-2? Probably not. It’s been tried and doesn’t appear to have benefit, although low dose is an arbitrary designation. That said, 214 really is sustained ultra low dose after all. Will FDA permit them to skip P3 and rely on historical data? Maybe given the new leadership of Scott Gottlieb. It would actually be pretty desirable and possibly justifiable in this setting.

So no Doc, I’m not suggesting that we tell patients to go off to hospice and die a horrible death because NKTR has not yet done a controlled study. And once again, not trying to influence anybody about whether to buy, sell, or hold NKTR. As much as anything, I am trying to draw out a robust discussion that might help me crystallize my own convictions because at this point, I don’t have any.

Cosmid

[GauchoRico]

If Nektar has comw up with this drug, it would seem that they have assembled the talent and built an enviroment that can innovate in this area. I know in my simple job, when I solve on problem it often leads the way to solving another.

If this is the case here, then wouldn’t this team be valuable in and of itself?

I couldn’t really tell you because I haven’t looked in detail at the management team. I don’t think I would be able to access the talent. My guess, though, would be that the people who work at NKTR are for the most part replaceable. I would think that the company and the program at NKTR would go on just fine even if they lost any one person.

I would also guess that NKTR’s value really lies with 2 aspects:

1. They have developed molecules that can modulate the immune system. I tried to fine what their molecules actually are but couldn’t find that information. Someone said that they are monoclonal antibodies but I don’t think that that is the case. I think that they are proteins, specifically, naturally occurring messenger proteins, that have been modified by adding molecules onto them to alter their pharmacology to direct various parts of the immune system to be activated/enhanced or to be deactivated/down regulated. In this way they can target components of the immune system to be recruited to target or destroy foreign material (cancer) in the body. They are adding polymers to these proteins and the polymers may change the activity, specificity, and/or half-life which can all be important in properly directing the immune system in a specific way. So they are using them either to 1) activate the immune system to target and destroy cancer, or 2) tune down the immune system to prevent autoimmune reactions in diseases like arthritis or psoriasis. So to summarize this point, the value is in the actual molecules that they have engineered; these specific molecules can be protected by patents for a period of 20 years from the filing date.

2. There is also value in the general technology that NKTR is using to modify molecules. There is some information about this on their website:

http://www.nektar.com/science/research-platform

In addition, NKTR has created value by advancing their drugs through the development process. The clinical success that they have demonstrated gives them a lead over other companies that haven’t advanced their drugs as far or without the same level of efficacy or tolerability.

NKTR has also created value by establishing partnerships. Doesn’t matter so much to me what BMS knows or doesn’t know. BMS is one of if not the most advanced pharma company in the I-O field, and the fact that NKTR has such a broad partnership with this leading company with many resources to provide to NKTR has created tremendous value to NKTR. The cash and expertise provided by BMS not only speeds their pipeline development but also greatly reduces the financial risk to investors on the NKTR investment (the chance of NKTR running out of cash or having future difficultly in funding its efforts is pretty much addressed).

To monitor NKTR’s success as an investment, we should be mainly following 3 things:

1. How successful are the clinical trials.

2. Are the drugs advancing to eventual approval. #1 directly influences #2. Each time NKTR advances a clinical trial or starts a new one, NKTR is moving toward approval to market.

3. New partnerships which allow NKTR to get more cash and advance more drugs for more indications. These will adding to the number of shots on goal that NKTR has. I expect that there will be several more partnerships, maybe 2-3 more announced during 2018: probably one for NKTR-181 for distribution and maybe a couple more for I-O or immunology for another autoimmune disease.

So, NKTR’s team is not something that I have looked to. I look to the success in all the other areas outlined above which tells me that NKTR is well run and has good people.

Chris

[XMFfuma102]

I’m not suggesting that we tell patients to go off to hospice and die a horrible death

Hospice and palliative are NOT dirty words. In fact, patients who go into palliative care tend to live longer than their equivalent, and a much happy and dignified death.

This is a huge problem with American society. We need to honor the wishes of those that have had a good run, and let go with dignity and compassion.

[qazulight]

This is a huge problem with American society. We need to honor the wishes of those that have had a good run, and let go with dignity and compassion.

I want to die by getting eaten by a crocodile while on mission trip to Africa.

The only thing you bring with you is your stories. Might as well be good ones!

Cheers
Qazulight

[HeartMD]

Cosmid,

I wasn’t making it personal, that wasn’t my intention. I just wasn’t sure where you were coming up with some of the statements you had put in quotation marks. I assumed you were quoting those of us on this board so that’s why I mentioned it. Color me confused. Mainly, I just wanted to correct the misunderstanding of what is happening with the response rates which IS a big deal. I don’t know you and don’t know your background and that’s why I went over the control arm issue… maybe a little too harshly, my apologies.

Why would we expect 214 to act any differently? Individual patients have different levels of tumor reactive (although dysfunctional) T cells when they enter the study, they have different tumor burdens, in sites with different levels of vascularity. The drug has different distribution kinetics in different patients. Tumor rejection requires the accumulation of a critical mass of cytotoxic T cells to mediate tumor regression. Given this, why would we not expect “delayed” responses?

Because it doesn’t always happen, that’s why we shouldn’t expect it. Don’t expect anything you aren’t assured of, otherwise it’s called hope. This isn’t the usual anti-cancer immunologic correct? It’s different. It makes you, the patient, stimulate the creation of more cytotoxic T-cells all the while upregulating the amount of expressed PD1. It’s more or less a synthetic cytokine. It’s synthetic, problem #1 right? Allergic reactions and/or formation of antibodies to the synthetic molecule which could potentially reduce it’s effectiveness would be the first reason to think response rates may not improve over time. Downregulation of CD122 receptors by cells in response to the overstimulation by 214. This happens all the time in medicine where a therapy has reduced effectiveness because of this problem. What if the NK cells being made in response to the overstimulation are somehow not as good? Not fully mature or too “blast” like? Also, what if the enhanced PD1 expression isn’t durable? What if it fades with time? There are just too many unknowns to “expect” increasing response rates with time, especially tumor disappearance on imaging. I personally know a guy on Humira for Crohn’s that has lost it’s effectiveness over time. Apples to oranges, I know, but just a quick example of time not always being in favor of a medication just because it’s an immunologic. You gave me a flu vaccine analogy which was a awful one, so I’m giving you an equally poor anecdote :).

There are so many reasons not to expect it, I have no idea why you would. Now if we hope to see improved response rates with time and build the trial design around it… that’s different. I imagine Nektar saw this in pre-clinical data, and hoped they would see it in humans. But, as Fuma pointed out in his post above, that rarely pans out in the long run. Just because you see it in the test tube doesn’t mean it will work in rats. Just because it works in rats doesn’t mean it will in primates… you get my drift.

One more thing, just because we expect something, does that make it any less awesome when it happens? When you had your children, they were expected, but it was still awesome when it happened wasn’t it? I’d argue it’s even more awesome when people get life back from the scourge of cancer, even if it was expected.

Cheers,

MC

[HeartMD]

Chris,

You are correct. These are synthetic cytokines, not mAb’s. At least that is what I gathered from this poster published on their website:

http://www.nektar.com/application/files/9914/7887/7065/2016_…

MC

[Cosmid]

Doc, I’ll give this one more shot, and then leave it to rest. You are right about comparing apples to oranges, but in this case, I think we are comparing apples to Plymouth Volares. I am not commenting at all about expectations for desirable results with these trials. I have high expectations for NKTR and the entire IO field. I hold a patent on a molecule that has an important role in Tregs and checkpoint blockade, been CO-I on three separate INDs involving IO, have over 100 peer-reviewed publications in basic and clinical immunology and have served as a consultant to firms with IP around IL-2. I reluctantly bring this up, but do so to demonstrate my commitment and high expectations for the field. So please, don’t conflate my skepticism about a single scientific point with an implication of a lack of an appreciation for the value of curing someone from the scourge of cancer.

Maybe all of nuances of medicine and technical speak around this has led to me being inarticulate and confusing. So let’s remove the technical bs and try another approach. Let’s suppose that I go into my backyard and plant 100 seedlings, remove things that might be a “blockade” and fertilize them with the best plant growth agonist (sorry, fertilizer) with the hope they will three months from now become trees. After one month my response rate (measured as those converted to trees) is 50%, at two months is 75%, and at three months, 90%. What does the increasing rate of success tell me about my process, especially if I am comparing it to nothing else? If my target was 90%, what does it matter what the RATE was? I hit my target, and I am elated. Some seedlings got off to faster start than others, other stuff happens. Should I attach value to the rate and use it to support my enthusiasm for the likelihood for an outcome in a future study? Nobody gives a hoot about the rate; they care about the outcome. If I have another method that produces only 10%, 20%, then 60%, is one of the methods better? Well, only if rates are the object of the study.

The issue I addressed (I couldn’t care less who raised it) was that of attaching value to the appearance of improving rates of responsiveness in serial studies. As far as expectations, my entire point was that in an environment that involves the amplification of an immune response, the observation of an increased fraction of responders during serial evaluations is entirely expected. There’s no value judgement here. This isn’t about the suffering caused by cancer; it’s about interpreting data. There is nothing good or bad about this being expected. Expectation is merely a statistical inference that either plays out or not. It can provide a level of comfort that the model is correct, but not necessarily the outcome. Some patients, for whatever reason, have a head start in the race, and others have a slower start but ultimately make it to the finish line. The finish line is all that matters, not the rate that was observed at different times during the race.

That’s enough from me…Hallelujah, Holy Ship! Where’s the Tylenol?

Cosmid

[HeartMD]

Cosmid,

We will have to agree to disagree on the expectations. Especially expectations accompanied by what I would consider a small percentage of side effects of the amplified immune response compared with other checkpoint drugs. I was taught to generate a hypothesis and to test it. I was also taught not to expect my suspected outcome. Boy was that teaching correct. Often we observed things completely unexpected, good and bad.

The tree planting is a pretty good analogy but you’re forgetting several factors. What’s the acidity of the soil? Acidic, neutral, basic? What is it composed of? Sand, clay, boggy moss? What is the fertilizer composed of you mentioned? You’ve oversimplified a complex process and that has been my point all along. To expect something is one thing, for it to happen in reality is completely different given all the factors that could make that reality you’re “expecting” pure fantasy.

As far as rate goes, you are assuming rate equals speed, but that is now how they are defining response rate. I am using their language, not mine. They aren’t talking about speed or acceleration. I wouldn’t call it the rate because it causes confusion obviously. It would be better termed the increased percentage of responders with time (which is a rate technically as it’s relative to time). I think you and I are on the same page here but the word rate has created some confusion. The outcome, in the end, is the most important thing, as you’ve stated perfectly. But their response rate, as they define it, IS IMPROVED OUTCOME, not how fast the patient got to the outcome. So no, I still don’t think we should expect that as they have defined it.

However, the rate even as you have defined it, is not irrelevant is it? If 214 doesn’t work quickly enough some patients will die even if it would have worked eventually, correct? If you had given that tree triple 13 instead of triple 8 maybe it would have stimulated it faster and it would have grown? I’m being picky, I know, but I’m just pointing out it isn’t inconsequential and that faster response could save a life or two.

Where’s the bourbon?

Cheers,

MC

Please keep posting. You obviously have valuable knowledge that is welcome on this board.

[branmin]

I think the knowledgeable posters on this board are astonishing. The constant information concerning NKTR for example and the work done here and on the NPI board to try and find out whether we have another(life changing) Amzn(for example)on our hands, in it’s very early stages, is superior to anything else you will find anywhere else. So Kudos to you all.

However and I possibly will be brought to task here, sometimes there is just so much(sitting on the fence) information and so much dilly dallying that you might be missing some serious returns.

https://www.finviz.com/quote.ashx?t=NKTR

I got in originally mid Nov last year and out on Friday. This huge increase in 4 months is one of the fastest percentage gainers I have ever had in this short time span(apart from some crazy pot stocks). Learnt my lesson big time in 2000. NKTR can go either way, like many of the riskier stocks we all follow can. But you know the saying…Pigs get slaughtered. How many of us got back in or added to Anet, between 239-260 recently? Why, because you believed and so far correctly, it was going to 300 in a short period of time. But you added at that price…can do the same with NKTR once one knows the direction its truly going in.

Point I am making, one can always get back in at any stage, regardless of the price and if you believe, and as Saul has mentioned, the small matter of short term tax consequences is irrelevant in the overall big picture. Is NXTR the real deal that will finally save 1000’s of lives and make us all rich. Don’t know and may not happen in my lifetime.

[GauchoRico]

Maybe all of nuances of medicine and technical speak around this has led to me being inarticulate and confusing. So let’s remove the technical bs and try another approach. Let’s suppose that I go into my backyard and plant 100 seedlings, remove things that might be a “blockade” and fertilize them with the best plant growth agonist (sorry, fertilizer) with the hope they will three months from now become trees. After one month my response rate (measured as those converted to trees) is 50%, at two months is 75%, and at three months, 90%. What does the increasing rate of success tell me about my process, especially if I am comparing it to nothing else? If my target was 90%, what does it matter what the RATE was? I hit my target, and I am elated. Some seedlings got off to faster start than others, other stuff happens. Should I attach value to the rate and use it to support my enthusiasm for the likelihood for an outcome in a future study? Nobody gives a hoot about the rate; they care about the outcome. If I have another method that produces only 10%, 20%, then 60%, is one of the methods better? Well, only if rates are the object of the study.

There’s in big difference in this analogy. What happens to the trees when no fertilizer is applied. Will they still grow? I’m pretty sure that all of those cancer patients’s disease would progress, not reverse, if they are given no treatment. Assuming that is true then the NKTR-214 are halting or reversing the disease in the majority of patients. Some patients just take longer to respond. If this phenomenon would happen with an alternate medicine then why would we need NKTR-214? I think that the whole point is that NKTR seems to be working and it continues to work as the treatment is continued; if the treatment wasn’t working then no amount of continuation would matter. HeartMD made just that point: this is not something that we normally see in oncology treatments…we normally need to move the patient to a new medicine with the hop that the new one will work where the initial one didn’t.

Chris

[projectchris]

What data impresses you most about 214? I happen to like the safety profile. I wasn’t very impressed with 1/7 response rate in second line rcc. I think the data are too early. Some great 1st line rcc data out there at 80% response rate. I wouldn’t be surprised if bmy did the deal out of desperation. They mis calculated in lung cancer and fell behind. They once had a large lead and others are catching up quick. I want to see more data before I am convinced 214 is magic.

BMY did the deal based on science more than anything at this point.

[projectchris]

Can 214/nivo compete against pembro/axitinib in rcc? I am not convinced with early 214 data myself but reserve the right to change my opinion. The pembro/axitinib phase 3 will readout in 2019 I believe.

Dr. Atkins. Axitinib + pembrolizumab in 1st line #kidneycancer. Unprecedented 73% ORR. Only 3/52 pts with PD as best response, only 6 pts have died, 2 deaths unrelated to RCC. OS curve staying high at 17 mo med f/up #GU18

[projectchris]

https://www.investorvillage.com/smbd.asp?mb=1086&mn=1752…

Take a look at cabo/nivo data in previously treated rcc patients.

Among the 13 patients with mRCC who were evaluable for response, ORR was 54 percent (7 PRs of 13 patients) and the DCR was 100 percent.

No treatment naive patients in rcc cohort.

214 is obviously active, but I wonder if bmy is betting on the safety profile of 214 will make it a winner. 214 comparable in efficacy, but early data doesn’t appear superior to other drug combos.

We’ll see when data matures to the point we can actually get long term OS and pfs data. Then we can really compare it to other drug combinations.

[projectchris]

" This is an insurance policy for Opdivo, and a smart one, at that."

I think your right, bmy had too much opdivo/ipi eggs.

Joeflow is a chemist and I happen to agree with his comment seen here.

https://www.investorvillage.com/smbd.asp?mb=1086&mn=1794…

[Cosmid]

Chris,

I’m not suggesting in any way that 214 doesn’t work. And of course, these patients would die if you did nothing. One of the counterpoints I was making was that I was cautioning against giving credit to the late responder effect.

I understand that this is something not commonly seen with other onc drugs. Most conventional drugs are directly cytotoxic. Once therapeutic levels are reached it becomes largely mass vs. mass. The tumors are sensitive or resistant. If no response, you stop giving it to them.

Blockade+ 214 works in an entirely different way. It reverses T cells that are held in check, then 214 gives them the ability to proliferate to a critical mass required for a measurable response. All else being equal, if patients have high numbers of pre-existing tumor-reactive T cells that are released from being checked, they reach the critical mass earlier. If they start with lower numbers of T cells that are being checked, they respond later.

So in the two scenarios above, I would not expect late responders with a directly cytotoxic drug, but would with a drug that required an indirect amplification step. The amplification step is exponential, and the rate of cell division is fixed by other biological effects. Even in a highly controlled system, a very tiny difference in baseline levels of target T cells leads to a major change in the time it takes to reach the critical mass required to measure an effect. This is not good or bad. It’s a fundamental reflection of mechanism, and one that occurs in ANY adaptive immune system and to any antigen. So my point was to be cautious about using it to bolster a conviction that this finding in and of itself speaks to effectiveness. The overall response fraction itself compared to opdivo alone is impressive enough that it doesn’t need to added to a list of reasons to be encouraged. I can almost assure you that no FDA panel member who would be on the fence about approval is going to be swayed by the appearance of late responders. It is not uncommon with Ipi, TIL, and IL-2 alone, so I am neither encouraged nor discouraged by the observation. The overall response fraction is encouragement enough for me.

At the level of the individual patient, the finding is meaningful. If you don’t respond early, you still have hope that you might respond later.

Cosmid