Maxim Jacobs
24 October 2016

Edison KOL call

CAR-T therapy

On October 19 we kicked off our KOL series, sponsoring an interview between Rafael Mejar, M.D., Ph.D and Max Jacobs (call leader). The conversation featured a discussion on the delivery challenges and potential solutions to administering CAR-T therapy more widely upon eventual FDA approvals. The discussion focused on the number of specialists needed, facility requirements and cost of delivery among other potential hurdles to use. Below is a link to a recording of the event and the transcript to the call.


Call Leader: Ok, so thanks Dr. Bejar for joining today. I want to introduce myself. My name is Max Jacobs, I’m Director of Healthcare Research for North America at Edison. I’m very happy to have you here today. Can you start off by describing your practice and your experience?

Doctor: Sure, I’m a physician/scientist at UC San Diego Moores Cancer Center. I split my time between doing research and clinical care. With patients mostly with mild malignancies like myelodysplastic syndromes. I don’t know what else you’d like to know about our institution. We’re a comprehensive cancer center, so we have a complete slew of clinical offerings including clinical trials, bone marrow transplants, and the like.

Call Leader: Ok great. I know you’re an MDS specialist I was just wondering would you be able to discuss the treatment paradigm for ALL, CLL and DLBCL patients?

Doctor: Yes, in general absolutely.

Call Leader: Yea in general. How would you describe the response rates for the various lines of those therapies?

Doctor: Well all those things depend sort of dramatically on which of the diseases you’re talking about and which patient population you’re speaking of. If you’re looking at DLBCL there’s a wide range of responses that depend on the subtype and the patient themselves. But, on average I would say about 50% of patients with Diffuse Large B Cells Lymphoma can be outright cured with chemotherapy alone. Then there are some that obviously relapse and if they are not salvageable after that fact…

The numbers are very different for ALL particularly in older individuals. You guys I’m sure know that younger patients with ALL will have survival rates that approach 90%. Whereas the older patients tend to have much more aggressive disease and relapse rate are quite high, and mortality is quite high. The long term survival rate is less than 50% in many of these patients, particularly if they have adverse cytogenetic.

In CLL it is a completely different disorder, it is a much more chronic disease. More patients can live for many many years, even go through many different lines of therapy, and often will maybe die of something else. Not necessarily directly caused by the CLL. These patients tend to be substantially older than patients with lymphomas or acute leukemias.

Call Leader: My guess based on what you’re saying: There is probably more choices for DLBCL patients for 2nd line, 3rd patients than ALL patients?

Doctor: That’s certainly true. ALL, you don’t have a lot of time to go to 15 different therapies. Patients tend to be sick relatively quickly, particularly after relapse. If you are fortunate you are able to get a second line of therapy in and in rare cases a third, if transplant isn’t an option. But usually if a patient has relapsed or even has high risk disease and is very likely to relapse, we’ll be looking for a transplant option relatively early in the course of the disease. That’s about it in terms of what we can provide.

Call Leader: That was very helpful, thank you. My next question is can you give us your general thoughts on CAR-T therapy and also some of the high-level challenges you see arising from treating patients at your facility?

Doctor: Sure. We have a few of the CAR-T cell trials open here. So we’ve had experience in the institution treating these patients, but personally have not had a patient on one of these trials since they are all aimed at lymphoid malignancies and most of my patients have myeloid lymphoid malignancies. I’m sure in the future more myeloid CAR-T cell options will become available.
They’re extremely impressive therapies. They have an incredibly high rate of response in patients that are typically extraordinarily refractory to most of our treatment options, because they have been through several lines of therapy in a very advanced disease.

I think we are still learning how best to give CAR-T cells. Up until now it has really been, well it still is really considered an entirely experimental therapy. But until now, we haven’t really understood the best way to give them. We’ve encountered a lot of problems along the way that in some ways have set us back a little bit.

You asked about the challenges of giving CAR-T cell therapy? I think some of the challenges are somewhat self imposed. In that we are restricting the use of these agents in clinical trials to the most sick patients we have. The patients that are truly refractory and really are at the end of all options.

So not only are you giving a therapy that has a lot of toxicity to a patient, you’re giving it to a patient who themselves have very little reserve. Or have a lot of comorbid conditions that are a consequence of their disease. So that in itself makes it more challenging than I think it might if we are able to use these therapies in earlier lines of treatment.

Call Leader: So it would probably be more interesting to have them- to see what CAR-T therapy would do in first or second line patients?

Doctor: I think they will end up being a little bit easier to give in first or second line. We may not want to give them by themselves in first line therapy. I think there will probably be a role to do some sort of Cyto wrapping treatment. But the real problem with these diseases isn’t that we can’t treat patients and get them to respond, it is that we can’t get them to maintain their response. Or at least if they lose their response, those are patients that are truly in trouble. I really see CAR-T cells as a really complementary therapy to some of the first line therapies we have now. That can put people into remission and then the CAR-T cells can essentially keep people there.

That’s a very different paradigm than giving CAR-T cells to people who have a tremendous burden of disease because their disease is prone to spike multiple lines of prior therapy. That causes acute complications in the first few days after treatment, that may not be as severe if the patient hadn’t been significantly cyto-reduced with some other treatment.
So I do think it will be easier in the future, when we move these products closer to first line.

Call Leader: Ok, so actually it sounds like the way you see CAR-T therapy used optimally is after they are given a first line therapy, use the CAR-T to mop up any remaining tumor, and that using it that way will probably limit a lot of the toxicities.

Doctor: Exactly right. These are essentially relapse prevention or consolidation therapies to provide long term immune vigilance.

Call Leader: Does it also make sense to use it as the sort of…a bridge to transplant therapy?

Doctor: It depends on the disease.

I think there are some scenarios where it will absolutely be a bridge to transplant. I think in the myeloid malignancies there is a lot of interest in targeting markers that are not unique to the tumor. Meaning, that if you didn’t go to transplant you would essentially eradicate someone’s myeloid which is not a good thing. You want people to be able to make neutrophils after your treatment.

But if you have a therapy that kills essentially all myeloid cells, it might be very effective in eradicating leukemia, you just need some sort of rescue that will replace myeloid cell production after that fact. So I think in the myeloid malignancies one of the first things we’re going to see is these agents as mechanisms to getting people to transplant.

Call Leader: Ok great, that’s very interesting. Can you see any sorts of patients where you really think CAR-T therapy would not be appropriate? ALL, CLL, the hematological tumors?

Doctor: I’m sure there are going to be some people that are not good candidates because of their overall health status. I think more importantly there may be people who don’t necessary need it. We think of allogeneic transplantation as being curative, but not everybody gets them. In part because people can be cured with less intensive therapy. So I think for good risk, DLBCL patients or more indolent CLL cases there is no indication to do a CAR-T cell type therapy at the moment.

Maybe in the future things become proven to be extraordinarily safe and easy to give, that might change. But at the moment we are reserving these things for people who we think have high risk and likely to relapse disease.

Call Leader: That makes sense. In terms of the overall risk reward of CAR-T therapy, what do you think that looks like? Is it really heavily weighted toward reward or are you concerned by some of the neurotoxicity, the cytokine release syndrome, etc.?

Doctor: I’m concerned about those things, but I don’t think that they are going to be as big a barrier to say conditioned chemotherapy is for allogeneic transplantation.

These are things that were striking, because they were in some ways relatively unexpected. These therapies were much more effective immediately than we thought they might be, so we saw a lot of cytokine release syndrome. But I think we’re also getting much better at dealing with that. We’re learning how to get patients through that.

I see that barrier coming down. The neurotoxicity is another great example. This was something that extraordinarily worried people when we first started seeing it, particularly when we started seeing it over and over again. But I think now that we understand it, we know people can get through it and be ok it on the other side of an experience like that.

As that happens I think it will become, we’ll get more experience and we’ll be more tolerant to it and it will become easier to deal with that.

Call Leader: What are some of the strategies to get patients through a cytokine release syndrome, a severe neurotoxicity?

Doctor: What we’ve done here, which I think is extremely useful, is to try and standardize our approach and not have people reacting immediately as everything needs to be solved within sixty seconds kind of thing. We are permissive. We let people have fevers, we set thresholds at which we will do something, but we let people go right up to those threshold to try and avoid doing things that might make their cytokine release syndrome better, but might actually impact the efficacy of the treatment.

For example, we wouldn’t want to be giving high dose steroids to a patient who has just gotten the T cell therapy because we’re going to essentially impair therapy’s ability to do its job. So having protocols in place, clearly define how high of a fever and how long we’re willing to tolerate. What kind of endo organ function we’re going to accept. How long a person needs…can tolerate being Ill from neurotoxicity before we really need to get worried about permanent damage are still being fleshed out. We’re still trying to figure them out. But having standardized rules in place makes it easier to get through things like that.

Mostly what we do is supportive care. Mostly what we try and do is not get in the way of the therapy, when we know the patient will be ok on the other side of it.

Call Leader: Those thresholds, are they generally standardized amongst patients or is it very variable? For example by their age, if they have diabetes or something?

Doctor: That’s a good question. I think now the major standardization is coming from the
fact that all these therapies are being given on clinical trials. So the clinical trials
have protocols that people follow very closely.

Call Leader: Yes sorry about that I guess we’re having technical difficulties. We were talking about how we want to let people get up to their threshold and not limit the therapy. And how people have different thresholds. I think you were saying that it was a bit of an unknown because all of these are being done in a clinical trial format?

Doctor: In part. I think they are standardized by the clinical trials, but they’ve evolved as we learn more and more about what the toxicities are. In the beginning we were more aggressive in trying to combat cytokine release syndrome. And giving drugs like tocilizumab and then even steroid when we thought it was severe enough.
Now we’ve relaxed the criteria a little bit, unless people continue to have fevers in some cases for many days without any intervention, as long as we can assure ourselves the root infection doesn’t need to be addressed.

We are changing what those guidelines are, but they are still pretty standardized because these patients are being treated on uniform clinical trials.

Call Leader: OK. From the point of view of the patients, I’m sure they understand all the risks.
Are they happy to go through this process?

Doctor: Even patients that have read all the nitty gritty details are knocking down our doors to get access to these therapies. I think the people in particular who are in the trials, are in a dire situation. The toxicity hasn’t really scared anyone off as far as we know. Patients do understand what these issues are and the families understand patients might very well be in the ICU for many days after the treatment.

All this is really in the context of anti-CD19 CAR-T cell trials. We don’t really have tremendous experience with other targets in other diseases. So that may not be the norm for all CAR-T trials going forward.

Call Leader: How many specialists do you need to monitor these patients as they are going through these different toxicities?

Doctor: I think the most important person ends up being the oncologist who knows when to intervene and when not to intervene. There are a lot of support personnel that need to help get the patient through it. I think you need to have nurses who are very attuned to what’s happening. You’re really in ICU level of care.

Even in patients who don’t necessarily go to the ICU, it’s really more care than you might. At least more attention than you might need on a regular floor patient for example. You need that kind of expertise, ICU level nursing, ICU level physician, who understand how to handle pressers and other things like that.

I think there is a level of acuity that’s required, but as we’re learning more and more about toxicities. Specialists like neurologist, for example, may become less critical. In some scenarios it could be useful to have access to a neurologist if something were atypical and you really wanted to differentiate between what you thought was treatment related neurotoxicity and something else, a stroke or something different.

But for the most part the major thing you need is expertise in the person who is ordering and directing the therapy.

Call Leader: Oh ok. It sounds like you worked in the community setting in the past. A lot of community hospitals will have oncologists, they’ll have neurologists, obviously they’ll have ICU physicians and nurses. Is CAR-T therapy something that can be handled by community hospitals?

Doctor: I think it will be. It may not be now. Again for some of the same reasons that I mentioned. We’re still really learning what the toxicities are and we’re often even being a little too conservative about addressing them. I think in the future when these products become more standardized and we understand them a little bit better, there certainly will be scenarios that will be given in the community hospital setting.

The community hospital that I worked in during residency and fellowship did have a small ICU. So we did have the capacity to put central lines into patients, to put them on pressers and ventilators if need be.

So I think you need to have that level of capacity available to you in case things don’t go well. But other than that, you just need to have a level of care that would be required for treating very sick chemotherapy patients. Someone who might run into an infectious complication, someone who might run into issues with cardiac or renal problems. Have that level of expertise available to you in the hospital. That typically is available to you in a community hospital setting.

Call Leader: I’ve seen estimates that 30% of CAR-T patients require ICU admission. Do you think that number is approximately right, or too high or too low?

Doctor: I think it might be 30% that really need need an ICU admission because they’re going to receive a therapy in the ICU that can only be given there. That could be something requiring pressors or sedation or something of that nature. There probably are more patients that need very close and careful monitoring. Right now that is happening in the clinical trial unit, which is not like a typical community hospital floor.

I think if you were in a community hospital you would see more patients in an ICU level of care. That is almost entirely going to be driven by the need for closer nursing and monitoring. Not necessarily because you’re going to need ICU only intervention.

Call Leader: Ok. In terms of drilling in on one specific toxicity, the severe neurotoxicity that JUNO saw in their trials. The alleged culprit is fludarabine. Have you had any experience with fludarabine and do you think that’s likely the culprit?

Doctor: I would separate a couple of the things you said there. I think the neurotoxicity is totally independent of fludarabine. There were 2 patients in the JUNO trial who received fludarabine and died as a consequence of their treatment and disease.

Fludarabine was blamed because it was the only thing they had in common and it isn’t something that’s necessarily in all regimens that people use with CAR-T cells.

But neurotoxicity can occur in the absence of that. I think that might be more of an antigen specific side effect. I don’t necessarily think that patients getting anti-mesothelioma CAR-T cell therapy or something like that are going to necessarily have CNS disease.

I think the short answer is I don’t necessarily know what the root cause of the neurotoxicity is. I don’t think it is the fludarabine, I think at least from the small number of patients that we’ve had to look at it’s possible the fludarabine complicated things, but those are separate issues.

Call Leader: Ok. Just going on to the more practical aspects of all this. Pricing. KITE had an analyst day yesterday and they seemed to imply, to justify a pricing between 300-450 thousand dollars per treatment. How would that work in your setting or a community setting? I know that a lot of times an oncology practice will have to pay for a drug first and then wait to be reimbursed. I was wondering if you could walk us through that.

Doctor: Yea, that could be a big challenge. It’s not just CAR-T cells that have that kind of challenge. I think in part they’re linking the valuation to comparing what else you might possibly do in a patient. Patients with lymphoma, think about autologous transplant. Autologous transplants is not an inexpensive procedure. It has a lot of the same upfront costs, having to collect stem cells from patients. Large cell B cells, you need a conditioning regimen, you have a prolonged hospitalization.

That’s really what they are basing their comparator plus the fact that CAR-T cells are at least in our early experience with them for B-Cell malignancies much more effective than autologous transplants might be.

So, I think that will be a limitation for some groups in terms of how to pay for them. I have a feeling that if these companies want to make these therapies accessible they’ll work with practices, hospitals, to figure out how to do that. It’s not necessarily hospitals that need to fund them. I think it will be part of the way these things roll out once they have been approved with some understanding that hospitals and insurance companies can get these things to people.

Call Leader: Just generally when you have to get reimbursement for one of these uber expensive drugs, what are the steps you generally have to go through beyond the initial request?

Doctor: For an allogeneic stem cell transplant case for example we go through a complete pre authorization process. We describe what we intend to do for the patient, what the indications are, what the alternatives are. It’s kind of a whole package that goes out to the insurance companies. In some cases they are so experienced in dealing with us that it is a pretty simple turn around. But others it takes quite some time to get full approval.

What we don’t want to do is assume that insurance companies are going to pay for it and then be on the hook as an institution or even worry about the patient being billed for what is an incredibly expensive procedure that continues to be expensive even after the procedure is done. People need follow-up and immunosuppression drugs and so on and so forth.

So really a lot of this is time to get pre-auth to do these procedures and explain what the costs are going to be. That works very well for allogeneic transplantation. I would think that would be the model for how we do things for expensive cell based therapies as well.

Call Leader:
In other words the hospitals are pretty…Because they already deal with this expensive transplantation process, they understand how to reimburse and have it go through.

Doctor: For drugs too.

Call Leader: How long does it take to get that preauthorization usually?

Doctor: Like I said for some insurance companies where this has become relatively routine, it can be a day or two it can be very quick. You just explain the indications and you’re approved thousands of these for us in the past, they just go through the indications. It depends on the insurance.

Call Leader: Can you say which insurance or payors are easier and harder?

Doctor: A lot of the state payors like Medicare are pretty straight forward. They deal with this on such a large scale they really get how this works. Now they might not reimburse as well as some of the private payors. Essentially the larger insurance companies have very little difficulty where I can’t even recall a scenario where we had a patient we thought met the needs for transplantation where we were denied or had to go through an appeal process.

The larger insurance companies and the state funded insurance companies will have a pretty uniform policy on accepting or not accepting patients.

Call Leader: In terms of the basic economics of all this. If you have a CAR-T patient at your hospital would you expect it to be a profitable patient? An unprofitable patient?

Doctor: That’s going to depend on how these therapies are reimbursed. If we get into the age of capitated medicine where we’re capitating groups of people or doing diagnosis based payments. Where we are saying for a Hodgkin’s Lymphoma you get x amount of money per patient. Then I think these will be considered liabilities by hospitals.

I think that these types of therapies are the things that break the bank not the kind of things that generate income the way they might in a fee for service type proposal.

That’s not my area of expertise, I’m not sure how you deal with that, but it certainly an issue that we have as well. Right now bone marrow transplantation is quite a good money maker for a hospital that has expertise and can do that. But in a capitated system that may no longer be the case. I’m not sure where you would fall. Would it fall as a separate fee for service type payment or into the diagnosis for treating patients payment.

Call Leader: Ok. You mentioned earlier that besides the cost of therapy there is the cost of follow-up. Immunosuppressants. If you assume the cost is between 300 and 450k just for the therapy. What do you think the total cost of a patient will be?

Doctor: That’s a good question. I drew the analogy to allogeneic transplantation. I think these therapies would be actually less expensive in the long run. For an allogeneic transplantation you not only have all the work that needs to be done to get donor cells to a patients, you have that prolonged hospitalization afterwards which at least for ‘allo’ transplant can be much longer than it would be for a CAR-T cell type treatment. And then the follow-up for an allogeneic transplant is substantially more complicated. You’re dealing with issues of graft versus host disease, and infection, and secondary complications from that.

So I think that in the longrun that the two options are CAR-T or allogeneic transplant, and at the price point that you mentioned, it would actually be less expensive to go the CAR-T cell route.

Call Leader: Great. That’s extremely helpful. Going back to the CAR-T therapies themselves, the trials that we’ve seen so far have been relatively small, and there’s always a chance of when they get bigger and we get more long term data that the numbers would change. Is there a minimum complete response rate or a minimum durability length that you’re looking for in order for you to use it in a large number of your patients?

Doctor: That’s a great question. I think putting aside the fact that these are expected therapies, they’re also not easy to give and to tolerate these, assuming we’d want to get a lot of bang for buck so to speak. I think that in the patient population they’re being tried in right now, any level of response is probably good enough because these patients are pretty ill and are very unlikely to respond to anything else. Even if we had only 30% response rates, or prolongation of survival was in the order of months - that these therapies would compare as well as anything else that would be considered in clinical trials, and they would be considered favorable.

If we’re starting to move these therapies into earlier lines of treatments, we’re going to really demand that they be able to do more for patients, and then we’re looking for potentially curative outcomes. I think that we’re looking for things that other therapies specifically don’t do for us. So in CLL in particular, with allogeneic transplantation, we really don’t have curative outcomes. If someone has very advanced CLL and can get a therapy like this and can potentially be cured or have a relapse that lasts in the order of years, that would be considered great.

So I think in all-comers, we’d really love to see these therapies have a better than 50% complete response rate, and have those complete responses be durable, meaning that they last for more than 12 months. If they start to be less than that, then they’re starting to compete with therapies that are much less expensive and much easier to give, but also obviously not terribly effective.

Call Leader: Great, that’s extremely helpful. What are your thoughts on autologous vs. allogeneic CAR-T therapies, do you think allogeneic CAR-T would have an effect on the use of autologous CAR-T?

Doctor: I think that’s really going to really vary by indication and what it is that you’re intending to do. I think the advantage of being able to do something allogeneic is that you might come close to having something that is a more off the shelf product, where you can treat someone from the time that you decide that you’re going to do it, to the time that you get the cells can be extremely short. You may already have 1,000 A cells premade. Whereas with the autologous approach you have to go through the whole aphaeresis, hope you have quality cells, hope you’re able to transmute them and grow them and then get them back to the patient. And even though the turnaround time is remarkably short, it still is not short enough for some patients, at least within the current clinical trials. There certainly are patients that you would like to treat, but you don’t think they could actually wait as long as they need to to actually get the cells.

Call Leader: Well how long have you had to wait for some of these patients?

Doctor: It varies. I think that the ideal turnaround time would be as little as two weeks, but there’s all sorts of things that can get in the way with that, and sometimes the ability, especially with lymphoma patients who have had a lot of lympho depleting therapies in the first place, your ability to get enough cells can be challenging. So even though you make a decision to treat, and you ‘aphaeres’ and you may need to do it again.

Then there are all sorts of QC issues that would have to be in place. For whatever reason a QC test didn’t work or gave an indeterminate answer, then the delay might be longer, so I’m not sure what the averages are in clinical trials, but it certainly isn’t something where if I decided to today, by next week I’m giving someone cells. It’s most often in the order of 4-6 weeks at the earliest.

Call Leader: Ok, and the question that’s on a lot of people’s minds is do you see any hope for CAR-T being a therapy for solid tumors? I know that’s not your speciality, but I was just wondering what you thought about that.

Doctor: Yeah I think that what we’re going to find with the CAR-Ts is that they’re not going to be as effective as they are in B-cell malignancies in every solid tumor. That there’s going to be some solid tumors where either the bulk of the disease or the ability of the cells to penetrate the disease and affect their functions is not going to be anywhere near as effective.

But there are some diseases now for which immunotherapies are highly effective, and CAR-T cells are an extreme form of immunotherapies, and I think that maybe for those disorders, CAR-T cells are going to be extremely effective. So I have high hopes that they will be effective for things like renal cancer for which we don’t have much else, or melanoma for which we now have many options, but it’s still a very lethal disease.

And maybe even for disease like lung cancer which we typically think of much more occasionally complex and challenging to treat, it may be possible that combination of CAR-T cells and immunotherapy might be substantially more effective than either one alone. I could see a role for CAR-T cells in that type of solid tumor setting as well.

Call Leader: Ok thank you. Back to some of the liquid tumors, I was just wondering - Do you think the FDA should require overall survival data prior to approval, or do you think you’ll be happy giving the therapy just with 6, 9, or 12 month CR and durability data?

Doctor: I think that for the patients that are being treated right now, overall survival could be looked at; their overall survival isn’t that long. I think that we understand pretty well that in these patients complete response is going to be very important, so I think approval on that basis alone is probably reasonable.

I think in patients who you may bring the therapy into earlier lines - having a therapy that works transiently isn’t going to be very effective. You’re really going to need to show that these therapies have prolonged responses, so either ongoing you need surveillance, or such a profound effect upfront that a patient is truly cured, that their disease is eradicated. So I think in those studies when we move these therapies closer to front-line, we will need to see longer follow-up and either a longer progression free interval, based on the order of years, or overall survival data.

Call Leader: Great. Well thank you. I think that’s all of my questions Dr. Bejar. This has been extremely useful. Thank you for all of your insights. I hope you have a wonderful day and thank you everyone for listening.

Doctor: Alright. Thank you.

 

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