COMMENTARY

CAR T Cells in the Community: Overcoming an 'Enormous Access Barrier'

Chadi Nabhan, MD, MBA; Jeff P. Sharman, MD

Disclosures

March 02, 2020

This transcript has been edited for clarity.

Chadi Nabhan, MD, MBA: Welcome to Medscape Oncology Insights. Joining me today is Dr Jeff Sharman, director of research at Willamette Valley Cancer Institute and medical director of hematology research for The US Oncology Network.

Personally, I don't like the hyperbole of certain names, such as "game changers," but chimeric antigen receptor (CAR) T-cell therapies have truly changed blood cancers. And yet, many see the community oncology setting as ill-equipped to offer these therapies. Suggested barriers as to what hinders CAR T-cell therapies from being offered to patients in the community setting include logistics, cost, and perhaps a lack of education about the therapies themselves. I think we can all agree that patients are best served when they have access to the right therapy that they need at the right time and in the right geographic location that they prefer.

My goal today is to help us understand what we can do to improve the ability of community oncologists to deliver CAR T-cell therapies. What are the challenges, and what are the strategies that could be used to mitigate them? How can we improve access?

Jeff, we all know that patients who were included in the clinical trials that led to the approval and commercial availability of CAR T-cell therapy may not always represent the actual patients seen in community practice. How do we reconcile these differences as patients come to the community clinic? Do we take these data at face value, or do we tailor them?

Jeff P. Sharman, MD: My experience has been that there are fairly substantial differences between patients represented in large clinical trials versus whom we actually see in the clinic. Oftentimes, the demographics themselves are just very different. There's always an effort to have representative populations in clinical trials, but if those representative populations are never actually being seen in the settings where these studies are done, obviously they can't be represented. In the community, we generally see a patient population who is older and might have less resources to travel to a major academic center. There are differences in the community between large, urban environments and areas outside those environments—some really substantial differences. What we're seeing in the clinical trial data is a fairly skewed subset of patients. It's still important data; but, it's important to understand these data in the context of what the real world looks like. We can't necessarily extrapolate from clinical trials to the entire patient population.

Nabhan: There were some data published recently about "real-world" experiences with CAR T-cell therapies, essentially suggesting similar outcomes.

Sharman: I cited some of these data as among the most important at the American Society of Hematology (ASH) conference. Even though they might not seem like a typical highlight of ASH, I think this is a circumstance where, at least so far, some of the early-type registry data—which has been mandated with these agents to understand how they're performing—are holding up and translating. These are very early data, and I'm still going to remain a little bit skeptical, but it certainly does challenge the notion that the data can't be extrapolated.

Nabhan: You're an accomplished researcher, you work in academia, you've worked in a large community practice, and you have a very broad view of the challenges in both settings. If I asked you the top three to four challenges or barriers to having CAR T-cell therapies administered effectively and safely in the community, what would those be?

Sharman: First and foremost is patient safety. These are not simple therapies, and the toxicities are unique and potentially severe. Patient safety has to be the number one consideration at all times.

To that end, I don't think that moving CAR T-cell therapies into the community can be undertaken lightly. We have to police ourselves and be extremely vigorous and careful in that when bringing these therapies to patients, we're not cutting any corners with regard to the patients' ability to get through the procedure. It should be stated that not every community center is capable of doing this. In fact, I would wager that it's probably a minority of community centers capable of doing it. However, data from 2018 show—and this is obviously going to be a moving target—there was still a majority of states that had only one place to get CAR T-cell therapy in the entire state. That represents an enormous access barrier.

I've had the experience multiple times—actually, four in a row—where I felt like a patient needed to be referred for CAR T-cell therapy because their disease was such that, without it, I expected that they would pass soon. In each of these four cases, when faced with the reality that they were going to have to relocate for a month to either Portland or Seattle, they said they couldn't do it. It's too far away.

So, patient safety, access, and cost—those are the barriers. I'll add a fourth, which is regulatory.

Nabhan: It's very clear we want access. You just had the experience with four patients who needed therapy, but you couldn't get it to them. How do we mitigate or improve upon these barriers?

Sharman: If we're able to expand access very carefully, that will help. Where I'm at in Eugene, Oregon, within an hour north, I have Corvallis and Salem; within an hour south, I have Roseburg. That actually represents a very substantial population. Although I don't know that any of these other communities would be able to provide CAR T-cell therapy, if we were able to, we can then allow patients in those communities to receive CAR T-cell therapy and stay at home. Expanding access simply by getting more centers capable of doing this safely is important.

Again, that dovetails with safety. Onboarding a center to be able to offer this—who gets to decide that? Is it the payers? Is it the manufacturers? Who's the arbiter of where this gets to be done? That's not really settled just yet.

Nabhan: As we try to bring this therapy to a community setting, are there set criteria that the community setting needs to have? And if so, who is setting those?

Sharman: This is an area where there are many moving pieces. Within Medicare guidelines, there was a proposed rule and then a final rule, and within that, one change was allowing this to be done outside of a hospital. That may seem like a very subtle thing, but in a practice like mine, I am not hospital affiliated. In fact, there are no oncologists who are hospital affiliated in my geographic region. This one change in language had a big impact.

FACT [Foundation for the Accreditation of Cellular Therapy] accreditation is probably going to prove to be a hot-button topic, and I need to be clear about it. Medicare does not require FACT accreditation. Thus far though, [CAR T-cell therapy manufacturer] Kite Pharma has only picked centers that have FACT accreditation. Juno Therapeutics is actively working with centers that don't have FACT accreditation. This is an area where the differences are going to have a substantial impact on how this transpires. In terms of getting a center ready, FACT is a very useful step. It may be that some of the payers are looking at FACT accreditation as an arbiter of whether or not they would certify a site. FACT accreditation may or may not be the final word on all of this.

Nabhan: So, there seems to be heterogeneity in the criteria. Some payers or companies may demand FACT, whereas others do not.

I'd like to go back to something you mentioned about outpatient versus inpatient administration. I think it might loop into site of care. How important is deciding the site of care—outpatient vs inpatient? What are the implications for our patients?

Sharman: It may actually depend upon which product you're talking about. We know that some products have a more rapid onset of toxicity. For those patients, it may very well make sense that they have to be treated within the hospital. There are other products that have a much slower onset of toxicity. This has been reproducible across multiple studies. If you have one product where the median time to onset of fever and so forth is 24 hours, it makes sense that the patient might need to be treated in the hospital. If the onset is 5 days, what are you gaining by keeping a patient in the hospital for those 5 days?

We have more CAR T-cell therapies than study centers capable of bringing them forward.

As community practice oncologists, we really take pride in trying to bend down the cost curve. That's very important to us. We've published data showing that our cost of care in the community setting is typically about 30% less for an individual cancer diagnosis than in a hospital-based practice. And that could literally be in the same office, whether it's hospital defined or outpatient defined.

When we're looking at these very expensive therapies that could cost $1 million per treatment by the time you factor in all the ancillary costs, if we're able to bring a 20%-30% cost savings to that, it has significant impact at a societal level.

Nabhan: Before there's an infiltration of CAR T-cell therapies into the community, how are community oncologists currently involved in the care of these patients? You shared with us your unfortunate experience when you tried to refer patients. Is anything being done to improve referral until we have CAR T-cell therapies in the community?

Sharman: In my experience, the referral sites have been great to work with. The places we send patients to have been fantastic. I have no criticisms at all. In many cases, the biggest barrier has been the requirement that a patient remain in proximity to the treatment center for a prolonged period of time. That creates financial hardship for the family, not to mention logistic barriers and other challenges. There has to be a caregiver present, which might present barriers as well. Taking individuals and their caregivers out of their homes for a month will put an artificial ceiling on how far this technology can go unless we can find ways around that.

Nabhan: We sometimes hear about off-the-shelf allogeneic CAR T-cell therapies. They're under investigation, and who knows whether they are going to be successful. But, if they are successful and proven feasible, do you think it will be a plus for patients who are treated in the community?

Sharman: I do. In my time in practice, the thought was that everybody who received a dose of rituximab had to be hospitalized for it. Clearly, that has changed.

Nabhan: At one point, we gave rituximab over 2 days.

Sharman: There were statements that paclitaxel (Taxol) should only be administered in the academic medical center because the allergic reactions were so severe. We were told that there was no possible way we could manage PD-1 or CTLA-4 antibodies in the community.

Nabhan: Also venetoclax.

Sharman: Yes. We're leading efforts on this. I genuinely understand patient safety has to come first, but I think there is a great deal of hubris to think that select community centers can't overcome these barriers.

Nabhan: Absolutely. We talked a little bit about the logistics and the cost. From a cost perspective, how involved are you as the referring physician versus the actual referral center?

Sharman: As it pertains to cost, right now, that's entirely borne by the center performing the CAR T-cell procedure. If I refer a patient, at this point, I really have nothing to do with the financial side of it. Of course, if we bring CAR T-cell therapy to our center, we will then be front and center on this.

What we are seeing in some of our pilot data—because our network is now engaged in doing some of these as outpatients—is that we can achieve less frequent hospitalizations and when somebody needs to be hospitalized, shorter hospitalizations. That is going to have significant impact on the total cost of care for delivery of CAR T-cell therapies.

Nabhan: Patients hopefully have a successful therapy; we realize not all of them do. How involved are you in the long-term care of these patients post-therapy? Is it just you or you and the academic site?

Sharman: We've had a very good relationship with the centers that have been performing CAR T-cell therapy. In many cases, those patients have been getting CAR T-cell therapy within clinical trials. When a patient returns to my community, there often is some communication that has to happen with the treating center, in part for study-related follow-up. These patients need to be followed for a long period of time. Hypogammaglobulinemia is an issue; successful CAR T-cell therapy probably should have hypogammaglobulinemia after it. Often, we're giving replacement intravenous immunoglobulin.

Nabhan: You give that locally?

Sharman: Absolutely. There is no reason for patients to travel for that.

Things come up where you need to talk to the study investigator to understand the circumstances. I had one patient who was treated for acute lymphocytic leukemia; she had multiple lines of therapy that failed, and then she received CAR T-cell therapy and is in remission now. This was an investigational product. She's on year four of remission, and she came into my practice and was pregnant. There was this sudden question of whether the CAR T-cell therapies persist. There was really interesting thinking that had to go on very quickly, and the study center was very good about talking with us in that situation. In some ways, I was glad to hear that her CAR T cells weren't persistent, so it wasn't an issue. I've had patients whose primary care physician may contact me because [their patient] had low globulin levels and they're trying to figure out what that means. We do remain as these patients' physicians after their CAR T-cell procedure.

Nabhan: Are we going to have an embarrassment of riches, where we have seven, eight, or nine CAR T-cell therapies suddenly? A few years back, there were no CAR T-cell therapies approved. Now, we have two, and there will probably be more in the next couple of years. Do you think we need that many constructs?

Sharman: We have more CAR T-cell therapies than study centers capable of bringing them forward. There's a figure that's been circulated that shows how many different CAR T-cell products are in development, and it is mind boggling.

Are they all going to survive? Clearly, no. If we can continue moving the needle on increasing the number of indications, [using these therapies] earlier in the disease, and reducing toxicity, I think we'll see incremental gains. I think there will be losers, too—companies who may have gotten out in front and then, for one reason or another, stumbled or got taken over by a challenger. It's going to be a very dynamic area for many years.

Nabhan: It's not really clear whether the cost curve will go down with more CAR T-cell therapies. We haven't seen that in other situations.

In 5 years, if we are having this conversation again, what do you think we'll be talking about?

Sharman: I think that there's a significant initiative and an enormous investment going into CAR T-cell technology. Much of that investment is specifically focused on how to reduce the associated biomedical toxicity. As that toxicity barrier is reduced, the ability to then disseminate that technology more broadly will be relatively obvious. I think that we will still be dealing with issues of cost.

Five years from now, I see improved safety profiles and broader distribution. And then, an expansion of indications and even movement of these technologies earlier in the course of disease for various different diagnoses. Therefore, patients might be able to get a CAR T-cell procedure and never have to deal with the cost of certain medications down the road.

Chadi Nabhan, MD, MBA, is executive vice president and chief medical officer of Aptitude Health, a hematologist/medical oncologist, and an adjunct professor in the College of Pharmacy at the University of South Carolina in Columbia, South Carolina. Jeff Sharman, MD, is director of research at Willamette Valley Cancer Institute and Research Institute in Eugene, Oregon, and medical director of hematology research for the US Oncology Network.

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