CAR-T Spotlight

When a physician makes the call that chimeric antigen receptor (CAR) T-cell therapy offers the best chance for survival in patients with relapsed large B-cell lymphoma, there isn’t time to spare. But data gathered over the past 2 years by a team from Cardinal Health Specialty Solutions revealed roadblocks community oncology practices encounter when trying to navigate payer approvals for CAR T-cell therapy are among the barriers that cause patients to run out of time—and this situation isn’t improving.^1,2 The most recent round of data was presented in December during the 62nd Annual Meeting and Exposition of the American Society of Hematology (ASH).²

With new CAR T-cell therapies in the pipeline—including treatments that promise less toxicity and new therapies for multiple myeloma—the findings raise concerns that disconnects among payers, providers, and patients could stall this life-saving treatment.

Data from hematologists/oncologists were gathered a year apart, first in February 2019 and then during the period of November 2019 to February 2020. The initial survey covered 59 physicians, who were all in some type of community practice; the second included 168. Each time, the share of patients referred for CAR T-cell therapy who were unable to receive was almost one-third. “High cost and toxicity continue to be potential deterrents to CAR-T consideration and appear to be increasing in significance,” the authors concluded.

For insights, The American Journal of Managed Care® (AJMC®) spoke with lead author Ajeet Gajra, MD, FACP, vice president at Cardinal Health, about identifying and removing the barriers for offering CAR T-cell therapy at the community practice level. The interview is edited for clarity.

AJMC®: It's normal for to have challenges with payers when a new therapy is approved. But your findings show that the percentage of patients who have been unable to receive CAR T-cell therapy after referral was about the same nearly a year apart, with the second survey coming more than 2 years after approval. What accounts for this?

Gajra: These are complex therapies—they are essentially living cells derived from, engineered, and to be used as therapy for a particular individual. Obviously, they are challenging in terms of logistics, and there’s also the cost factor. The issues are twofold. One rests with the providers: they need to be very clear in terms of who they're referring for CAR T therapy. The labels are very explicit—2 prior therapies and progression, and also in terms of medical comorbidities. This is not just something that you can try as CAR-T therapy needs planning and following each step of a detailed process. The other piece is, as we all know, with payers, there's a complex prior authorization process. For some of these patients, it can be daunting for the managing team to collect all the information needed in a timely fashion to satisfy a payer’s requirements. That would include the diagnostic biopsy, and the history of therapies and regimens received thus far, [whether] they've had bone marrow transplant—the payer would need those records. If care has been fragmented—especially if the patient was treated at another facility, or say, a tertiary center where they went for care or a transplant—all that information has to be populated. That is a potential barrier, which leads to delays. Diffuse large B-cell lymphoma is not the disease that you can temporize with simple measures. If it's recurring a third time, these patients tend to be quite ill. A delay of a week or two sometimes can force the hand of the provider to go an alternative route, because they feel “My patient is deteriorating, I still don't have the authorization, what am I to do?” And they have to craft an alternative plan. So, we may be capturing some of those issues when it comes to factors leading to delays. So, there are patient factors, provider factors, and payer factors, which [contribute] to these delays.

AJMC®: As you noted, the payer delays can lead to the to the patient not receiving the therapy at all. Do providers need more support to navigate the process, whether it would be from a professional organization or from the manufacturers themselves?

Gajra: Absolutely. I feel strongly that additional support would be valuable. We found that most providers thought that they are quite well-versed with the science behind CAR T. But many of them may still not be aware of the complexity of the process involved in getting a patient on to CAR T and then managing them afterward. I feel it still starts with education—you don't want to refer the wrongpatients, because ultimately, they're going to go through the rigmarole and not end up getting the treatment, which is also something we captured where patients were being referred to CAR T centers, but ultimately not getting the treatment. So, there is that piece.

Second is support, support, support. We have these results while we had only the 2 CAR T products as of the summer of 2020. We now have 3 CAR T-cell products approved—with 1 for mantle cell [lymphoma]. CAR-T therapies are to be administered at designated CAR T centers, and but about 1 in 6 providers didn't have a CAR T center in their geographic vicinity, which is a barrier. Also, there's a question of, can there be reciprocity? Must each center be approved for every therapy that they're going to administer? That’s a piece that manufacturers can help with. Patient support and access services sponsored by pharma companies can help with streamlining the prior authorization process, to expedite how quickly patients can check all the boxes—get all the i's dotted and the t's crossed so that they can be at least evaluated sooner. Hopefully, patients can be approved by the payer sooner when appropriate, to move to the next step.

AJMC®: We talked about toxicity as being one of the big challenges with CAR T-cell therapy--that's been the case from the time it was approved. Is this a bigger challenge at the community level—in terms of the patient who's more concerned about the looming threat of CRS? Or is it more the provider who has the concern? Or is it a combination?

Gajra: It’s a great question. I certainly agree that the specter of toxicity is still [quite] strong, and that community practices have a lower threshold or a greater concern for toxicity than the academic centers. This has come out loud and clear at [live meetings] when we engage with providers, [which are] often includes a mix of largely community oncologists, but also some academic representatives as well.

Patients are concerned, but for the most part, with appropriate counseling, most patients are willing to receive therapy because they realize they are running out of options. I would also highlight is that as the field evolves, there have been remarkable improvements in the management of toxicity, so a lot of it can be mitigated and managed early. The thresholds have improved in terms of identifying CRS, but also neurotoxicity, which can be quite scary and devastating.

When we look at a scientific literature, there's definitely improvement in management of toxicity especially now with real world use of CAR-Ts being reported. Patients for the most part can be quite eager to receive what many of them would probably perceive as lifesaving and/ or significantly life-prolonging therapy. But [it’s a different challenge] for community physicians, especially those that are not attached to a large tertiary care hospital. They don't have immediate access to critical care—to an [intensive care unit] ICU. If your patient’s health is declining, they are going to land in the ICU. There's been a lot of work [done] on the disparities in rural settings or smaller communities, and I think there's definitely more apprehension with these therapies in the smaller, more remote practices.

AJMC®: In data that you presented at ASH, the emergence of the cost factor as a barrier is very apparent in the second round of data collection. What accounts for this?

Gajra: We learned from our initial work that cost was a major concern in the minds of the treating oncologists. Thus, we decided to reassess as a follow up: This was a larger sample size than in [the first survey], and was 2-plus years post-approval of the initial therapies. And the research showed that aside from intake and toxicity concerns, cost remains a major barrier or major concern in the minds of the providers [due to gaps between the treatment list price and reimbursement rates, especially from Medicare]. That gap has perhaps never been completely bridged. … From what we know the [list price] is about $373,000 for treatment. Certainly, attempts have been made with NTAP, the New Technology Add-on Payment [in Medicare], to reduce that burden, [and not rely on hospitals] where majority of CAR-T is being administered to just supplant the funding for the facilities. It cannot be denied that it is still a very high cost therapy.

Some of this cost sensitivity may arise from the fact that providers are looking at longer term outcomes. If providers are [committing] to a complex process and an expensive therapy, then do the outcomes bear that out? Especially if there are a lot of early failures of therapy, then perhaps, this is a barrier.I don’t have evidence for this,but it has been brought up by providers during discussion at live meetings on the subject as a possible barrier.

In my mind, if there was a greater confidence in being safely able to administer these therapies in the clinic versus in the hospital, I think there will be greater interest in these therapies. Because otherwise, it's really the hospital that's sort of bearing the cost. Whereas if you do it as an outpatient infusion, then it becomes a proposition for the practice, given that it's a very expensive infusion…. The community practice planning on outpatient administration has to assess the risk of the patient getting sick and getting admitted for toxicity. But as we learn more, community oncologists will become more confident about preventing toxicity and ensuring that they can safely administer these treatments on an outpatient basis. I think that's where the future is. And I think that will really help CAR T-cell therapies take off.

AJMC®: You mentioned the gap in Medicare funding. How does this compare with reimbursement for patients with commercial coverage?

Gajra: I think this is one of the questions [for which] we don't have an answer yet. We haven't teased that out. And that's just the honest truth. That wasn't part of what we've surveyed thus far. I believe that this question will be more suited for CAR-T centers performing the actual infusions.

AJMC®: Fair enough. I’d like to ask about coronavirus disease (COVID-19). It would seem that during the pandemic there would be an interest in not keeping patients in the hospital any longer than necessary. COVID-19 emerged since you gathered your information, but I'm wondering what it’s been like since then—does the pandemic make it favorable to administer CAR T-cell therapy in the community setting?

Gajra: Absolutely. We’re actually redoing the survey as we speak. And, we hope to get a decent sample size of current practices; we wanted to redo it in the context of the fact that we now have 3 products approved. And, hopefully in 2021, we'll see more CAR T therapies coming down the pike, as some data are looking really good coming out of ASH 2020. There seems to be anecdotally a lot of interest, especially amongst the larger practices, in terms of taking on outpatient infusion of CAR T cell therapies, especially among practices which are geographically close to a hospital setting. And we certainly got that during our discussion the last time, which was, admittedly in the springtime. So, we're trying to recalibrate that and see if that change has actually transpired. …

[COVID is a driver for outpatient care] for everything, including CAR T. We must recognize that with the initial 2 products, one of them implied in the label that it should be given in the hospital, which is not the case for the other product. So, I feel that the labelling or the implications of the label also impact practice. As we see new products emerge, if there's no direction that they should be given in a hospital, I think that will encourage the use of these therapies in the outpatient setting. But the COVID pandemic, as we all know, has been a driver to push care away from the hospital and into the clinic.

AJMC®: We've covered a lot of ground. Is there anything that we didn't cover that you'd like to add?

Gajra: First of all, even though now it's been 3-plus years since the original approval, there is still room for educating and keeping the community provider especially engaged. It’s not every day or every other day that a community provider will have the opportunity and will have the appropriate patient for a CAR T-cell therapy. It’s not like hormone-positive breast cancer that they're seeing every day of their life. So, I think, as more and more indications become amenable to CAR T therapy, that ongoing engagement with be essential from the manufacturers, from organizations, or from AJMC—whatever avenue there is.

Number 2, is the prior authorization process. Streamlining that process for the appropriate patient is so critical, and anything that can be done to simplify that facilitate that, both from the payer perspective and the manufacturer side would really help drive this therapy further. And then third, perhaps manufacturers can help identifying the pain points at the CAR T centers. These are typically large academic or tertiary care cancer centers. We’ve encountered concerns from community oncologists such as the patient was referred for CAR T, but was ultimately treated with a transplant, or a finite percentage of patients never ended up getting CAR T at the CAR T center, or that there wasn't adequate communication in terms of what should the community provider do when the patient returns after CAR T cell therapy.

We’ve heard that the intake of the CAR T was so slow. So here you have a patient, you’ve moved heaven and earth for prior approval authorization, and you referred them but then they couldn't get in or it took too long. So, I think that is another area where we can shave some time off in terms of getting the patient in line for CAR T.

Another potential barrier to CD-19 directed CAR T therapies in LBCL is the recent approval of tafasitamab (Monjuvi), a CD-19 directed monoclonal antibody, which is easy to give in the office and technically targets the same antigen. What is not known clearly is whether prior exposure to tafasitamab leads to impaired response with CAR T-cell therapy and vice versa.

One other thing that we learned is, and I think the community physicians are learning this as well, is that patients are likely to need bridging therapy while they are awaiting CAR T-cell therapy. In the early days, they were sort of taken aback like oh, “What am I supposed to do now? You're not going to have your product for another 6-8 weeks?” But you know, now they're learning that there has to be something else to hold the disease i.e., bridging therapy while awaiting the CAR T product, so it’s really a multipronged approach. And I feel manufacturer, CAR T center, provider, and the patient, and then the payer, are in it together and little tweaks can streamline the process somewhat better than it is now.

References

1. Gajra A, Jeune-Smith Y, Kish J, Yeh TC, Hime S, Feinberg B. Perceptions Perceptions of community hematologists/oncologists on barriers to chimeric antigen receptor T-cell therapy for the treatment of diffuse large B-cell lymphoma. Immunotherapy. 2020;12(10):725-732. doi: 10.2217/imt-2020-0118

2. Gajra A, Hime S, Jeune-Smith Y, Feinberg B. Adoption of approved CAR-T therapies among US community hematologists/oncologists. Blood. 2020;136(suppl 1):34-35. https://doi.org/10.1182/blood-2020-141990

Every day, chimeric antigen receptor (CAR) T-cell therapy seems to break more barriers in blood cancers—for example, an FDA approval in multiple myeloma seems not a question of if, but when. But significant hurdles remain to deploying this technology against solid tumors, and that’s especially true when it comes to glioblastoma—the deadly form of brain cancer that killed Arizona Senator John McCain and Beau Biden, son of the now President-elect.

Glioblastoma is famously hard to treat because the tumors tend not to be self-contained; they have tendrils that extend into the brain and may not be easily removed. Most patients have a prognosis of about 15 months; very few live 5 years.

A recent paper in Nature Cancer offered a potential solution for letting CAR T-cell therapy do its job in glioblastoma. This approach calls for pretreating the cells that line the blood vessel walls, which normally do offer the right kind of structure to allow the CAR T-cells to reach the tumor; by paving the way, this pretreatment allows the immunotherapy to attack the cancer.

The work involved a series of deliberate, painstaking steps, which the study’s co-corresponding author Yi Fan, PhD, discussed in a recent interview with The American Journal of Managed Care® (AJMC®), to find the right enzyme to target to create the tumor microenvironment. Then, the team implanted glioblastoma tumor cells in the mice; they found that by limiting PAK4, they reduced vascular abnormalities and appeared to allow T cells to penetrate the tumor. “Interestingly, PAK4 knockout robustly stimulated T cell infiltration into the tumors, probably contributing to the inhibition of tumor growth,” the authors wrote in the paper.

They reported that approximately 80% of the PAK-knockout mice survived for at least 60 days after the experiment ended; by contrast, all the wild-type mice died within 40 days of having the tumor cells implanted, despite having a T-cell infusion.

“We suggest that the therapeutic efficacy associated with enhanced T cell delivery and homing by PAK4 inhibition can be further improved when combined with other immunotherapy approaches capable of increasing T cell persistence by inhibiting T cell exhaustion and/or by stimulating T cell activation in the tumor microenvironment.,” the authors wrote.

This could have implications beyond glioblastoma and even immunotherapy. Returning blood vessels to their normal state by reducing oxygen deprivation, known as hypoxia, could improve results across a range of cancer treatments, from targeted therapy, to radiation, to chemotherapy. The work builds on Fan’s earlier work on vascular detransformation, which proposes a new approach in fighting cancer.

Fan, who is an associate professor of Radiation Oncology in the Perelman School of Medicine at the University of Pennsylvania, discussed how they study addressed the central issue that confronts scientists who work with CAR T-cell technology: blood vessels are needed to carry T-cells to the tumor, but the vascular structure surrounding the cancerous tumor is typically inhospitable for this purpose. So, it must be altered.

In 2019, Fan’s paper, “Vascular Detransformation for Cancer Therapy,” proposed that endothethial transformation “fuels cancer progression” and can cause resistance to treatment. New therapies that return the vascular system around the tumor to its precancerous condition “may serve as an effective next-generation antivascular approaches in cancer treatment.”

Experiments outlined in the Nature Cancer paper represent the next step of putting the idea behind vascular detransformation into action. Unlike leukemia cells, which Fan said “are really good at migration and proliferation,” and thus create a tumor microenvironment where T cells can work, genetic reprogramming is needed for the endothelial transformation required to allow CAR T cells to reach their target in glioblastoma.

But just what programming would work?

“So, we screened the whole human catalogue—more than 500 kinases,” Fan said. “We screened one by one—it’s actually a lot of work.” The team found that by limiting PAK4, it could regulate blood vessel activation in endothelial cells, and the team then developed a PAK4-knockout mouse model for one type of experiment.

And then experiments confirmed the screening tests. When the PAK4 inhibitor was added to the CAR T-cell therapy in one experiment, Fan said, “you can see the tumor becomes wrinkled.”

AJMC® asked, given the difficulty of CAR T-cell therapy with solid tumors, why keep trying this approach despite all the challenges? Aren’t there other strategies?

“CAR T is one of the most exciting immunotherapy approaches available,” Fan said. After all the successes in leukemia—many of which were first seen at Penn Medicine—the challenge of treating other cancers, an figuring out how to use CAR T-cell therapy for very different tumor cells and entirely different microenvironments—remains the “big, big question” that scientists can’t resist chasing. Plus, the need is huge. What’s good about the strategy explored in the Nature Cancer paper, Fan said, is that is can likely be replicated for other solid tumors.

“I think this is a pretty common mechanism for most solid tumors, so probably we can also use our strategy for treating other types of cancer including breast cancer, pancreatic cancers—all kinds of different solid tumors,” he said.

AJMC® discussed with Fan the labor-intensive mechanics of trying kinases one by one and asked—if more than 1 kinase if found to be effective in enabling the effectiveness of CAR T-cell therapy, would it make sense to target multiple kinases in this vascular detransformation approach?

“That's a brilliant idea,” Fan said. Even though the targeting PAK4 greatly increases the efficacy, “I don’t think you will be at 100% efficacy. So, in the future probably, I would target more than 1 of the kinases at the same time.”

So, AJMC® asked, where do we go from here? What are the next steps in advancing this concept?

From this point, Fan expects to see more preclinical work and setting the stage for commercialization of this concept. “I think maybe 1-2 years from now probably we can say some good results from clinical trials. So that's what we are expecting,” he said.

Reference

Ma W, Wang Y, Zhang R, et al. Targeting PAK4 to reprogram the vascular microenvironment and improve CAR-T immunotherapy for glioblastoma. Nat Cancer. Published online November 30, 2020.

Chimeric antigen receptor (CAR) T-cell therapy is moving into to new treatment areas, as the year 2020 brough an approval in mantle cell lymphoma and the recent 62nd meeting of the American Society of Hematology (ASH) saw scientists share results for the treatment in multiple myeloma.

Among them was the December 5, 2020, virtual presentation of CARTITUDE-1, the phase 1b/2 results for ciltacabtagene autoleucel (cilta-cel), Janssen’s investigational B-cell maturation antigen (BCMA) CAR T-cell treatment for patients whose multiple myeloma has progressed after as many as 6 treatments.

Deepu Madduri, MD, of The Tisch Cancer Institute at Mount Sinai, New York, and the principal investigator of CARTITUDE-1, presented results that showed an overall response rate (ORR) of 97% and a stringent response rate of 67% with a median follow-up time of 12.4 months. Of note, median duration of response and progression-free survival (PFS) were not reached.

In an interview with The American Journal of Managed Care®(AJMC®), Madduri explained that patients with multiple myeloma have a poor prognosis if their disease progresses after 3 treatments. But in CARTITUDE-1, cilta-cel has produced deep responses in these patients.

The following interview has been edited for length and clarity.

AJMC®: In 2019 at ASH, you presented data from CARTITUDE on 29 patients. Now, there are 97 patients with data. How have patient responses remained similar to what you reported last year? Are there any new important observations about the patients who have received treatment?

Madduri: At this year's ASH, we presented the CARTITUDE-1 study, which was the combined phase 1b and phase 2 portions of the study, which had a total of 97 patients who were treated. They were heavily pretreated, as their median prior lines of therapy was 5. Despite having this heavily relapsed/refractory population—and as we know from the MAMMOTH study, patients who are penta-refractory have an overall survival of less than 6 months—we saw on the CARTITUDE study, we haven't met the median PFS [progression-free survival]. We haven't reached the median PFS yet. The overall response rate on this study was 97%, with 67% of these patients being in stringent CR [complete response] and about 93% of the patients having VGPR [very good partial response] or better. Even more exceptional is that 72% of these patients were still maintaining their response at the time of data cutoff, which was about 12.4 months.

AJMC®: What did investigators learn about adverse event (AE) occurrence in CARTITUDE-1 vs CAR T-cell treatment in general?

Madduri: In the 97 patients that were treated on this study, we had a total of 14 deaths during the study, which 5 of them were due to progressive disease; 3 were due to adverse events unrelated to treatment, such as pneumonia and acute leukemia; and 6 patients had AEs related to the treatment.

With CAR [chimeric antigen receptor] T-cell therapy, one of the known side effects is cytokine release syndrome [CRS], which is the body's reaction after the CAR T cells are infused, and this is a very known complication. And another complication is CAR T-related neurotoxicity. So, looking at the study, we actually saw mostly grade 1 and 2 CRS. And what was interesting is our median time of onset with CRS was about 7 days. And regarding the CAR T neurotoxicity, any-grade neurotoxicity was about 21%, with 10% having grade 3 or higher.

In terms of managing these toxicities, we have a lot of supportive measures we can use, particularly atezolizumab, steroids, and anakinra. And I think as investigators get more and more comfortable in managing CAR T-related symptoms and side effects, we tend to give tocilizumab much earlier now, not necessarily waiting until grade 2 CRS. So, I feel like these patients are managed very easily with the supportive care that we have, and particularly, they're not that high-grade CRS that we're managing to begin with.

AJMC®: What have investigators learned about adverse events (AEs) that may be specific to this therapy compared with CAR T-cell treatment in general? Are there strategies for preventing AEs in the future?

Madduri: With CAR T-cell therapy, one of the known side effects is cytokine release syndrome (CRS), which is the body's reaction after the CAR T cells are infused; this is a very well-known complication. Another complication is CAR T-related neurotoxicity So, in looking at the study, we actually saw mostly Grade 1 in CRS. And what was interesting is our median time of onset with CRS was about 7 days. And regarding neurotoxicity, any grade neurotoxicity was about 21% with 10% having grade 3 or higher. In terms of managing these toxicities we have a lot of supportive measures we can use, particularly tocilizumab, steroids, and anakinra. As investigators got more and more comfortable in managing CAR T-related symptoms and side effects, we tend to give tocilizumab much earlier now—not necessarily waiting until grade 2 CRS. I feel these patients are managed very easily with the supportive care that we have, and particularly, they're not that high grade CRS to begin with.

AJMC®: Minimal residual disease (MRD) was an important marker in CARTITUDE. Can you explain why it’s become an important marker for cancer therapy?

Madduri: MRD has become more of a landmark study [marker] that we do for most clinical trials in multiple myeloma, and trying to achieve MRD negativity in some studies is [now] their primary end point or secondary end point. Here in the CARTITUDE study, it was a secondary end point. Fifty-seven patients were evaluable for MRD, and 53 out of the 57 patients were MRD-negative. And that was about 93%. And this MRD was done by Adaptive [Biotechnologies], and it was 10 ⁵.

AJMC®: One striking aspect of CARTITUDE is how many prior treatments these patients received, and yet many are still responding to treatment. Are there any differences in responses based on the type or the number of treatments patients have previously received?

Madduri: That’s a very interesting question. In the 97 patients that we treated, we had a median of 6 prior lines of therapy, and it ranged anywhere from 3 to 18 prior lines of therapy. Unfortunately, we didn't see any correlation between the number of lines of therapy that they had, whether less lines of therapy meant that they had more response. It’s just nice to actually have something to offer to these patients—who are heavily refractory [and] have a median overall survival of less than 6 months. So, I think a one-time treatment to give these deep durable responses is what we need in our myeloma patients. It's one step closer to getting a cure.

AJMC®: Are there any important differences in this study population versus that of LEGEND, which would give us insight into how CAR T-cell therapy could work for different patient populations?

Madduri: Compared with the LEGEND-2 study where the update was presented at ASH last year, we know a lot of those patients weren’t daratumumab exposed, which is what you expect in China. Not a lot of patients [in China] end up getting anti-CD38 therapy. So, in our study … we actually had 96 out of the 97 patients been exposed to anti-CD38. They’re also penta-refractory—42% of these patients are penta-refractory. ... So, in looking at the [CARTITUDE] patients, they are a little bit more heavily pretreated compared to the patients in China. But at the same time, those patients have had more than 1 transplant, or they've had a lot of different lines of therapy as well, but just not penta-refractory.

AJMC®: Data cut off was made 2020 about two months after lockdowns began in the United States due to the pandemic, how has COVID-19 affected the clinical trial process?

Madduri: As for the COVID-19 process, in particular I can speak from the experience in New York City. New York City was an epicenter; we actually had to hold all our clinical trials. And all of us were deployed into managing acutely ill COVID-19 patients. So, I think in terms of data, we adapted very quickly, we were able to do tele visits and remote visits, and patients were going to local labs and drawing their bloodwork when they needed to at their time points, and they were mailing [the bloodwork] in. So, I feel like we tried to keep up with data as much as we can during the pandemic. And the patients actually really enjoyed seeing us via video because a lot of these patients travel from far to come to an academic center to have CAR T. So, I was able to see patients in New Mexico patient at one of our patients actually went to Portugal. We were able to see him in Portugal and in Florida. I think it helped out, we are still able to collect the local labs, at least for these patients. And whenever the COVID pandemic eased up, we brought them back in. And another thing that Janssen has implemented is to do home monitoring. We’re in the process of working on a contract, where they will send somebody to draw these patients labs, so they won't miss any central labs during this pandemic.

AJMC®: Do you think this pandemic has the potential to fundamentally change medicine and patient interactions going forward?

Madduri: I think we have learned a lot from COVID-19. As I mentioned, not only [during] clinical trials, but during the initial COVID-19 phase when we didn't understand what was going on and how it was going to impact our patients. We were switching a lot of our patients to oral chemotherapy; we were switching a lot of patients to telehealth because [they had] a lot of comorbidities; they may be in the high-risk category for getting COVID. And we wanted to kind of protect our patients as well. Since the [beginning] of COVID, it has gotten a little better in New York City. Now obviously, it's getting worse again. But during the time where it's gotten better during August and September, some of our patients still continue to prefer video visits because they were still a little hesitant to come out of their house until the vaccine comes out. We were able to still take care of the patient. We're offering even more treatments because we're able to see more patients, but not restricted to New York City alone. So, we're seeing patients out of state [and even] out of the country and doing initial consultations with them, helping them guide them through their treatment. I feel like we're all learning from it and we're making the best out of what we can.

When the first chimeric antigen receptor (CAR) T-cell therapy was approved in August 2017, the headlines spoke of the miracle it offered for some patients with incurable forms of leukemia. But most stories let the other shoe drop: the price tag for the first treatment was $475,000. And that was just for the treatment itself, before any hospital costs were added.

On its face, it might seem ridiculous that a cancer treatment costs more than most homes in the United States. But then health care analysts waited for the data to come in. And it turns out that when one compares the total, real-world costs of CAR T-cell therapy with its alternatives, including autologous or allogenic hematopoietic cell transplants (HCT), the newer technology compares pretty well.

An abstract presented recently at the American Society of Hematology examined costs during the period 6 months before and after these procedures, and compared CAR T head to head with transplants. Researchers from Avalere Health included data from matched pairs of 175 patients each for the comparison of CAR T-cell therapy to autologous HCT, and 142 patients each for the allogenic HCT comparison. All cohorts had a median age of 69-70 years, with mostly white and mostly female. Of the group, only 10% to 15% were dual eligible. Patients in the autologous HCT group had slightly more comorbidities on average than the allogenic HCT group.¹

The analysis by Avalere Health made the following comparisons:

• Mean medical costs of autologous HCT were higher than CAR T by 35% ($85,382 vs $63,081) during period prior to the procedure. Post-procedure cost slightly favored auto HCT, but by a smaller amount ($25,277 vs $33,876).
• In the allogenic HCT comparison, transplant mean costs were higher prior to the procedure ($92,119 vs $70,105) except emergency department visits. However, post-procedure costs were substantially higher for the allot HCT procedure compared with CAR T ($82,847 vs $34,477).

The American Journal of Managed Care® (AJMC®) asked Karl Kilgore, PhD, a senior research scientist at Avalere Health, to discuss the real-world data gleaned from Medicare fee-for-service (FFS) Part A and B claims. The data set go back to the beginning of CAR T-cell therapy administration in Medicare FFS, so AJMC® asked Kilgore: Could the data confirm the anecdotal reports that clinicians are getting better at CAR T-cell administration? Could the numbers tell us that costs are coming down?

The short answer: not yet. Kilgore explained that because this year’s abstract was a follow-up of one presented in 2019 (with a much smaller number of patients), Avalere didn’t alter how it evaluated the costs. But the question of how costs are changing over time is one that payers and others want to know.

“It's definitely a focus on the Avalere side. We are designing studies … to try to address those very questions,” Kilgore said. “We are hearing exactly the same thing.”

Below are excerpts from the AJMC® interview with Kilgore, edited for clarity:

AJMC®: How do real-world data on chimeric antigen receptor (CAR) T-cell therapy presented last year at ASH compare with updated data you presented this year?

Either in terms of the utilization or the costs, you may recall the CAR T sample that we used a year ago at [the American Society of Hematology annual meeting] was literally the first year of real-world CAR T experience. And we used the Medicare fee-for-service database the same as we used the claims database, same as we used for this study here.

More data [are] becoming available rapidly, both in terms of the frequency of CAR T occurring and it appearing in our data assets that we have. This study, however, because of the design, we decided it was best to stay with our initial CAR T sample.

So, the CAR T sample is still that original sample of a little over 200 patients that represent the initial CAR T experience. Then we took our other samples for the same time period to make them comparable in terms of the timing. … The number of CAR T events that we are seeing in our data is doubling about every 6 months. And if we were to do this study again now with fresh data, we would probably have 1000 patients that we could use and be able to trend that over time. One of the limitations of the earlier study was we didn't have any [Medicare] Part D data, prescription drug data, at all. Now we do, all the way up through 2019. And so, while I unfortunately don't have any trend data on cost for utilization to share, it's definitely a focus on the Avalere side. We are designing studies, talking to our clients just to try to address those very questions, because our clients and we are hearing exactly the same thing.

Costs are going down, adverse events are going down. We're having those discussions, and I can't wait to get my hands on some data that I can share with the community that quantify what people are observing, kind of idiosyncratically.

AJMC®: Basically, as clinicians get better at the administration of a very new technology, the outliers will get reined in, and health systems will get better get better at predicting who should get CAR T in the first place.

Kilgore: I think that's true. And think of [intensive care unit] stays, per se. We know from this study, for example, that ICU stays are slightly more likely in the CAR T patient than in the stem cell transplant patient. Although the length of stay in the ICU tends to be longer for the transplant and for the CAR T patient, we know from our discussions with clinicians, and from their own experience that they're seeing as time goes on, is that patients are much, much less likely to go to the ICU now during their stay. The clinicians have become more used to seeing what the impact of CAR T is on the patient. And they know a little better not to be so quick to pull the trigger and transfer the patient to the ICU. We will definitely have data on that as well, as we as we move forward. That's a key that's a key contributor to the cost of that stay over and above the cost of the drug itself.

And our anecdotal evidence suggests that ICU stays are going down as well. I do find it interesting that that our data in this study do support that, in that ICU stays for the CAR T patients, while slightly higher in prevalence during the inpatient stay, they stayed in the ICU for less for a shorter period of time than for both auto- and allo- stem cell transplant patients.

AJMC®: There's been a lot of discussion over the last 2 years about whether CAR T cell therapy should be administered earlier in the course of cancer treatment, when patients are still relatively healthy. The idea is that the treatment would work better, that it would avoid some poor outcomes; and avoid treatment patients with therapies that aren’t going to work. The idea is, “Maybe we would avoid the complete cost of one therapeutic regimen completely and go straight to CAR T.” Is there anything in these data, or other data that you’re working with, that would speak to this issue?

Kilgore: Yes, in this study, these were matched samples of patients. As you may recall, between CAR T auto and allo (HCT); in one of the we matched them on patient characteristics, and ECOG performance status and the presence of certain comorbidities, which impact the treatment decisions in this sample.

What we were unable to do was … to look backwards in time, as far as we could, so that we could match patients based on prior treatments to get a better sense of where these patients were. These are relapsed refractory DLBCL [diffuse large B-cell lymphoma] patients; it's an aggressive disease, and they're going to treat it aggressively. And so, can we match the patients on how much prior treatments that they have had? We couldn't do that in this study, because our sample was small. And as we look backwards in time, our sample got smaller and smaller …

What we did identify as we tried to match them and look back is that the stem cell transplants tended to have standard first line, CHOP plus rituximab, or related and then a single course of chemotherapy, which was preparatory for their transplant of a small number of patients had maybe 3 lines of treatment prior to stem cell. But in general, the pattern came out very clear. In contrast to the CAR T patients that we looked at, who tended to have prior to their CAR T, 2, 3, 4, 5 prior lines of chemotherapy.

We ultimately a sample got too small to take that into account. And so that is data that that is kind of behind the scenes data I wanted to share.

At the same time, we do have another study at ASH. While it's not a CAR T study, it looks at burden of illness of stem cell transplants in this same population-- the relapsed refractory DLBCL patient.²

We found that so these were patients who were in our Medicare fee-for-service data, so they’re elderly with relapsed refractory DLBCL. Seventy-five percent of the patients with relapsed refractory never even received a chemotherapy regimen using NCCN guidelines as intended to get a stem cell transplant, [but] these patients had a fair number of third, fourth and fifth lines of treatment after that.

In addition, when we looked at the patients in this population, who got a second-line treatment that was intended for stem cell transplant about 75% of those patients who got a second-line treatment intended [as preparation] for stem cell transplant, they never got a stem cell transplant, either. What they did get in about 30% to 40% of the cases was additional lines of treatment, …30% to 40% of them had third, fourth, fifth line of chemotherapy beyond that second line treatment. And that suggests a while not specifically to your question about [having treatment] earlier, that suggests that there is a large population out there who are deemed inappropriate for stem cell transplant and who never get it, or never get a preparatory regimen. Even those who do may not respond well or they have trouble tolerating therapy, and that presents an opportunity for CAR T to be considered a little sooner than to just continue to try additional lines of therapy.

AJMC®: It's a lot to consider. That’s the argument that some are making—you’ve spent all this money, you've put the patient through all of this treatment and it doesn’t work. But if you had tried CAR T right out of the gate, it might have worked better, and you would spend less in the first place.

Kilgore: That’s right. We can look at the cumulative cost. But there’s the opportunity costs, the humanistic outcomes as well. Chemotherapy is hard on a patient.

AJMC®: Is there anything that we haven't covered on this topic that you'd like to discuss?

Kilgore: One of the key takeaways from this study is that CAR T is new, and that stem cell transplants, whether they be autologous or allogenic, are well understood. The variation in costs are less. They have their own drugs, and that of course leads to a certain consistency and treatment.

In CAR T, the field is still gaining knowledge and a comfort level. What we need to remember is that despite those advantages to stem cell transplants, they are not free. They have costs before the procedure itself. In our study, we looked at 6 months pre vs 6 months post, examining health care utilization, and costs tended to be higher than CAR T prior to the procedure for both auto and allo transplants, Costs were higher during the 6 months post for allo HCT, and were materially higher than Carty. This leads to potential cost offsets, which tend to offset some of those costs associated with the CAR T and stem cell procedures themselves. If you just look at the procedure, you're only getting half the story. You need to look at what happens before and what happens after when you consider the full course of therapy.

References

1. Mohammadi I, Purdum AG, Wong AC, et al. Cost and health care utilization in relapsed/refractory diffuse large B-cell lymphoma: a real-world analysis of Medicare beneficiaries receiving chimeric antigen receptor T-cell vs. autologous and allogeneic hematopoietic cell transplants. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; Virtual, December 5-8, 2020. Abstract 2500.

2. Kilgore KM, Wong AC, Snider JT, et al. Burden of illness and outcomes in the second-line treatment of large B-cell lymphoma: a real-world comparison of Medicare beneficiaries with and without stem cell transplants. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; Virtual, December 5-8, 2020. Abstract 2548.

More than 3 years after FDA approved the first options in chimeric antigen receptor (CAR) T-cell therapy, Bristol Myers Squibb (BMS) awaits word on whether its investigational treatment, lisocabtagene maraleucel (liso-cel) will be approved. On November 16, 2020, BMS announced that FDA would not meet its target approval date due to the agency’s inability to complete inspections at a third-party manufacturing site, because of travel restrictions related to the coronavirus disease 2019 pandemic. A new target date has not been announced.

If approved, liso-cel will give patients another option for the treatment of relapsed or refractory (R/R) large B-cell lymphoma, if their disease has progressed after at least two prior therapies. Like its predecessors, liso-cel targets CD19, a surface glycoprotein seen in B-cell development that remains present when the cells become malignant. According to information from Bristol Myers Squibb, the liso-cel CAR mechanism features the following:

• an anti-CD19 single-chain variable fragment targeting domain for antigen specificity
• a transmembrane domain
• a 4-1BB costimulatory domain intended to increase T-cell proliferation and persistence
• a CD3-zeta T-cell activation domain.

In addition, liso-cel’s distinct manufacturing process creates a defined composition of CD8+ and CD4+ T-cells, which may reduce product variability; however, the manufacturer states, “the clinical significance of defined composition is unknown.”

For insights on what the arrival of liso-cel could mean in the treatment landscape, The American Journal of Managed Care® (AJMC®) turned to Tanya Siddiqi, MD, director of the Chronic Lymphocytic Leukemia Program at Toni Stephenson Lymphoma Center and associate clinical professor, Department of Hematology & Hematopoietic Cell Transplantation at City of Hope, Duarte, California.

Siddiqi was an investigator for ZUMA-1, which led to the approval of axicabtagene ciloleucel (axi-cel), sold as Yescarta, and the TRANSCEND NHL trial for liso-cel.She has addressed major scientific meetings on the challenge of managing the toxicities associated with CAR T-cell therapy—and discussed how liso-cel represents a step forward over its predecessors.

This interview, conducted before the BMS announcement, has been edited for clarity and length.

AJMC®: We're anticipating an FDA decision on liso-cel before the end of the year. Can you discuss the need of the patients who would take this new CAR T-cell therapy?

Siddiqi: So, for CAR T-cell therapy targeting CD19-positive B-cell lymphomas—specifically aggressive B-cell lymphomas—we already have a couple of FDA-approved options. The question is: what is liso-cel? How is it different? Why would people pick this over other things? In the trials that we've conducted, we found that liso-cel seems to have lesser toxicity in terms of the specific CAR T-cell side effects of cytokine release syndrome or hyper-inflammation, as well as neurotoxicity. We've just seen fewer severe adverse events so much so that at some [cancer] centers across the country, we’ve been able to give liso-cel CAR T-cells to patients in the clinic or outpatient setting rather than having to admit them to the hospital , depending on the patient's situation.

Those are the strengths of liso-cel—less toxicity and thus, a better chance of giving it in the outpatient setting with hospital admission available to anyone who develops a fever or other side effects. This means fewer days of inpatient hospitalization for these patients, so it may be less costly overall. I don’t think the efficacy is necessarily different—meaning that it seems to work as well as the other FDA-approved products already commercially available. But for the reasons that I've listed, I think it might be a very good option for older patients, maybe patients who are bit more frail, or younger patients who just don't want to be admitted to the hospital—they just want to try to do it in the outpatient setting.

AJMC®:You touched on this already, but can you discuss how Iiso-cel differs from earlier CAR T-cell therapies—both in the way it's manufactured and how it works, and what that reduced variability means for patients?

Siddiqi: Liso-celis manufactured in a way that it gives very precise, equal numbers of CAR cells that are labeled CD4 and CD8, in a 1:1 ratio. All of us have T cells to fight infections with, and these T cells are what we take from patients. Then, we modify them in the lab by genetic engineering in order to produce CAR T-cells so that now instead of looking for infections, these CAR T cells are going to look for B-cell lymphoma cells and fight lymphoma.

The other products are given back to patients as a bag of CAR T cells mixed with potentially varying ratios of different types of T cells—CD4+, CD8+, etc. With liso-cel the manufacturing process actually separates out the CD4+ and CD8+ types of T cells first, and then manufactures CAR-T cells out of them separately. So, when we give the cells back to patients, we give it in a 1:1 ratio of CD4+ and CD8+ cells. We know exactly how many CD4+ and how many CD8+ T-cells these patients receive. And the thought is, the researchers and the drug manufacturer feel that this helps to have an expectation of what expansion you will have of these cells in the body.

Therefore, we potentially have an idea of what type of side effects or how severe the side effects might be. It may limit some of those side effects, or at least make them a little bit more predictable or controlled.

AJMC®:That’s a great way to shift to your own work on length of stay due to CRS. What do we know about the key variables in determining whether a patient will experience a side effect that requires an extended stay in the hospital, and can more be done to avoid lengthy hospital stays?

Siddiqi: That's a very important question. Because lengthy hospital stays, especially in the [intensive care unit], really adds to the bill and the financial burden of these treatments. We know that people who have a big burden of disease going into CAR T-cell therapy, meaning they have a lot of lymphoma in their bodies, they tend to be at higher risk for more side effects like cytokine release syndrome and neurotoxicity. Probably because there's so much inflammation that’s generated while these CAR T-cells are trying to fight the lymphoma. What we know is that people who come to us for CAR T-cells with lesser disease might have fewer side effects potentially and a better overall outcome.

So, we always try to advise our referring physicians, and educate patients, at conferences, to try to send these patients to us before they are at the end of the line—before they’ve tried and failed everything, and now there’s just rampant disease. … [At that point,] you're dealing with a situation where the patient is going to have more side effects and will not be able to tolerate the CAR T cells as well. Instead, if they fail two lines of therapy and the disease is still small in volume, but it's starting to progress, we can treat them more effectively with CAR T cells and with fewer side effects potentially.

AJMC®:That brings up the next topic—there have been discussions that CAR T-cell therapy should be given earlier during treatment. As you said, if it’s not given as the last resort, patients might respond better. Where do you see those patterns heading in the future? And would that be truer for some patients than others?

Siddiqi: With aggressive diffuse large B-cell lymphoma, there's about a 60% to 70% chance of curing that in the frontline setting. With the line of chemo-immunotherapy, you can cure 60% to 70% of patients so that it never comes back. But the rest of them—when it just relentlessly keeps coming back and it's hard to cure—once those patients relapse they tend to keep relapsing. So, our mainstay in the relapse setting is to give them salvage chemo-immunotherapy, collect stem cells, and take them to autologous stem cell transplantation if they've achieved a remission with the salvage chemotherapy. If they haven't achieved remission with that salvage chemotherapy, then they should go on to CAR T cells directly instead of waiting and trying more and more chemotherapies. After failing second line therapy, the FDA approval allows us to try CAR T cells. There are studies that are now ongoing that are comparing CAR T cells to autologous stem cell transplantation after failing first line therapy. So, once patients relapse the first time, these studies are comparing giving them salvage chemotherapy and transplant, versus taking them straight to CAR T cells. Once we have that data, we'll know better whether we can do CAR T cells even earlier in the lines of therapy.

AJMC®:We’ve been hearing for some time more about allogeneic or “off-the-shelf” therapies. What progress has been made on in that technology?

Siddiqi: I'm not too involved with these trials myself, but I know we have trials at City of Hope that are ongoing with off-the-shelf therapy. What I can tell you is that it's very attractive in that you don't have to collect T cells from patients, keeping their lymphoma under control while these T cells then go to the lab and CAR T cells are manufactured in 2-4 weeks depending on which product it is, and then they come back and get infused. With off-the-shelf products, you can just grab it and go as soon as you know the patient needs it.

The initial concerns were because the cells are not from the patient themselves—the cells are from donors. Across the board there might be concerns of rejection and what's called graft-versus-host disease and things like that. So far, I don't think in the trial they've come up with such side effects to any significant extent. What I don't know is whether they've come up with a good result yet. Is it looking like the benefits of taking off-the-shelf CAR T cells are as good as autologous CAR T cells, meaning patients’ own CAR T cells? I think that remains to be seen. If they are, then it's much easier to use off-the-shelf CAR T cells. Maybe at the American Society of Hematology annual meeting in December we will see more data.

AJMC®: How is COVID-19 affecting the clinical trial process for CAR T cell therapy?

Siddiqi: When the pandemic kind of started surging early in the year, and when we went into lockdown mode from March onward, we and other centers across the country took a lot of steps to slow down our clinical trial enrollment. Our staff started staggering who would come into work which day of the week and who could work from home. For those in the clinical trials office, there was a lot of need for safety and logistical reasons for us to slow down enrollment onto clinical trials. And there were other questions, such as, who would take care of patients at home once we discharged them after they received CAR T cells? What if their caregivers were exposed and got sick? Logistically, it was difficult to safely do many trials, especially CAR T cell trials and transplants earlier in the year.

Since the end of summer, we ramped up again, and we're now doing as many transplants and CAR T cells as we were probably doing last year. So, we're pretty much all the way up again, but I don't know how this winter will go because COVID is surging again.

As far as just CAR T cells themselves, we had to also think about travel for the cells because Juno Therapeutics is in Seattle, and Kite Pharma is here in Los Angeles, but Novartis is elsewhere. Just the movement of these cells was a concern because of travel restrictions during COVID-19. But as far as I know, the companies did not lose that commitment—they told us, we’ll get the cells to you, we will find a way to do it. I don't think any patients went without cells who should have received cells.

AJMC®: What advice do you have for community oncologists interested in CAR T cell therapy for their patients?

Siddiqi: There’s good news for community physicians. We may soon have a therapeutic option of liso-cel CAR T cell therapy which seems to have lesser side effects. So, this might make things cheaper due to less need for hospitalization potentially without compromising the chance of cure. We want these patients to try CAR T cell therapy sooner rather than later in their relapses. You can always try multiple cycles of chemotherapy at some other time if you relapse again, but if you can be cured with CAR T cells such that you never need treatment again, why not try that first? For the patients who respond well to CAR T cells, the treatment works extremely well. And that's the Holy Grail – to find the cure for all patients.

Maybe only half the patients will currently have a very good and durable response—but those patients may never relapse again. So why not try it sooner rather than later? And of course, we're always looking for trial patients, because now we need to improve these results even further. So, community oncologists should also refer for trials, because I think that it’s very important to have trials with different combinations—CAR T cells plus another immunotherapy agent—to see if we can improve upon the response rates even more.

As clinicians gain knowledge of the nuances of chimeric antigen receptor (CAR) T-cell therapy, the opportunities arise for treatment to occur beyond the walls of the academic medical center. But the academic medical center is still an important partner in this treatment evolution, said Amit Kumar Mehta, MD, who has several roles at the University of Alabama at Birmingham. Mehta is associate professor and director of the Lymphoma Program director of the Immune Effector Cell/CAR T-cell Program at the O’Neal Comprehensive Cancer Center.

Mehta discussed the evolution of CAR T-cell therapy with The American Journal of Managed Care® (AJMC®) this week. (This interview has been edited lightly for clarity.)

AJMC®: Can you discuss how the knowledge base for determining which patients would most benefit from CAR T cell therapy has evolved over the last several years?

Mehta: Primary antigen T-cell receptor therapy has been in practice now for a period of 5 years, and it was a fantasy 5 years back. There are 2 products, which are approved in lymphoma space and a specific indication. The clinical trial told us that is a process for preparation of CAR T, and that process involves collection of T cells and preparation of those T cells; then, you infuse those T cells in patients.

Why it is important? Because there is a time period in between when the CAR T cells are selected or prepared, and that time period is critical, because these patients are relapsed lymphoma patients. If you don't select the patient, then during this preparation time, the disease might progress, and ultimately, they will not be able to receive the CAR T product. So, selection of the patient is the key in the setting.

After learning from various clinical trial, and now [with] this therapy being in practice for a period of 2 years, we realize that selecting the patient is the key—as these patients are having active disease, and they've already failed couple of lines of therapy. If the patient has high risk disease, bulky disease, very high lactate dehydrogenase (LDH), these are the patients that you would be very skeptical to go through the process because they don't have time to wait. …

So [this knowledge] has evolved from clinical trial findings as well as real world experience. And that was presented at cancer congresses and meetings, that the intent-to-treat population in this patient group is very key, not those patients who could receive the cells, but how many of those patients could not receive the cells? And what were the reasons for most of the patients? The reason was progression of disease. That is why it is very key that we don't select a patient who has very aggressive, raging disease who cannot wait for the therapy.

AJMC®: How has the management of cytokine release syndrome evolved over time in in your practice? Are patients as likely to have extended hospital stays as they were 3-5 years ago?

Mehta: When the clinical trials related to CAR T came into existence, we did not have formal guidelines for cytokine release syndrome (CRS). You know, everybody remembers the case of Miss [Emily] Whitehead, who was a young patient who first underwent a CAR T-cell therapy who got very sick, and responded very well to tocilizumab, and that created a foundation for treating cytokine release syndrome.

Over a period of years, we have learned a lot about CRS. The criteria that we were using before was Lee criteria; now, we have consensus guidelines on grading of CRS. We [now] know a lot about CRS—when it starts and how to handle it, what the signs and symptoms are, and how to treat it. All the [CAR T] products that FDA approved have a mandated REMS program, [which require] 2 doses or tocilizumab per patient available before even you decide to treat. That is key—management is not only identifying symptoms and signs of CRS, but management has also evolved over a period of time, and it has become better and better. From initial fears of CRS, we are at a point that we know how to have a patient prepared for CRS.

We are learning from the products we have there are two costimulatory domain(s); in the CAR T products that we have approved, one is called 4-1BB and the other one CD-28. And each has a different timeline for CRS as well as neurotoxicity. Now, if you look at the data, the 4-1BB product has a little bit delayed onset of CRS, and not as intense as with CD-28. So, in those patients who are 4-1BB, technically, you can still handle this patient as an outpatient, or they may not need that longer hospital admission compared to CD-28 products. Again, those patients who have bulky disease, hybris disease, very active disease, and those who end up with multiple complications—they may end up in the hospital for a longer period of time.

At our center, we were near the point of doing it as an outpatient in a select group of patients with a select product. But with this COVID-19 pandemic, things have changed. And we've decided not to experiment that as an outpatient at this point. Because if the patients get sick, they must come in [to the hospital]. And if COVID-19 patients have occupied the beds, then the CAR T patients may not be able to come in when needed. So that's why we have moved forward with all inpatient hospital admission. But on an average, we see about 7 to 10 days of inpatient hospitalization for a wide variety of reasons; the CRS could [lead to] neurotoxicity, or tumor lysis syndrome.

AJMC®: The American Society of Clinical Oncology has published guidelines about improving the diversity of patients in clinical trials. How has this issue applied to your work in CAR T-cell therapy?

Mehta: This is a burning national question right now—the inclusion of minority patients or underserved patients—and I'm proud to say that we have a good program here. We have a Patient Navigator program and we are nationally recognized [in this area], so that we can address the issues for the minority patient as well as the underserved patient. And that applies not only for people across the clinical trials, and it is a priority to make sure that we have a true representation of the community among those we treat in the academic center. We have community engagement programs, and we have a lot of education program for the patient themselves.

In Alabama, as we all know, there is a long [and difficult] history involving minority patients and the underserved population being involved in clinical trials. So that's why we are very sensitive in that issue and [provide] support to our patients. … We also have shown that patient enrollment has increased not only in clinical trials, but also in the commercial program of CAR T. We engage patient navigators in the community with patients as well as their physicians, we also get engaged with the community doctors. This has helped a lot in engaging these stakeholders in patient management, and it shows in the results.

AJMC®: What improvements in the next generation of CARs or you feel are going to make the biggest impact.

Mehta: CAR T is still in its early phase. But we now know, based on the products that are available, that on average at a year to a year and a half, about half the patients will be in remission and half the patients will progress. So, why do they progress? What happens? Do they have immune checkpoint pathways, which get upregulated or delusory 19? Or [do] they exhaust the T cells that were prepared? There are a wide variety of reasons [for progression], and nobody at this point is pinpointing at one cause that why these patients progress.

Second, we also know that this process of preparation of CAR T varies from 2 weeks to 4 weeks, depending on the commercial product. So that's the second challenge, as we addressed before, that [affects which patients] I want to treat with CAR T, whether I have enough amount of time to wait.

Among the improvements we have seen, one is dual antigen CAR T, with CD-19 and CD-20, which has shown promising results. And that could be because tumor cells [are] losing CD-19 expression; so, we feel comfortable, and there are early data to suggest that dual-antigen CAR T has higher responses and sustained responses. Second, is whether we can avoid the whole process of preparation, when we harvest a patient's own T cells and prepare them, rather we have those cells available on the shelf. This would allow us to bypass the wait time of 2-4 weeks. And that's the next generation that we are seeing, the off-the-shelf or allogenic CAR T. We are also seeing CAR NK [natural killer] cells, which are off the shelf or they're getting from donors or we are getting it from cord blood. So, I think this are the excitement for the next-generation CAR piece.

Also, [when it comes to] identifying CRS and neurotoxicity early in the course and treating it effectively, we still don't have good prognostic markers for which patients will develop CRS. If we can do that, there are 2 benefits. Number 1, there’s the [ability] to improve safety of the patient. Number 2, we can [decide] whether to handle the case as outpatient or not, which is a critical question, especially for such a costly therapy. And there is a wide difference in reimbursement for inpatient versus outpatient.

AJMC®: Speaking of reimbursement, you have published papers discussing the reimbursement challenges with CAR T. How has reimbursement changed since treatment reached the market?

Mehta: I will say that the reimbursement has improved compared with [prior years]. There were many challenges before; there was palpable resistance from the academic centers, especially for financial health of the institution, if we decided to do multiple patients. Also, CMS has now kept up with the third-party payers, and they're also increasing their reimbursement. So that improved at this point, compared to a couple of years back.

But this is very costly treatment, there is no doubt about that. And we don't have a single payer system, so everybody has different reimbursement. Especially with Medicare and Medicaid, as we discussed about patients who are below the poverty line or if they have a financial challenge, they absolutely cannot get this CAR T-cell therapy. So, those challenges are still there. We don't have a compassionate use program as we do with many other cancer drugs, because of the cost.

AJMC®: There’s been discussion about using CAR T-cell therapy earlier in the life cycle of the disease when perhaps the patient is healthier. At this stage, the therapy might work better before the patient's system is so depleted. What are your thoughts on this strategy?

Mehta: I will address this question 2 ways. One is you're exactly right. You know, we don't want the patient to be so sick that they cannot get the Carty and there are a bunch of clinical trials already going on the way the cancer drug approvals happen in the United States is you know, they enter at a lower relapsed refractory stage of the disease and they slowly climb back up. So, there are trials ongoing, which will help us know whether that is beneficial or not. But what in my viewpoint, what is important is those patients who are high risk, you know, there are certain characteristic in every cancer, if you look at diffuse large B cell lymphoma, we know that double hit double expressor, those who are activated diesel subtypes, they are high risk patients. So those are the patients who should get this therapy earlier in the course. And why do we have to wait till their relapse? I think it's depends on the label and the clinical trials that were done. But I would be extremely interested down the line for those high-risk patients, that they get CAR T [treatment] earlier, when they have first remission as a consolidation, so that that disease does not come back down the line. I think there are a lot of interest in that setting. There are many clinical trials are ongoing at this point. And hopefully it will climb back as we go. And especially with the cost, we are looking at the cost effectiveness in every everything. So those specifically for high risk patient, we should address it earlier.

AJMC®: It’s been pointed out that if you give the therapy earlier and it works, then you've also avoided the cost of whatever other therapy you would have given that would have failed.

Mehta: Absolutely. So why do we have to wait till the relapse? And then we struggle to find a good treatment for that patient.

AJMC®: Finally, let’s talk about the process of bringing CAR T-cell therapy into the community. You mentioned this in your previous answer, but can you discuss the role of the academic center in collaborating with the community practice? It sounds like you have long-range plans about this therapy working in the outpatient or the community practice setting.

Mehta: This is the issue dear to my heart. I feel that if the therapy is [too] expensive, that is this is not an option for treatment. And secondly, if it is not widely available, then it will not be successful. So, when we say “community,” we want to make it make sure that it is safely administered in the community. There are multiple ways that we can do this; either we can engage the academic center in the catchment area with their hospital so that they are up and ready. They are factor created, they are supervised and making sure that everything happens as per the REMS requirement. And the second entity that can get involved is the pharmaceutical company themselves. They have a team of physicians, nurses, pharmacists, who are available in the community setting so that if [the physicians] have any question they can always ask.

I envision down the line that we will have a mechanism where there will be a community program for administering CAR T under strict supervision of an academic center in the catchment area, and with a team of pharmaceutical companies, a specialist in that setting, which could be physician, and of course nurses and pharmacists available 24 /7 for help if the patient gets sick. …

If you have that mechanism, only then can you safely administer [CAR T in the community]. Those physicians must repeatedly go undergo training to handle this patient. As we all know with CRS, if you don't identify it early, and if it gets out of control, it is extremely risky for patients—it’s life-threatening.

AJMC®: Any final thoughts?

Mehta: I would say that the treatment is extremely exciting. I personally have multiple patients who would not be with me without this treatment, because this was a life-saving treatment for them. And I've also lost a few patients who had out of control side effects. So, this is a two-edged sword, and you must handle it extremely carefully. The second part, which I'll bring up is cost-effectiveness; it's expensive treatment. And we are lucky that we are in United States can offer this treatment for our patients; at many centers throughout the world, they have even not seen or heard or read about this treatment. I think there is a long way to get this to the patients who really need it, and I get a lot of international referrals [for patients] who need this treatment. So, that tells us that it’s very effective, but at the same time it is not available to everyone. … I'm more excited for off-the-shelf CAR T so that we don't have to wait.

Three years ago, chimeric antigen receptor or “CAR” T-cell therapy set off a revolution in cancer treatment. Customizing a patient’s own cells to fight certain leukemias and lymphomas offered promise to patients who had run out of treatment options. Soon, FDA is expected to act on lisocabtagene maraleucel (liso-cel), which could offer another choice for patients with large B-cell lymphoma who have failed prior therapies. Liso-cel incorporates a manufacturing process that separates CD8+ and CD4+ T-cells to create a therapy with a defined ratio of each type; results from the TRANSCEND trial show an overall response rate of 73% and a complete response rate of 53%, but with fewer adverse effects from cytokine release syndrome than seen previously.

The revolution of CAR T-cell therapy came with a steep price tag. The first 2 treatments, tisagenlecleucel (Kymriah) and axicabtagene ciloleucel, or axi-cel (Yescarta) reached the market in 2017 at $475,00 and $373,000, respectively. Duncan Allen, MHA, now vice president of Clinical Services for the community oncology network OneOncology, experienced the growing pains of paying for CAR T-cell therapy up close: he served as administrator for one of the country’s very first programs at Vanderbilt University Medical Center in Nashville, which is also the home base for OneOncology.

The American Journal of Managed Care® spoke with Allen recently about bringing CAR T-cell to community practice, where the challenges include guiding patients and families through the financial process and managing the side effects, which can be considerable. (This interview is edited slightly for clarity).

AJMC®: What makes it challenging to bring CAR T-cell therapy into the community practice setting?

Allen: The emergence of the immune effector cell therapeutic class in general—and specifically CAR T, the most successful therapy in that class today—has been groundbreaking for patients suffering from specific hematologic malignancies. Where the challenge lies with CAR T therapy is that the scientific data is relatively new, and this presents some challenges when trying to determine how these half-million dollar, cutting-edge therapies should be thought of in relation to their therapeutic peers.

In addition, the therapy brings certain manufacturing complexities. It requires two weeks or more to make. There are specific toxicity considerations that require the use of a specialized steroid, and that can be upwards of $2,000 per administration. And quite frankly, this is a very resource intensive treatment process that requires intense monitoring of the patient for over 30 days. … There are a significant number of challenges in the current generation of CAR products, but I do see that changing over time.

AJMC®: Are there any advantages of administering CAR T-cell therapy in the community practice level?

Allen: Absolutely. CAR T administration is largely in its infancy in the community setting. As this therapeutic class evolves from our current generation of CARs into future generations, where you may have [allogenic] off-the- shelf products, the advantages of administering and monitoring in a community setting are relatively straightforward: there’s access to timely administration, and convenience in close-to-home treatments, which I think is very important, given the level of monitoring required and the ability to administer in a REMS-certified outpatient facility. ... I think that really is a game changer, and really makes the community setting ideal for future CAR generations.

AJMC®: What are the constraints that are holding back growth of CAR T-cell therapy as a primary treatment?

Allen: Many of the initial barriers to reimbursement and administration have begun to be addressed, after intensive efforts to push for payment out of CMS. I think there are still many questions about how to sustain coverage for CAR T-cell therapy, given the price tags. With the advent of value-based care, a core tenet of OneOncology, we’ve seen that we are going to have address matching price to outcome. And CAR T-cell therapy is at the top of that list.

Lastly, I think last time I looked, there are over 1000 trials for cellular therapies, and many are beginning to be tested on solid tumors. So, we’ll have to think ahead about the scalability of cellular therapy, should solid tumor come into play in the future, so we can ensure that patients have access to these cutting edge therapies. And I think the community setting is uniquely positioned to help with that scale.

AJMC®: Can you describe the reimbursement landscape compared with 2017, when the first CAR T-cell therapies reached the market?

Allen: As someone who personally has sat with families and walked them through the reimbursement journey for CAR T, I can tell you that it has gotten much better. There were periods where patients simply would be waiting on their payer to cover their therapy. Luckily, I think we've seen the maturation of the coding and reimbursement environment over the past 2 years, largely thanks to that advocacy from the American Society for Transplantation and Cellular Therapy, the American Society of Hematology, and other cellular therapy groups. Today, around 90% of plans have coverage for CAR T. But as we know, they're still nuances. For starters, it's not just about the cost of the therapy, but the associated costs for delivering a therapy, including leukapheresis, to the administration of steroids and freezing and other related costs. The coding considerations have not been inclusive of the full cost surrounding CAR therapy and this has been presented in a number of forums. But it impacts patients and providers and practices, and I would like to see this improve over time as cellular therapy becomes mainstream. I think with increased policy advocacy, we can definitely get to a healthier state.

AJMC®: Are some CAR T therapies and indications more appropriate for the community setting than others?

Allen: As different products are tested, there will be clear winners that are more suitable for the community setting. And those will likely [be] therapies that have lower toxicity profiles, so that you can ensure you're not going to have to admit your patient to the hospital. With the current generation of CAR therapies, most folks would say that there have been different experiences with the two primary players. But over time, I think we will have definitively determined which immune effector cells are more appropriate from an outpatient perspective and which are more suitable for inpatient administration. So, I think the verdict is still largely out.

AJMC®: Today community practices are involved in CAR T clinical trials, but can you be more specific about which ones?

Allen: Sure, so I would say, when you look across the national landscape in the community setting, I would say most all major groups that have cellular therapy assets are working with community practices. As I mentioned, I think there are over 1000 trials in cellular therapy. What's most important is that we're identifying the appropriate trials for our patient populations in the community setting, and ensuring that they're offered up to 2 each … There's really availability at the local setting for all those cellular therapies, and that's something that we are very focused on doing and making available to all patients.

AJMC®: Will we be able to see how the community practice patients fare in these trials relative to say, the academic center patients?

Allen: Sure. I think that's something that OneOncology is also uniquely positioned to address. We obviously are very focused on real-world data, on the real-world experience of the patient. For a therapeutic class as young as CAR T therapy, I think real-world data studies are going to be an area of focus not just for community practices, and not just for providers, but also, I think these are going to be things that we see increasingly more mandated by the FDA. And I think the FDA will be really interested in monitoring how those therapies evolve over time. Again, we're only a couple of years out still from the initial administration. I think as we go forward, there will be increasingly more pressure to look at scaling research efforts for CAR T therapy. And I think real-world data will play a large part in that.