Sequencing, Sustainability Are Hot Topics in CAR T- and Gene Cell Therapies Discussion

With approvals for bispecific antibodies coming in the weeks before and after the 11th Annual Patient-Centered Oncology Care® meeting,^1,2 chimeric antigen receptor (CAR) T-cell therapy moving to second-line treatment can be summed up this way: It’s complicated.

And so began the discussion, “CAR T- and Gene Cell Therapy: Finding Value as Innovation Moves Upstream,” which went beyond clinical and payer implications of the 2022 approvals for second-line use of axicabtagene ciloleucel (Yescarta)³ and lisocabtagene maraleucel (Breyanzi)⁴ in diffuse large B-cell lymphoma (DLBCL).

In a panel moderated by Ryan Haumschild, PharmD, MS, MBA, director of pharmacy services at Emory Healthcare and Winship Cancer Institute of Emory University, the discussants also examined challenges with CAR T-cell manufacturing capacity and patient referrals. They also debated whether the promise of CAR T-cell therapy in solid tumors would be realized, and if so, what this would mean for the sustainability of these costly therapies in reaching eligible patients.

The panelists included the following:

• Melissa Johnson, MD, program director of lung cancer research and associate director for drug development at Sarah Cannon Research Institute in Nashville, Tennessee, and a medical oncologist with Tennessee Oncology.
• Joseph P. McGuirk, DO, director of the Division of Hematologic Malignancies and Cellular Therapeutics at the University of Kansas Cancer Center in Kansas City.
• Amitkumar Mehta, MD, director of the Lymphoma Program and CAR-T Program and medical director of the Clinical Trials Office; O’Neal Comprehensive Cancer Center at the University of Alabama at Birmingham.

Johnson is involved in multiple clinical trials with bispecific antibodies in solid tumors, as well as those exploring the use of CAR T-cell therapy in solid tumors; thus far, the success seen with CARs in blood cancers has not been repeated. McGuirk, whose center performs about 325 stem cell transplants a year along with CAR T-cell treatments and clinical trials, sounded more optimistic than Johnson about eventually seeing success with CAR T in solid tumors.

McGuirk’s overall enthusiasm for the success of CAR T-cell therapy was offset by his frustration with the lack of bandwidth to provide certain treatments, especially ciltacabtagene autoleucel (Carvykti) in multiple myeloma. This leaves cancer centers such as his selecting only 1 or 2 patients for treatment from among dozens awaiting care.

For his part, Mehta noted that his academic center strives to work with community providers in bringing CAR T-cell therapy to more patients, and the pandemic set this process back. A major issue with CAR T-cell administration is that “it takes a village to establish a local program,” but perhaps bispecific antibody administration at the local level will require less infrastructure.

“There is always a learning curve” Mehta said. He explained that one of his challenges has been the departure of experienced personnel, something seen across oncology and within the pharmaceutical industry as well.

Signs of progress. Haumschild asked for comment on advances in managing adverse events (AEs), particularly cytokine release syndrome (CRS), the acute inflammatory response that is associated with CAR T-cell therapy. Johnson noted that CRS is more likely to be managed in the hospital with CAR T-cell therapy and in the clinic with bispecific antibodies.

“One of the innovations that we’ve seen is a recognition of the importance of drugs like tocilizumab,” she said, a drug that has experienced shortages but is now available in the emergency department for patients who present with symptoms. “We’ve figured out how to manage our CAR T toxicity, specifically CRS, and how it also manifests itself with drugs such as bispecifics, where it is more acute,” Johnson said.

“Unquestionably, we’re making remarkable progress,” McGuirk said, pointing to long-term results for clinical trials in LBCL that showed durable complete remission in 35% to 40% of patients. “That’s curative therapy, 5 years now, in 2 trials,” he said. “And these were patients who had nowhere else to turn.”^5,6

McGuirk’s excitement in the solid tumor area stems in part from work by Nobel laureates Jennifer A. Doudna, PhD, of the University of California, Berkeley, and Emmanuelle Charpentier, PhD, of the Max Planck Unit for the Science of Pathogens in Berlin, Germany.⁷ In particular, he highlighted “their discovery of how bacteria protect themselves from viral infections,” along with the development of tools to gene edit T cells “and make them do things that they otherwise wouldn’t do.”

Of note, McGuirk said, the current FDA-approved CAR T-cell therapy platforms are still “second generation.” Today, third-, fourth- and even fifth-generation platforms are being studied, and investigators are gaining knowledge every day of the biology that will someday make CARs work in more types of tumors.

CAR T or bispecifics? Haumschild then turned the discussion to a major topic in cancer care today: Some patients with DLBCL or multiple myeloma who have had their first relapse face a choice of CAR T-cell therapy or a bispecific therapy (a bispecific antibody in DLBCL and a bispecific T-cell engager, or BiTE, in multiple myeloma). What clinical features help a physician decide which is best? What other factors come into play? “How are you going to manage the different CRS rates?” Haumschild asked. “From a clinician standpoint, there are a variety of responses that can occur.”

Mehta delved into some core tradeoffs between the 2 types of treatment. CAR T-cell therapy is more complex to administer—and thus more challenging to bring to a community setting—but it is a one-time treatment. Bispecifics, by contrast, may be easier to administer but are not one-time treatments. “I do see that the bispecifics have a lot of positives being administered in the community—in the clinic—as long as we understand and learn the curveballs,” he said.

What about patient recruitment, Haumschild asked. CAR T-cell therapy is approved for second-line use in some types of blood cancer, but are clinicians and patients aware?

Johnson, whose research is in solid tumors, said there is a big difference between her area of expertise and blood cancers, where CAR T-cell therapy is now well established. Her colleagues at Sarah Cannon who treat patients with lymphoma may have 25 patients at a time who are eligible for therapy, and the challenge is getting the product manufactured and available. In solid tumor trials, it is quite different. “For me, it’s 2500 patients who are interested and maybe 1 or 2 eligible based on the tumor antigens that the current drugs are targeted against,” Johnson explained. With solid tumors, “we have a much harder time identifying targets. There is no CD19. There is no CD33 for solid tumors,” she said. And targets such as EGFR are expressed in parts of the body where AEs would make this treatment approach a challenge.

For these reasons, she said, “I tend to think about bispecifics being more tenable in a solid tumor patient population, because they are off the shelf.”

McGuirk pointed out that although data show CAR T-cell therapy can offer superior outcomes to bispecifics, depending on the therapy, there is a pragmatic reason why bispecifics may appear to be the best solution in patients with aggressive disease: they don’t require customized manufacturing. Then McGuirk held forth on what he called “bad planning” by CAR T-cell manufacturers of multiple myeloma therapies.

“The manufacturing is abysmal and unconscionable…. We have a wait[ing] list of 50 patients with myeloma who need Carvykti [ciltacabtagene autoleucel], and Carvykti’s being promoted—rightfully so,” he said.

However, the manufacturer only allows 2 treatment slots a month for the University of Kansas, which serves 5 states, leaving McGuirk’s team to select 2 from among 50 patients in need of treatment. “So I say shame on the industry, and not just to the Carvykti folks, but more broadly, for not having prepared. They knew that this was coming, and they can’t meet the need.”

He is troubled that precious treatment slots will now be allocated for an upcoming randomized trial. Additionally, he is also concerned that the same manufacturer is now marketing a recently approved bispecific antibody, teclistamab, to treat multiple myeloma. For McGuirk, this seems like a conflict of interest, “and, again, very poor planning.”

McGuirk pointed to data from the Surveillance, Epidemiology, and End Results Program showing that about 30% of eligible patients are receiving CAR T-cell therapy, a figure that has plateaued. He sees barriers to access as a factor. “If you can keep somebody near home and give them more chemotherapy,” McGuirk said, bispecific antibodies may be easier to use. But they have not been shown to be curative, he added.

Are referrals taking place? Haumschild asked the panel to discuss how referrals work in day-to-day practice. Mehta said that for UAB, the arrival of CAR T-cell therapy offered an opportunity to engage more deeply with community practices.

“We are now partners in the patient’s care,” he said. Today, if a patient must be referred to the academic center for second- or third-line therapy or a transplant, the UAB team is readier to receive that patient. They are more prepared to work with the insurer and more knowledgeable about the patient’s risk factors.

McGuirk said the proof is in the data. He was a coauthor of a study involving real-world data that showed that even patients who would not have been eligible for CAR T-cell therapy clinical trials have survival outcomes that are comparable to the trial results.⁸

Johnson said “a great divide” is whether patients have access to a hospital that can manage CRS. When FDA approved tebentafusp-tebn, a bispecific antibody for melanoma, Tennessee Oncology developed a protocol to ensure safety by having the first 3 treatments administered in the research setting; after that, CRS is less common, and the patient transitions back to their community clinic.

For lymphoma especially, sequencing will be key, Mehta said. “That’s why a collaboration is very helpful [between] the original treating doctor and a center that has the capabilities.”

What about cost? The panel discussed how the thinking toward financing CAR T-cell therapy has shifted over time. When the first treatments were approved in 2017, both payers and institutions lacked systems to approve them, so sign-off on therapies that cost nearly $500,000 required the signature of a hospital CEO. This was quite burdensome, but Mehta said he has seen the transition over 7 years to a process that is much smoother. “I’ve seen that culture change. And that has been very impactful for the patient.”

The bigger question, the panelists agreed, was whether the use of these high-cost therapies would be sustainable if CAR T-cell therapy and other high-cost therapies continue to move into earlier lines of care in blood cancers—or, as might happen someday, solid tumors, including much more common cancers such as breast, lung, or prostate. McGuirk and Mehta agreed that these therapies cannot be limited to academic centers if they are to reach all eligible patients. But the situation with patients who rely on Medicaid in particularly challenging.

“I don’t see [how] it will be sustainable unless we come up with a solution,” Mehta said. Relatively speaking, he continued, the United States is far ahead of other nations, some of which still do not offer patients ibrutinib, for example. “So, we have that advantage.”

“But to sustain that, the cost has to come down,” he noted, and not just the therapy cost. With hospital admission and management costs, a single CAR T-cell therapy treatment can exceed $1 million.

McGuirk agreed. Although allogenic constructs may drive down costs somewhat, “we have a long way to go to respond to the challenges.”

Johnson put the cost of CAR T-cell therapy in perspective. If a patient with lung cancer is taking an immune checkpoint inhibitor that costs $25,000 a month for a minimum of 2 years, then balking at $500,000 for drug costs “is a little shortsighted, because over a 2-year course for a [patient with] metastatic lung cancer, a payer is absolutely spending that much for their care.”

Bundled payments may be one solution, she said. “If the prospect is a curative therapy, then there will be a way forward.”

References
1. FDA approves teclistamab-cqyv for relapsed or refractory multiple myeloma. FDA. October 25, 2022. Accessed January 24, 2023. http://bit.ly/3HpVs0P
2. FDA grants accelerated approval for mosunetuzumab-axgb for relapsed or refractory follicular lymphoma. FDA. Updated December 23, 2022. Accessed January 24, 2023. http://bit.ly/3kGqud1
3. FDA approves axicabtagene ciloleucel in second-line treatment of large B-cell lymphoma. FDA. April 1, 2022. Accessed January 24, 2023. http://bit.ly/3RqnXzB
4. FDA approves lisocabtagene maraleucel for second-line treatment of large B-cell lymphoma. FDA. Updated June 27, 2022. Accessed January 24, 2023. http://bit.ly/3J7v3aq
5. Jacobson C, Locke FL, Ghobadi A, et al. Long-term (≥4 year and ≥5 year) overall survival (OS) by 12- and 14-month event-free survival (EFS): an updated analysis of ZUMA-1, the pivotal study of axicabtagene ciloleucel (axi-cel) in patients (Pts) with refractory large B-cell lymphoma (LBCL). Blood. 2021;138(suppl 1):1764. doi:10.1182/blood-2021-148078
6. Chong EA, Ruella M, Schuster SJ; Lymphoma Program Investigators at the University of Pennsylvania. Five-year outcomes for refractory B-cell lymphomas with CAR T-cell therapy. N Engl J Med. 2021;384(7):673-674. doi:10.1056/NEJMc2030164
7. The Nobel Prize in Chemistry 2020. The Nobel Prize. October 7, 2020. Accessed January 25, 2023. https://www.nobelprize.org/prizes/chemistry/2020/summary/
8. Hansen DK, Sidana S, Peres LC, et al. Idecabtagene vicleucel for relapsed/refractory multiple myeloma: real-world experience from the Myeloma CAR T Consortium. J Clin Oncol. Published online January 9, 2023. doi:10.1200/JCO.22.01365