Earlier Use of CAR T Cells Holds Promise in Blood Cancers, but Access Remains an Issue

A symposium at the annual meeting of the American Society of Clinical Oncology focused on the current chimeric antigen receptor (CAR) T-cell therapy landscape for large B-cell lymphoma (LBCL) and multiple myeloma, including new trial results with a focus on translation to clinical practice, but also emphasized the disparities in access to these therapies and potential strategies to mitigate them.

Caron Alyce Jacobson, MD, medical director of the Immune Effector Cell Therapy program at the Dana-Farber Cancer Institute, kicked the session off with background on CAR T-cell therapies in later lines of hematological cancer treatment.

CD19-targeted CAR T-cell therapies were initially approved for LBCL in the third line and beyond, Jacobsen explained. In relapsed or refractory (R/R) multiple myeloma, B-cell maturation antigen (BCMA) was being investigated as a target at the same time CD19 was being assessed in leukemia and lymphoma, with initial BCMA-targeted CAR T cell approvals in the fifth line and beyond.

While these therapies have shown impressive response rates and curative potential compared with other available therapies, challenges such as treatment resistance remain with CAR T-cell therapy. Decreased CAR T cell efficacy may be due to several factors, including patient characteristics, T cell characteristics, and tumor microenvironment traits.

“Investigation of all of these mechanisms or associations of resistance is definitely necessary to make CAR T cells better for more patients, but if we focus on the aspects specifically related to the T cell factors, we might hypothesize that treating patients in an earlier line of therapy could lead to better outcomes,” Jacobson said.

Jacobsen highlighted data from the ZUMA-1 trial, which led to the approval of axicabtagene ciloleucel (axi-cel) as a third-line option in LBCL. In addition to positive outcomes, data from ZUMA-1 also show improved CAR T cell quality in patients who had undergone fewer lines of treatment prior to CAR T-cell therapy.¹ Similar findings emerged in the phase 2 ZUMA-12 study of axi-cel in the first line, which showed a better complete response rate compared with the ZUMA-1 study, improved progression-free survival (PFS), and a higher proportion of CAR T cells enriched for phenotypes that are linked with better outcomes.²

The ZUMA-12 results do not establish CAR T cells as a frontline treatment option for LBCL, Jacobson said, but the findings sparked an ongoing randomized trial investigating axi-cel vs standard-of-care chemoimmunotherapy for high-risk LBCL in the first line.

Research into novel ways to optimize T cells, including deriving them from allogeneic donors to manufacture “off-the-shelf” CAR T cells that are not impacted by underlying disease or manipulating the tumor immune profile, will be crucial going forward to address the range of factors that affect CAR T cell efficacy.

“CAR T cell-therapy has clearly revolutionized the treatment options for our patients and definitely is superior for certain high-risk patients compared with standard-of-care regimens even in earlier lines of therapy, but it's through explorations like these and investigation of these other mechanisms of resistance that I think we're really going to be able to improve CAR T cell access and success for more patients,” Jacobson concluded.

New Results for CAR T Cells in Earlier Lines of Therapy

Binod Dhakal, MD, associate professor of medicine at the Medical College of Wisconsin, presented the first phase 3 results of the CARTITUDE-4 study of cilta-cel vs the standard of care in lenalidomide-refractory multiple myeloma.³

The primary end point in the study was PFS in the intent-to-treat (ITT) population, and the 12-month PFS was 76% in the cilta-cel cohort vs 49% in the standard-of-care group, with a HR of 0.26 (P = .0001). Whether patients had 1 or 2-3 prior lines of therapy, cilta-cel improved PFS over the standard of care. At longer follow-up, data on outcomes in patients with 1 vs additional lines of therapy will be assessed, Dhakal said.

When informally compared with CARTITUDE-1, in which patients had undergone 3 or more prior lines of therapy, patients in CARTITUDE-4 showed superior PFS and depth of response, and safety data were consistent with the known cilta-cel profile. Dhakal noted that rates of treatment-related adverse events suggest cilta-cel was better tolerated when used in earlier lines of treatment.

“Overall, cilta-cel has the potential to be a new standard of care in lenalidomide-refractory myeloma after first relapse,” Dhakal said.

Jason Westin, MD, MS, FACP, director of the Lymphoma Clinical Research Program at Texas MD Anderson Cancer Center, presented the final overall survival (OS) findings from the phase 3, randomized, international ZUMA-7 study of axi-cel vs standard-of-care treatment (chemotherapy followed by high-dose therapy and autologous stem-cell transplant) in R/R LBCL.⁴ Based on positive event-free survival (EFS) outcomes, axi-cel was approved for the second-line treatment of R/R LBCL in many countries, Westin noted.

OS was a key secondary end point in the trial, and at a median follow-up of 47.2 months, the HR for OS in the axi-cel cohort was 0.726 (95% CI, 0.540-0.977; one-sided P = 0.0168). Median OS was not reached for axi-cel, while the standard-of-care arm had an OS of 31 months. The 4-year OS rates were 54.6% and 46% in the axi-cel and standard-of-care arms, respectively.

“We believe our data represent a paradigm shift. Axi-cel in the second line improves overall survival for patients with refractory or early relapsed large B-cell lymphoma vs the previous paradigm,” Westin said. “The risk of death was reduced by 27.4%, despite 57% of patients in the standard-of-care arm receiving subsequent cellular immunotherapy off protocol. This conclusively demonstrates that trying chemotherapy in the second line and saving cell therapy for third line is an inferior approach.”

These results confirm axi-cel as a second-line standard-of-care therapy for R/R LBCL, he concluded.

Presenter Asher Chanan-Khan, MD, professor of medicine at the Mayo Clinic Cancer Center, agreed that the treatment paradigms for both LBCL and multiple myeloma should be reassessed based on the results presented by Westin and Dhakal. But he also posed a question: Have we reached “the promised land” with CAR T cells, defined as the right treatment for the right patient at the right time—and for the right cost?

Chanan-Khan noted that unanswered questions remain, including whether CAR T cells with the same target have different efficacy in the same indication.

While some indirect comparisons can be drawn, no direct comparisons between the same CAR T cells for the same indication have been done. Therefore, Chanan-Khan said, it may not be clear which CAR T cell therapy is the most appropriate when there are multiple approved for the same indication.

Addressing Disparities in Access to Cellular Therapy

Christopher S. Lathan, MD, MS, MPH, Chief Clinical and Access Equity Officer at the Dana-Farber Cancer Institute, applauded the progress in CAR T-cell therapy development, but also highlighted the disparities in access to these and other cutting-edge treatments.

“These new developments are really changing what we can do for our patients in so many different areas, but unfortunately, with new science comes the same patterns,” Lathan said, highlighting that the diffusion of such innovations has long been unequal.

He noted that most clinical trials predominantly include White patients—a trend that extends to CAR T-cell therapy trials. Geographic and racial disparities in multiple myeloma CAR T-cell therapy trial access were seen in one study,⁵ and another analysis highlighted a lack of Black patients on 7 CAR T-cell trials that led to approvals.⁶

The effects of historical barriers, including structural racism, have persisted in the medical space and US society overall, Lathan said, noting that even artificial intelligence—often touted as objective—can still be biased. Intent and impact are often separate, he added, noting that doing the right thing on an individual level cannot undo the systemic damage still impacting medicine.

Without prospective, consistent integrated efforts to combat bias and acknowledge past damage, Lathan said, progress will not be made.

“Implementation science is supposed to be the place where we fill in the gaps, but here's the problem: there's still limitations with the real-world structural barriers that are not included in the conceptual models of our implementation science, and we can't continue to ignore these issues again and again expecting new results,” Lathan said.

He urged the medical community to consider access and implementation from the start, think about transdisciplinary research, and consider prospective community engagement.

Barriers to Access Impact Patients and Providers

Leyla Shune, MD, medical oncologist at the University of Kansas Cancer Center, echoed the importance of improving access to CAR T-cell therapy, noting that the notoriously high list prices for CAR T-cell therapies are hardly the only barrier for patients.

Patient-level, provider-level, and manufacturing challenges all come into play. Patient barriers include the limited number of CAR T-cell therapy centers; the cost of travel, loss of wages, and caregivers; type of insurance coverage; out-of-pocket costs; and significant toxicities, including cytokine release syndrome and neurotoxicity.

Measures such as improving patient education, expanding assistance programs to include travel and housing for patients receiving CAR T cells, lowering out-of-pocket insurance costs, and increasing community engagement and clinical trial enrollment among minority populations may help mitigate the barriers to CAR T-cell therapy, Shune said.

The limited number of CAR T-cell therapy centers is also a barrier for providers, as most cancer therapy is delivered by community oncologists, Shune noted.

“CAR T treatment centers should be in the community. It belongs to the community, because it will help us overcome referral challenges, and it’ll help us overcome logistics with CAR T follow-up,” Shune said. “But to achieve a CAR T treatment center in every community, we need huge investments in staffing and accreditation. That’s a challenge that may not be overcome in the near future, but ultimately, therapy should be close to where the patient lives, and it should be provided by their community oncologist whom they completely trust.”

Manufacturing challenges, including a lengthy timeline from T cell collection to therapy initiation, also hinder access and therefore outcomes for patients. Shune recalled instances where patients have entered hospice care or even passed away while waiting for a slot to receive BCMA-targeted CAR T-cell therapy at the center where she practices.

Pharma companies must prepare to scale up as demand surges with new data and subsequent approvals, and the decentralization of CAR T manufacturing should be considered, Shune said. The potential of off-the-shelf CAR T-cell therapies is also an area of interest to reduce access barriers.

While CAR T-cell therapy holds promise in earlier lines of therapy for hematological malignancies, “CAR T-cell therapy is associated with complex barriers that will require innovative solutions to achieve health equity and access,” Shune concluded. “Together, I believe we can deliver on the promise of CAR T.”

References

1. Neepalu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Eng J Med. 2017;377(26):2531-2544. doi:10.1056/NEJMoa1707447

2. Neelapu SS, Dickinson M, Munoz J, et al. Primary analysis of ZUMA-12: A phase 2 study of axicabtagene ciloleucel (axi-cel) as first-line therapy in patients with high-risk large B-cell lymphoma (LBCL). Blood. 2021;138(suppl 1):739. doi:10.1182/blood-2021-148009

3. Dhakal B, Yong K, Harrison S, et al. First phase 3 results from CARTITUDE-4: cilta-cel versus standard of care (PVd or DPd) in lenalidomide-refractory multiple myeloma. J Clin Oncol.2023;41(suppl 17):LBA106. doi:10.1200/JCO.2023.41.17_suppl.LBA106

4. Westin J, Oluwole OO, Kersten MJ, et al. Primary overall survival analysis of the phase 3 randomized ZUMA‑7 study of axicabtagene ciloleucel versus standard‑of‑care therapy in relapsed/refractory large B-cell lymphoma. J Clin Oncol. 2023;41(suppl 17):LBA107. doi:10.1200/JCO.2023.41.17_suppl.LBA107

5. Alqazaqi R, Schinke C, Thanendrarajan S, et al. Geographic and racial disparities in access to chimeric antigen receptor–T cells and bispecific antibodies trials for multiple myeloma. JAMA Netw Open. 2022;5(8):e2228877. doi:10.1001/jamanetworkopen.2022.28877

6. Al Hadidi S, Schinke C, Thanendrarajan S, et al. Enrollment of Black participants in pivotal clinical trials supporting US Food and Drug Administration approval of chimeric antigen receptor–T cell therapy for hematological malignant neoplasms. JAMA Netw Open. 2022;5(4):e228161. doi:10.1001/jamanetworkopen.2022.8161