Results include a landmark study that involved seamless collaboration across adult and pediatric patient groups, leading to a highly diverse study population. Other coverage addresses access to novel therapies and what's coming in the pipeline, including CAR T-cell therapy with tyrosine kinase inhibitors.
Nivolumab Cuts Risk of Disease Progression or Death by 52% in Untreated Hodgkin Lymphoma Compared With Brentuximab Vedotin
In patients newly diagnosed with classic Hodgkin lymphoma (cHL), the immune checkpoint inhibitor nivolumab (Opdivo) plus chemotherapy reduced by half the risk of disease progression and death compared with the CD30-targeted therapy brentuximab vedotin (Adcetris) and the same chemotherapy combination.1
Results announced in the plenary session at the annual meeting of the American Society of Clinical Oncology (ASCO) highlighted the remarkable journey in the treatment of patients with cHL. This landmark study involved collaboration among all North American clinical trial groups and a trial whose design allowed seamless participation across adult and pediatric cHL populations. The result was good news for patients of all ages.
“Traditionally, adults and children with advanced Hodgkin lymphoma in the United States have been treated with different chemotherapy regimens, and the majority of children also receive radiation treatment, whereas the use of radiation has been uncommon in adult patients,” Alex Francisco Herrera, MD, lead author and associate professor, Division of Lymphoma, at City of Hope in Duarte, California, said in a statement from ASCO.2
In this trial, adult and pediatric cooperative groups achieved a consensus on both the control and experimental regimens “with the goal of harmonizing the treatment of Hodgkin lymphoma across all ages, which is a truly unique outcome,” Herrera said.
Just last year at ASCO, long-term data from the ECHELON-1 trial showed that after 6 years, brentuximab vedotin plus the chemotherapy combination of doxorubicin (Adriamycin), vinblastine, and dacarbazine reduced the risk of death by 41% over an older combination of bleomycin, vinblastine, and dacarbazine.3
But as Herrera explained in a news briefing, that success came at the cost of increased toxicity. On the pediatric side, he said, the disease’s tendency to strike young adults meant maximizing doses of radiation and chemotherapy to stave off a relapse. “That was decades ago; we’ve been slowly, steadily over time trying to walk that therapy back—and de-escalate therapy.”
The results push the therapeutic bar higher, with the use of a PD-1 inhibitor in first-line treatment.
“This trial was an unprecedented effort across all North American clinical trial cooperative groups to improve the cure rate in advanced stage Hodgkin lymphoma and harmonize treatment approaches between pediatric and adult patients,” Oreofe Odejide, MD, an ASCO commentator who is an assistant professor at Dana-Farber Cancer Institute, said in the statement.2
“The collaborations across adult and pediatric groups helped pave the way for a new standard of care that is better tolerated and results in a higher proportion of patients with durable remissions.”
In their abstract, investigators discussed rationale for their approach: When patients developed relapsed or refractory (R/R) cHL, “The PD-1 pathway is central to the pathogenesis of HL, and PD-1 blockade is effective in R/R HL.”
SWOG S1826 evaluated 976 people 12 years or older who had not previously been treated for cHL, which is characterized by the presence of large white blood cells that may have more than 1 nucleus. Median follow-up was 12.1 months. Enrollment was as follows:
Herrera said the cooperation among the trial groups allowed enrollment to run ahead of schedule. At the planned second interim analysis, which occurred when the trial reached 50% of the total progression-free survival (PFS) events, the SWOG Data and Safety Monitoring Committee recommended that the primary results be reported, as 30 events had occurred in the nivolumab group vs 58 in brentuximab vedotin group. With a median follow-up of 12.1 months, the following data are being reported:
“I can’t emphasize enough how important neuropathy is as a side effect in these young patients,” who may face these effects for the rest of their lives, Herrera said. “It’s fantastic to be cured from your cancer, but it’s tough to live with.”
And, according to data from ASCO, many do survive cHL but live with toxic effects of today’s therapies. An estimated 8830 new cases (4850 men and 3980 women) of Hodgkin lymphoma will receive a diagnosis in the United States in 2023, and an estimated 900 deaths (540 men and 360 women) will occur. Although the 5-year survival rate for advanced disease is 83%, some patients do not benefit and/or cannot tolerate the effects of current therapeutic options.
Herrera emphasized that the benefits of nivolumab were consistent across age groups, and that harmonization of care appears here at last. Although the trial format allowed patients to receive radiation if needed, less than 1% did in the nivolumab group. “I started by telling you that 55% to 60% of patients receive radiation therapy,” Herrera said. “So that’s an incredible reduction in the use of radiotherapy, and hopefully delays the effects that these patients might experience.”
Diversity of Study Population. Herrera was visibly proud of the diversity of the study population in SWOG S1826. A quarter of the patients were members of minority groups: 11% were Black, 12% were Hispanic, and 3% were Asian. In a disease that affects large numbers of young adults, the median age was 27 years, with a range of 12 to 83 years; 25% of the patients were younger than 18 years, and 10% were older than 61 years. The study included patients who were HIV positive as well: 10 (2%) in the nivolumab group and 5 in the brentuximab vedotin (1%) group.
And, Herrera said, the trial completed registration for the trial in just over 3 years. “That’s actually a year ahead of schedule.”
More Studies Underway. During the plenary session, Herrera noted that a study is under way that combines nivolumab with brentuximab vedotin. Officials from Seagen, which makes the therapy, noted this in an email sent to Evidence-Based Oncology.
“Early SWOG data are promising but longer-term proven outcomes including overall survival data are important in a curative setting such as Hodgkin lymphoma. [Brentuximab vedotin] is the only regimen with a demonstrated overall survival benefit with a Category 1 NCCN guidelines recommendation.”
The message continued, “Our ultimate goal is to achieve the highest cure rate possible by combining the 2 most active agents in [brentuximab vedotin] and an anti-PD1 and, as a result, further reduce chemotherapy burden for patients.”
The SWOG S1826 study was funded primarily by the National Cancer Institute with some funding from Bristol Myers Squibb.
1. Herrera AF, LeBlanc ML, Castellino SM, et al. SWOG S1826, a randomized study of nivolumab(N)-AVD versus brentuximab vedotin (BV)-AVD in advanced stage (AS) classic Hodgkin lymphoma (HL). J Clin Oncol. 2023;41(suppl 17):LBA4. doi:10.1200/JCO.2023.41.17_suppl.LBA4
2. Nivolumab reduces risk of disease progression or death in untreated Hodgkin lymphoma compared to brentuximab. News release. American Society of Clinical Oncology. June 4, 2023. Accessed June 14, 2023. https://bit.ly/3N7lrwE
3. Ansell SM, Radford J, Connors JM, et al; ECHELON-1 Study Group. Overall survival with brentuximab vedotin in stage III or IV Hodgkin lymphoma. N Engl J Med. 2023;387(4):310-320. doi:10.1056/NEJMoa2206125
SPOTLIGHT: Andrew Evens, DO, MBA, MSc, Discusses the SWOG S1826 Trial and Changing Landscape of Hodgkin Lymphoma
Andrew Evens, DO, MBA, MSc, associate director for clinical services at Rutgers Cancer Institute of New Jersey, spoke with Evidence-Based Oncology (EBO) about the ways in which the SWOG S1826 trial (NCT03907488) results will build on current knowledge of Hodgkin lymphoma treatment. Results showed that nivolumab plus a chemotherapy combination was more effective in newly diagnosed advanced-stage classic Hodgkin lymphoma than brentuximab vedotin plus chemotherapy.1
This interview is lightly edited for clarity.
EBO: This year, the American Society of Clinical Oncology Annual Meeting brought results from the SWOG S1826 trial comparing brentuximab vedotin + AVD [doxorubicin (Adriamycin), vinblastine, and dacarbazine] with immunotherapy (nivolumab) + AVD. How will these results build on existing knowledge in treating Hodgkin lymphoma?
Evens: I think we’ve known—it’s fair to say we’ve known for not just years, but decades—that Hodgkin lymphoma is a very treatable and curable cancer, which is great. With that said, [the cure has] been really on the back of combination chemotherapy. And so, that’s No. 1. Number 2 is that even though it’s a high remission rate, and even cure rate, we’re always trying to outdo ourselves and go higher and higher and better. But a critical goal—in part because the cure rate is already so high, but also because the majority of patients are younger in their 20s and 30s—is that we also want to mitigate toxicity and side effects. And when we say side effects and toxicity, it’s through a couple of different lenses. One is acute toxicity during treatment. I’ll say a second phase is what we’re coining “postacute”—right after treatment, and let’s say for years 1 to 10 [after that]. And then—since, again, many of these patients are in their 20s and 30s—late effects [as well], 10 or 20 years down the road.
What we do in these trials is try to maximize all of that. We try to have the highest and best progression-free survival—meaning go into remission, never relapse, and hopefully extend life as long as possible. But again, also to avoid toxicity, and sometimes toxicity comes in the form of death later in life. You can have side effects, [such as] some of those post-acute side effects [that] don’t just cause morbidity , they can cause mortality as well. So, obviously, we also look at overall survival. But overall survival is always in the long-term lens. It’s never going to be in 1 or 2 or 3 years for Hodgkin lymphoma.
EBO: Today, clinicians treating lymphoma have choices across many drug classes. Are standards emerging for the sequencing of these different options? What are the most important considerations when selecting a regimen?
Evens: Of course, you want that starting regimen to be kind of the same theme as we’ve been talking about, [which] is highly efficacious. Of course, our goal is 100% progression-free survival. If we could have a treatment that [gives] 100% progression-free survival with [minimal or no] um side effects, if any, that’s our holy grail. So we’re continually pushing that envelope to be able to do that through randomized clinical trials, and that won’t happen through new and more chemotherapy. The way that’ll happen is through novel targeted, smart, strategic biologic therapy, whether it’s an antibody-drug conjugate, a checkpoint inhibitor, some other immunotherapy, or a novel therapeutic.
We have to remember that it’s hard, though. With all that said, it’s a very high bar. Remember, the 6-year progression-free survival rate with A-AVD [brentuximab vedotin (Adcetris) plus AVD] was right around 82%, and the 6-year overall survival was 94%
. So those are pretty high bars to beat. But the hope is that we can be both of those goals, and again, do it with similar or possibly fewer side effects.
This study is 1 step on that journey. We’ll have to see the results of it, and then we’ll build upon whatever those results are. And we’ll have to see where we’ll start designing that study. Maybe it will be even less chemotherapy than is currently being used. Of course, we have to be cautious. We don’t want too much therapeutic adventurism, you could say, because you don’t want to stop giving chemotherapy and [find that] the cure rate drops—you do have to do it incrementally. And certainly, you never want to compromise treatability and curability.
I think that’s where we’re going, and other end points [are so] critical, too. Of course, progression-free and overall survival [are important], but other critical end points are going to be quality of life and financial analyses. Also, hopefully, whatever treatment regimen is developed or discovered will be relevant not just in the United States, but [one that] can be used across the world.
1. Herrera AF, LeBlanc ML, Castellino SM, et al. SWOG S1826, a randomized study of nivolumab (N)-AVD versus brentuximab vedotin (BV)-AVD in advanced stage (AS) classic Hodgkin lymphoma (HL). J Clin Oncol. 2023;41(suppl 17);abstr LBA4. doi:10.1200/JCO.2023.41.17_suppl.LBA4
2. Ansell SM, Radford J, Connors JM, et al; ECHELON-1 Study Group. Overall survival with brentuximab vedotin in stage III or IV Hodgkin’s lymphoma. N Engl J Med. 2022;387(4):310-320. doi:10.1056/NEJMoa2206125.
Axi-Cel Shows Favorable Safety, Efficacy in Real-World Study of Early Follicular Lymphoma Outcomes
In the largest report of real-world axicabtagene ciloleucel (axi-cel) outcomes among patients with relapsed or refractory follicular lymphoma (R/R FL), including patients who would have been ineligible for the pivotal ZUMA-5 trial, the chimeric antigen receptor (CAR) T-cell therapy showed safety and efficacy results consistent with trial outcomes.1 The findings were presented during a poster discussion session at the 2023 American Society of Clinical Oncology Annual Meeting.
In the pivotal ZUMA-5 trial of axi-cel in R/R FL following at least 2 lines of therapy, the primary analysis found a 94% objective response rate (ORR) and a 79% complete response (CR) rate in patients who were treated with axi-cel.2 Regarding safety, cytokine release syndrome (CRS) grade 3 or higher occurred in 6% of patients, and neurologic events occurred in 15% of patients.
In this new analysis, the patient population is significantly broader than that of the ZUMA-5 trial. Of 230 patients in the real-world study population, 40% would have been excluded from the ZUMA-5 trial, mainly because of comorbidities.
The median patient age was 62 years, and 60% of patients in the study were male. Patients had had a median of 4 lines of therapy prior to receiving axi-cel, 14% had undergone prior autologous stem cell transplantation, and 9% had received bridging therapy. Patients who received previous nontransplant cellular therapy, including prior CAR T-cell therapy, were excluded.
Among 151 patients with follow-up data at a median of 6.2 months, the ORR was 93% (95% CI, 88%-97%) and the CR rate was 84% (95% CI, 77%- 89%). The estimated progression-free survival (PFS) and overall survival (OS) were 88% (95% CI, 81%-92%) and 96% (95% CI, 91%-98%).
“Despite a broader patient population and relatively limited follow-up in the real world, early results demonstrate favorable effectiveness and safety outcomes with axi-cel in patients with relapsed or refractory follicular lymphoma that are consistent with those observed in the pivotal ZUMA-5 trial, supporting postauthorization use of this CAR T-cell therapy in this setting,” said lead study author and presenter Caron A. Jacobson, MD, MMSc, medical director of the Immune Effector Cell Therapy Program at Dana-Farber Cancer Institute and assistant professor of medicine at Harvard Medical School.
CRS considered grade 3 or higher by American Society for Transplantation and Cellular Therapy consensus occurred in 2% of patients (95% CI, 0%-6%), and immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 13% of patients (95% CI, 8%-19%). The median cumulative incidence estimates of CRS and ICAN resolution were 5 days and 4 days, respectively. Among 150 patients who were alive at day 30, prolonged cytopenia occurred in 11%.
Notably, PFS and OS at 6 months posttreatment were similar regardless of patient eligibility by ZUMA-5 trial criteria. However, those who would have been eligible for ZUMA-5 showed lower rates of grade 3 or higher ICANS and quicker ICANS resolution.
1. Jacobsen CA, Hemmer MT, Hu ZH, et al. Real-world early outcomes of axicabtagene ciloleucel for relapsed or refractory (R/R) follicular lymphoma (FL). J Clin Oncol. 2023;41(suppl 16):7509. doi:10.1200/JCO.2023.41.16_suppl.7509
2. Jacobsen CA, Chavez JC, Sehgal AR, et al. Axicabtagene ciloleucel in relapsed or refractory indolent non-Hodgkin lymphoma (ZUMA-5): a single-arm, multicentre, phase 2 trial. Lancet Oncol. 2022;23(1):91-103. doi:10.1016/S1470-2045(21)00591-X
SPOTLIGHT: ZUMA-7 Findings Show Earlier Is Better for Axi-Cel Use in R/R LBCL, Jason Westin, MD, MS, Says
Jason Westin, MD, MS director of the Lymphoma Clinical Research Program at The University of Texas MD Anderson Cancer Center in Houston, shared insights with Evidence-Based Oncology (EBO) into overall survival findings1 from the ZUMA-7 trial (NCT03391466) of axicabtagene ciloleucel (axi-cel) in relapsed or refractory large B-cell lymphoma (LBCL) and the implications in the broader LBCL landscape. Full findings were presented during the American Society of Clinical Oncology (ASCO) 2023 Annual Meeting.
EBO: Can you discuss the significance of the overall survival outcomes among patients treated with axi-cel vs the standard of care in ZUMA-7?
Westin: Axi-cel is a CAR [chimeric antigen receptor] T cell targeting CD19, and it has approvals in the third line and now in the second line for patients with large B cell lymphoma. In the ZUMA-7 clinical trial, we showed a significant improvement in event-free survival, and at the ASCO 2023 meeting we [presented results of] an improvement in overall survival. This is the first time that, in the curative intent setting in second line, there has been improvement in overall survival for nearly 30 years. So we’re pretty excited about that finding.
EBO: Can you describe response and complete response rates among patients who received axi-cel compared with standard-of-care therapy?
Westin: In the ZUMA-7 clinical trial, complete response rates were significantly higher in the axi-cel arm versus the standard-of-care arm—nearly double the difference. In the axi-cel arm, [more than] 60% of patients had a complete response vs chemotherapy, which was [approximately] 30%.1 That’s important because, for patients who are on the standard-of-care arm, chemotherapy usually leads to high dose therapy and autologous transplant if they respond to treatments. On the axi-cel arm, 94% of patients received what we call definitive therapy, which was CAR T cell. On the standard-of-care arm, it was only 36%. [There was a] nearly 3-fold difference in [the number of] patients who could receive the intended curative therapy between these arms on the ZUMA-7 trial.1
EBO: What implications do these findings have in the broader LBCL treatment landscape?
Westin: The axi-cel arm on the ZUMA-7 clinical trial showed that more patients live longer if they receive axi-cel as a second-line treatment.1 The debate in the lymphoma world for 3 decades has been [over] an establishment of standard of care chemotherapy followed by [autologous stem cell] transplant. Over the past few years there has been a debate of whether second-line CAR T-cell [therapy] is the preferred approach, or should you try chemo in second line and if it doesn’t work, then use CAR T-cell [therapy] as a backup?
In our trial, we showed definitively that CAR T-cell [therapy] in the second line is the preferred approach, because on the standard of care on ZUMA-7, more than half of the patients did not respond to chemo and went on to get a subsequent cellular immunotherapy—57% did that and still had a significant improvement in overall survival.1 So effectively, saving CAR T-cell [therapy] for later is an inferior approach, and axi-cel should be a second-line treatment option.
Westin J, Oluwole OO, Kersten MJ, et al. Primary overall survival analysis of the phase 3 randomized ZUMA7 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
Earlier Use of CAR T Cells Holds Promise in Blood Cancers, but Access Remains an Issue
A symposium at the 2023 American Society of Clinical Oncology Annual Meeting 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 A. 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, Jacobson 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.
Jacobson 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, 2, or 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, director of the Lymphoma Clinical Research Program at the University of 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; 1-sided P = .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 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 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, she 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 long time line 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.”
1. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl 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 ZUMA7 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
Looking Ahead at CAR T-Cell Therapy for R/R Acute Lymphoblastic Leukemia
Less than a decade ago, the big news in treating relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL) was the accelerated approval for the bispecific T-cell engager blinatumomab (Blincyto; Amgen), which has since received full approval to treat both adult and pediatric patients with R/R B-cell ALL or those with minimal residual disease at baseline after remission.1
Since that time, approvals in chimeric antigen receptor (CAR) T-cell therapy have revolutionized treatment of B-cell ALL. First came tisagenlecleucel, or tisa-cel (Kymriah; Novartis) for pediatric and young adult patients,2 followed by brexucabtagene autoleucel, or brexu-cel (Tecartus; Kite) for adults.3 But after brexu-cel reached the market, questions remained: What about patients with comorbidities or central nervous system (CNS) lesions, who had been excluded from clinical trials? Could more be done to limit toxicity?
And can the basic strategy of CAR T-cell therapy—collecting healthy T-cells and engineering them to fight cancer—be reconfigured for the 25% of adult ALL patients who have T cell–driven disease?4
Three abstracts examining these questions led the June 2 oral abstract session on Leukemia, Myelodysplastic Syndromes, and Allotransplant at the 2023 American Society of Clinical Oncology Annual Meeting. A discussant, Rawan Faramand, MD, from H. Lee Moffitt Cancer and Research Institute, highlighted the challenges of deciding where stem cell transplant and other therapies fit into the treatment sequence with the arrival of CAR T-cell therapy, and how the ability to measure minimal residual disease (MRD) has been a “game changer,” but raised its own questions.
Split dosing with obe-cel in FELIX. Claire Roddie, PhD, FRCPath, MBChB, MRCP, associate professor at University College London, presented topline results for the pivotal FELIX study (NCT04404660) examining obecabtagene autocleucel (obe-cel) in adult R/R B-cell ALL.5 Obe-cel is an autologous CD19 CAR that Roddie said employs “fast on, fast off” binding domain, which is designed to limit immunotoxicity and improve persistence. The therapy is being studied in adult and pediatric patients in FELIX, a multicenter, global, single-arm, phase 1b/2 study involving patients with morphologic disease, meaning that blasts constitute 5% of the bone marrow.
Roddie presented results for adult patients; 112 were enrolled and 94 were infused. Primary end point was overall remission rate (ORR), which was the proportion of patients achieving a complete remission (CR) or complete remission with incomplete count recovery (CRi), as assessed centrally. Secondary end points were duration of response (DOR), event-free survival, overall survival, MRD-negativity rate, and safety.
Roddie described how FELIX uses a split-dosing strategy, in which patients received doses on day 1 and day 10; the dosing schedule is based on the percentage of bone marrow blasts prior to preconditioning for CAR T-cell treatment, a strategy designed to limit toxicity. As she explained, patients have the first dose and then “can proceed with the day 10 dose, provided they haven’t had dose-limiting immunotoxicity in that intervening period.”
For the day 1 dose, she said, if patients have less than 20% of bone marrow blasts prior to preconditioning, they have a flat dose of 100 million CAR T cells. “But if you have more than 20% blasts, you’ll receive a flat dose of 10 million in CAR T cells.
“Now, you can go on to receive the second dose to take you up to the total dose of 410 million CAR T cells,” Roddie continued. “And it’s important to note that 94% of the patients on this study received both obe-cel infusions.”
Patient characteristics included the following:
Results included the following:
“What’s more, those responses were deep responses—97% of our responders were 10-4 by flow symmetry,” Roddie said, noting that 61% of responders were in ongoing remission without additional therapies for 9.5 months.
Overall, incidence of cytokine release syndrome (CRS) was largely grade 1-2; 75.5% of patients had CRS, with 3.2% having CRS of grade 3 or higher. More patients with bone marrow blasts above 20% had CRS. Patients with bone marrow blasts above 20% were also more likely to develop immune effector cell–associated neurotoxicity syndrome (ICANS) and develop cases grade 3 or higher. ICANS affected 25.5% of patients, including 7.4% with grade 3 or higher. There was 1 death on study attributed to obe-cel, from hemophagocytic lymphohistiocytosis and neutropenic sepsis.
Roddie pointed to a graph that highlighted the high initial expansion of the CAR as well as “durable persistence up to and beyond 3 years in a proportion of patients.”
“This is a safe product to give to those older comorbid patients,” she said. “I think we really need to acknowledge the manufacturing. Despite the adverse conditions for the manufacturer, the circulating disease…the manufacturing process was very robust.”
Obi-cel is being developed by Autolus Therapeutics.
Real-world results for brexu-cel. Greg Roloff, MD, senior hematology/oncology fellow at the University of Chicago, presented the first results on behalf of ROCCA (Real World Outcomes Collaborative of CAR T-cell Therapy in Adult ALL), which was created in 2022 after brexu-cel reached the market.6
“Despite the fact that most individuals respond well to up-front therapy, relapse rates approach 50% in some series,” Roloff said. “And some expected survival falls precipitously with subsequent relapse episodes.”
Allogeneic transplant works for some, but most patients do not proceed to this step. “Newer agents like blinatumomab or inotuzumab have proven critically important. But responses for some patients [with] these agents are not incredibly long-lasting. Therefore, the development of newer therapies capable of producing durable remissions is an important objective in our field,” he said.
Enter ZUMA-3 (NCT02614066),7 which showed that brexu-cel, a CD19-directed autologous CAR T-cell therapy with a CD28 costimulatory domain, showed a 71% CR/CRi in the first assessment of patients with B-cell ALL, with 58% relapse-free survival at 6 months. Following FDA approval in October 2021, Roloff said, “Within the first year of use, there was interest brewing among the cell therapy doctors to get a sense of how this product was performing on the ground.”
Starting with 13 centers, the ROCCA effort began using a HIPAA-complaint database to build a comprehensive data set on R/R B-cell ALL. Data collection began in October 2022, a year after brexu-cel approval, he said. At the time of ROCCA’s submission to ASCO, the cohort covered 76 patients who had received brexu-cel. Among key patient characteristics were the following:
Roloff presented the toxicity data first, showing that 17% had no CRS, while 62% had some CRS, most of it low grade. Five patients (6.6%) had grade 3-4 CRS.
“Neurotoxicity was more of a mixed bag,” he said, noting that 30 patients had no ICANS, but 28 patients (38%) had severe (grade 3 or 4) ICANS and 17 patients (22%) had low-grade ICANS.
For responses, 70 patients reached a day 28 evaluation; some had clinically deteriorated and did not have an assessment. Of the 70, 64 (91%), had a CR or CRi, and 80% of these were MRD-negative remissions. Of the 10 patients (11%) with CNS, 80% saw clearance of leukemia from their CNS, including 7 of 8 with category 3 disease.
At 6 months post-infusion, results were as follows:
An analysis to identify predictors of achieving MRD-negative CRD did not yield factors of significance except that younger patients fared better than those older than 60 years, Roloff said. In time, it is expected that more data will yield more meaningful results. The ROCCA effort has now grown to more than 30 centers, he said. “I’m excited to see what we do with the data next.”
Adding TKI to CD5 CAR T in T-ALL. LaQuisa Hill, MD, assistant professor in hematology/oncology at the Center for Gene Therapy, Baylor College of Medicine, offered a 2-part solution to overcome the challenges of CAR T-cell therapy in T-cell ALL.
Unlike the advances in treatment for B-cell ALL, Hill said, “development of autologous CAR T-cell platforms for T-cell driven malignancies has lagged behind, and that is due primarily to 3 major challenges.” She listed them:
fratricide, or self-targeting of the CAR T cells given shared antigen expression “resulting in impaired expansion and efficacy”; targeting or normal T cells, causing T cell ablation and immunodeficiency “that is not easily corrected” as in B-cell driven cancer; and risk of transduction of malignant T cells, which could create a mechanism of immune evasion.
As Hill explained, CD5 is highly expressed in 85% to 95% of T cell–driven ALL, and earlier research showed that CD5 CAR T cells expanded “with minimal fratricide” due to the loss of CD5 expression on the cell surface. Thus, the MAGENTA trial (NCT03081910) opened to evaluate patients receiving a single infusion of CD5 CAR T-cells at 1 of 3 dose levels.8 Initial enrollment was 33 patients—24 adults and 9 pediatric patients. For this group, 27 lines of therapy were manufactured; 3 were not released. Fourteen patients were treated: 8 adults, and 6 pediatric patients.
Hill first reviewed characteristics from 8 patients in cohort 1, who ranged in age from 11 to 51 years and had received a median of 5 prior lines of therapy. Although the safety profile was encouraging, the responses were not: 2 patients had low-grade CRS, 1 had ICANS, and 1 had a grade 3 infection. But only 1 patient had CR with MRD-positive, which lasted 6 weeks; the rest had stable or progressive disease.
“At the time of progression or disease reevaluation, none of the patients had demonstrated loss of CD5 on the surface of the malignant blast,” Hill explained. Investigators examined the final cell products and saw that the CD5 CAR T cells “were undergoing chronic CAR signaling, which resulted in progressive depletion of both naïve T cells and central memory T cells during the manufacturing process,” which would harm both T cell function and anti-tumor activity.
Thus came the shift to using TKI inhibitors during expansion, which would block T-cell activation by inhibiting certain T-cell receptor kinases. The team used ibrutinib and dasatinib during expansion. “We were able to see a significant improvement in the number of naïve T cells when compared with the control CD5 CARs,” which had been made without the TKIs, Hill explained. “We noted an impressive improvement in the expansion of the CAR T cells.”
With a modified protocol, TKI use was added to the manufacturing process on the next cohort of patients. Hill presented data from patient samples, explaining, “When we manufactured the CAR T cells in the presence of TKIs, we saw significant increases in the naïve T-cell repertoire, as well as had CAR T cells that had a nonexhausted phenotype.
In addition, the team studied patients who received donor-derived T-cells manufactured with TKI for patients who had failed a prior transplant. “What we saw was that healthy donor T cells from the prior donors were significantly more enriched, more naïve to the cytotoxic T cells.”
One pediatric patient who did not respond in cohort 1 reenrolled; thus, 7 patients in cohort 2 were treated with TKI-manufactured products (4 with autologous CD5 CAR T cells, 3 with donor-derived T cells) and there were 4 total responders who achieved MRD-negative remission—2 in each group. “Overall, there were no big differences between the groups,” Hill said. Two patients later proceeded to allotransplant.
Surprisingly, there was no increase in CRS or ICANS, but Hill cautioned 2 patients had elevated Epstein-Barr virus (EBV)-related posttransplant lymphoproliferative disease (PTLD), including 1 patient who had a reaction many months later. “More data and monitoring will be needed to determine the true relationship of the EBV reactivation in PTLD as it is related to the CAR T cells,” Hill said.
“Much Ado About CAR T in ALL.” Faramand said the title of her talk highlighted how far the field has come since the blinatumomab approval in 2014.1 “Is obecabtagene the next therapy to be approved?” she asked.
Faramand, listed as second author on the ROCCA abstract, traced approvals from blinatumomab through brexu-cel, noting that efficacy end points have steadily improved, as has management of CRS and ICANS. With obe-cel, there is another leap in toxicity management, she said, along with “excellent expansion and persistence.”
These successes raise questions. “Does persistence of these CAR T cells inform durability of response?” she asked. What is the role of consolidated allogeneic stem cell transplant?
“As we have a growing number of CAR T-cell survivors, what about late toxicities, such as cytokines and/or infections?” She noted these can be related to higher doses of lymphodepleting drugs.
Faramand asked whether trials are enrolling enough minority patients, noting that Hispanic patients are more likely to develop ALL, as seen in the ROCCA group study.
The real-world data produced by ROCCA also raises questions. Among them: Is including patients with CNS the reason ICANS rates are higher? What about the lack of uniformity in MRD testing?
“We know that MRD testing has been a game changer for ALL,” she said. “What is the optimal way to measure MRD and monitor these patients?”
Data from Hill’s study on the use of TKI with CAR T-cell therapy for T-cell driven ALL will need to mature to fully understand durability of responses and long-term complications, Faramand said. Nonetheless, “I’m encouraged by this data and look forward to further studies looking at CAR T-cell therapies in this population.”
1. FDA grants full approval for Blincyto (blinatumomab) to treat minimal residual disease-positive B-cell precursor acute lymphoblastic leukemia. News release. Amgen. June 21, 2023. Accessed June 26, 2023. https://prn.to/46pqZvh
2. FDA approves tisagenlecleucel in B-cell ALL and tocilizumab for cytokine release syndrome. News release. FDA. September 7, 2017. Accessed June 26, 2023. https://bit.ly/3XsYitb
3. FDA approves brexucabtagene autoleucel in relapsed or refractory B-cell acute lymphoblastic leukemia. News release. FDA. October 1, 2021. Accessed June 26, 2023. https://bit.ly/3mciuB1
4. Haseltine WA. CAR T-cell like therapy to treat T-cell leukemia (T-ALL). Forbes. February 13, 2023. Accessed June 26, 2023. https://bit.ly/440NHrY
5. Roddie C, Sandhu KS, Tholouli E, et al. Safety and efficacy of obecabtagene autoleucel (obe-cel, AUTO1), a fast-off rate CD19 CAR, in relapsed/refractory adult B-cell acute lymphoblastic leukemia (r/r B-ALL): top line results of the pivotal FELIX study. J Clin Oncol. 2023;41(suppl 16):abstr 7000. doi:10.1200/JCO.2023.41.16_suppl.7000
6. Roloff G, Faramand R, Aldoss I, et al. Outcomes following brexucabtagene autoleucel administered as an FDA-approved therapy for adults with relapsed/refractory B-ALL. J Clin Oncol. 2023;41(suppl 16):abstr 7001. doi:10.1200/JCO.2023.41.16_suppl.7001
7. Shah BD, Ghobadi A, Oluwole OO, et al. KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study. Lancet. 2021;398(10299):491-502. doi:10.1016/S0140-6736(21)01222-8
8. Hill LC, Rouce RH, Smith TS, et al. Enhanced anti-tumor activity of CD5 CAR T cells manufactured with tyrosine kinase inhibitors in patients with relapsed/refractory T-ALL. J Clin Oncol. 2023;41(suppl 16):abstr 7002. doi:10.1200/JCO.2023.41.16_suppl.7002
Study Explores Real-World BTK Inhibitor Use Patterns in Mantle Cell Lymphoma
A real-world analysis of patients with mantle cell lymphoma (MCL) treated with Bruton tyrosine kinase (BTK) inhibitors at community oncology practices in the United States suggests treatment duration and adherence was higher among patients receiving zanubrutinib compared with acalabrutinib or ibrutinib.
Zanubrutinib (Brukinsa, BeiGene), and acalabrutinib, (Calquence, AstraZeneca) are second-generation BTK inhibitors, while ibrutinib (Imbruvica, Janssen) is a first-generation BTK inhibitor.
The findings were published in an issue supplement in the Journal of Clinical Oncology, a publication of the American Society of Clinical Oncology (ASCO), featuring abstracts from the ASCO Annual Meeting. The study was conducted to provide insight into real-world BTK inhibitor treatment patterns in MCL, as current data are limited.
The retrospective, observational study included a total of 402 patients with MCL treated with BTK inhibitors according to electronic medical record (EMR) data from 18 community oncology practices. EMR data included medical history and at least 6 months of follow-up, with index date defined by the use of any of the 3 BTK inhibitors included in the study. EMR and claims data through the end of follow-up were used to calculate treatment duration.
Among the overall population, 44 patients were treated with zanubrutinib, 161 acalabrutinib, and 197 ibrutinib. The median (range) patient age was 75 (56-89) years in the zanubrutinib group, 76 (36-89) years in the acalabrutinib group, and 72 (36-89) years in the ibrutinib group. Aside from age, the 3 groups were similar in terms of baseline characteristics.
The researchers found that half of the patients in the zanubrutinib group had received other BTK inhibitors in previous lines of therapy. Further, 31.8% switched to zanubrutinib from other BTK inhibitors within 60 days of treatment initiation. Among those treated with acalabrutinib, 29% were treated with other BTK inhibitors in prior lines of therapy.
Mean follow-up periods were 493 days in the zanubrutinib group, 701 days in the acalabrutinib group, and 746 days in the ibrutinib group. The authors noted that the zanubrutinib group’s shorter follow-up time was due to a later approval date vs the other therapies.
Despite a shorter follow-up period, patients who received zanubrutinib had longer median treatment duration than both the acalabrutinib and ibrutinib groups (292 days, 259 days, and 149 days, respectively; P < .01).
“Real-world EMR data from US community-based oncology practices suggested significantly longer treatment duration and adherence in MCL patients treated with zanubrutinib compared with acalabrutinib or ibrutinib,” the authors concluded. “Further analyses on long-term utilization are needed upon data maturation.”
The study was sponsored by BeiGene, the maker of zanubrutinib.
Shah BD, Xue M, Yang K, Liu S, Tang B. Real-world treatment patterns of Bruton tyrosine kinase inhibitors (BTKi) in patients with mantle cell lymphoma (MCL) in community oncology practices in the United States (US). J Clin Oncol. 2023;41(suppl 16):e19525. doi:10.1200/JCO.2023.41.16_suppl.e19525