ASCO studies reveal ‘unprecedented’ benefit with CAR-T as earlier treatment
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Now that chimeric antigen receptor T-cell therapy has become part of the treatment landscape in hematologic malignancies, researchers are focused on developing more potent, less toxic agents that can be used in earlier treatment settings.
Several studies presented at ASCO Annual Meeting highlighted tremendous progress in this quest for certain groups of patients with blood cancers, including those with large B-cell lymphoma or multiple myeloma.
Healio provides an overview of the most impactful cell therapy research presented at ASCO, with insights from investigators and third-party perspective from other experts.
Safer option
Seventy-six percent of adults with relapsed or refractory B-cell acute lymphoblastic leukemia achieved complete response to treatment with obecabtagene autoleucel (AUTO1; Autolus Therapeutics), interim results of the pivotal phase 2 FELIX trial showed.
Individuals treated with the investigational CAR T-cell therapy exhibited low levels of cytokine release syndrome and neurotoxicity.
“The results were really heartening to us,” Claire Roddie, PhD, FRCPath, MBChB, MRCP, associate professor in hematology-oncology at University College London, said during a presentation. “There were deep, durable responses in this study cohort.”
Obecabtagene autoleucel — often called obe-cel — is a unique autologous CD19 CAR “with a fast off-rate CD19-binding domain,” Roddie said. “It was designed that way to mitigate for the safety and persistence concerns we had with other CD19 CAR T cells.”
Obe-cel previously had been evaluated in a phase 1 study of adults and younger individuals with B-cell ALL. The FDA granted regenerative medicine advanced therapy designation to obe-cel in May 2022 for treatment of adults with relapsed or refractory B-cell ALL.
The multicenter phase 2 FELIX trial enrolled 112 patients, 94 (median age, 50 years; range, 20-81; 50% women) of whom received treatment with obe-cel. The study population included 25 patients (26.6%) with Philadelphia chromosome-positive disease. Twenty-nine patients (30.9%) had received at least three previous lines of therapy.
Investigators reported a 75.6% (95% CI, 66-84) overall response rate, including 54.3% with complete response and 21.3% with complete response with incomplete blood count recovery (CRi).
Sixty-one percent of responders remained in remission as of data cutoff without use of additional anticancer therapy. Ninety-seven percent of patients achieved minimal residual disease (MRD)-negative status as determined by flow cytometry.
Researchers reported a median response duration of 14.1 months (95% CI, 5.9 to not estimable).
Seventy-one patients (75.5%) experienced treatment-related CRS. Three (3.2%) experienced grade 3 or higher symptoms.
Additional safety results revealed that 24 patients (25.5%) developed immune effector cell-associated neurotoxicity syndrome (ICANS). Six of the seven patients who experienced grade 3 or higher ICANS had bone marrow blast levels greater than 20% during an evaluation prior to preconditioning lymphodepletion.
The results should be viewed within the context of treating a high-risk population, Roddie said.
“Despite all of these odds being stacked against the product, obe-cel was able to achieve CR or CRi in 76% of infused patients,” she said. “Those responses were deep, MRD-negative responses, and I think we also need to acknowledge that this is a safe product to give to those older, comorbid patients, with very low levels of grade 3 CRS or ICANS.”
Interim results from the FELIX study are encouraging and suggest that obe-cel may be safer than commercially available CD19-directed CAR-T, according to Lee Greenberger, PhD, chief scientific officer of The Leukemia & Lymphoma Society.
“However, a head-to-head analysis is necessary to confirm this finding because this reduction in CRS and ICANS events could be associated with better overall care or even patient selection,” he told Healio in an exclusive perspective.
The efficacy results for obe-cel appear similar to FDA-approved therapies, Greenberger said.
“Overall, these findings represent a promising development with some questions left to be answered,” he said. “I am intrigued to see what the PFS and OS data are when available in the coming years.”
‘Superior treatment strategy’
Second-line therapy with axicabtagene ciloleucel (Yescarta, Kite Pharma/Gilead Sciences) significantly extended OS compared with standard care among adults with relapsed or refractory large B-cell lymphoma, results of the randomized phase 3 ZUMA-7 study showed.
Treatment with the CAR T-cell therapy reduced the risk for death by 27.4% compared with standard care, according to updated findings presented at ASCO and published simultaneously in The New England Journal of Medicine.
“This definitively establishes axi-cel as a superior treatment strategy among those who do not respond to first-line chemotherapy,” Jason Westin, MD, MS, director of lymphoma clinical research and section chief for aggressive lymphoma at The University of Texas MD Anderson Cancer Center, told Healio. “Axi-cel as a second-line treatment should be a standard approach.”
Axicabtagene ciloleucel — often called axi-cel — is an autologous, gene-edited, CD19-directed CAR-T.
FDA approved axi-cel last year as initial treatment for relapsed or refractory large B-cell lymphoma based on data from the ZUMA-7 trial.
ZUMA-7 examined the safety and efficacy of axi-cel vs. standard of care among 359 adults with relapsed or refractory large B-cell lymphoma treated at 77 centers worldwide.
Standard of care consisted of a platinum-based salvage combination chemoimmunotherapy regimen followed by high-dose therapy and autologous hematopoietic stem cell transplantation for those who responded to chemoimmunotherapy.
Investigators randomly assigned patients 1:1 to preconditioning chemotherapy plus a single infusion of axi-cel (n = 180) or standard therapy (n = 179).
ZUMA-7 investigators previously reported interim OS data at the time of the primary EFS analysis. At ASCO, researchers presented data from a prespecified primary OS analysis to be conducted after 210 deaths or no later than 5 years after random assignment of the first patient in the trial.
A primary analysis showed significantly longer median OS among patients treated with axi-cel than standard therapy (31 months vs. not yet reached; HR = 0.72; 95% CI, 0.54-0.97).
More than half (57%) of patients treated in the standard therapy group received subsequent off-protocol treatment with cellular immunotherapy, Westin said.
Investigators reported superior median PFS among those treated with axi-cel than standard therapy (14.7 months vs. 3.7 months; HR = 0.51; 95% CI, 0.38-0.67). They also noted a significantly higher estimated 4-year PFS rate in the axi-cel group (41.8% vs. 24.4%).
Treatment-related toxicities appeared consistent with those previously reported in the ZUMA-7 trial, Westin said.
CRS occurred among 92% of patients in the axi-cel group, with 6% of events being grade 3 or higher. Meanwhile, 80% of those in the standard care group developed cytopenia, with 75% being grade 3 or higher.
The results thus far show axi-cel to be superior second-line therapy for large B-cell lymphoma across all subgroups in the trial, Westin said.
“The results signal the need for a paradigm shift,” he added. “Based on these data, the paradigm should no longer be a [chemotherapy]/transplant strategy but instead a CAR-T.”
The previous template resulted in curative treatments for only approximately 10% of those who went on to receive HSCT as second-line therapy, Westin said.
Based on the current second-line indication for axi-cel, the new approach should be dictated by the time to relapse from initial therapy, Westin said. If that time is less than 1 year, he advised clinicians to pursue CAR-T, provided their patient is eligible.
“This will increase the number of people who go on to receive definitive therapy, while also improving overall survival,” Westin told Healio.
“Extremely encouraging PFS data showing a plateau in the survival curve among the axi-cel arm of ZUMA-7 has led to a change in clinical practice,” Saad Z. Usmani, MD, MBA, FACP, chief of the myeloma service at Memorial Sloan Kettering Cancer Center and Healio | HemOnc Today Editorial Board Member, told Healio in an exclusive perspective.
The emerging trend in the field is to offer CAR-T in lieu of an autologous HSCT, he added.
“As a result of this OS data readout, few doubts should remain about the role of CAR-T in this setting,” Usmani said. “These results augment the clinical practice changes that many transplant and cellular therapy centers have adapted for patients with lymphoma.”
‘Unprecedented’ benefit
Ciltacabtagene autoleucel (Carvykti; Janssen, Legend Biotech) significantly extended PFS compared with standard therapy for adults with relapsed and lenalidomide-refractory multiple myeloma, results of the randomized phase 3 CARTITUDE-4 study showed.
A single dose of the CAR T-cell therapy — often called cilta-cel — reduced risk for disease progression or death by 74% compared with either of two standard-of-care regimens, according to data presented at ASCO and published simultaneously in The New England Journal of Medicine.
“Median overall survival in this patient population is poor, at approximately 9 months,” Binod Dhakal, MD, MS, associate professor of medicine in the division of hematology at Medical College of Wisconsin, told Healio. “Cilta-cel provides benefit lasting almost 3 years, which is unprecedented in this setting.”
Cilta-cel is a B-cell maturation antigen-directed CAR T-cell therapy.
The FDA approved the agent last year for treatment of patients with relapsed or refractory multiple myeloma who received four or more previous lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody.
Lenalidomide is used extensively as early-line therapy for multiple myeloma in the United States. However, most patients become refractory to treatment.
“This represents a patient population with a clear unmet need commonly seen in clinical practice,” Dhakal said. “The CARTITUDE-1 study [conferred] a median PFS of approximately 3 years in heavily pretreated patients with multiple myeloma, so we aimed to test cilta-cel in earlier lines against effective standard-of-care treatments.”
CARTITUDE-4 evaluated the safety and efficacy of cilta-cel vs. one of two standard-of-care regimens — pomalidomide, bortezomib and dexamethasone, or daratumumab (Darzalex, Janssen), pomalidomide and dexamethasone — for 419 adults with relapsed or lenalidomide-refractory multiple myeloma who received one to three previous lines of therapy.
Investigators randomly assigned 208 study participants (median age, 61.5 years; range, 27-78; 55.8% men; 75.5% white) to preconditioning lymphodepletion followed by an infusion of cilta-cel at a target dose of 0.75 × 106 CAR T cells/kg. The other 211 participants (median age, 61 years; range, 35-80; 58.8% men; 74.4% white) received physician’s choice of standard regimens.
CARTITUDE-4 met its primary endpoint, showing significantly longer PFS in the cilta-cel group (median, not reached vs. 11.8 months; HR = 0.26; 95% CI, 0.18-0.38). Investigators reported 12-month PFS rates of 75.9% (95% CI, 69.4 to 81.1) in the cilta-cel group and 48.6% (95% CI, 41.5 to 55.3) in the standard care group.
Researchers also reported a higher overall response rate (84.6% vs. 67.3%), higher complete response rate (73.1% vs. 21.8%) and longer median duration of response (not reached vs. 16.6 months) in the cilta-cel group.
A slightly higher percentage of patients assigned cilta-cel developed grade 3 or grade 4 neutropenia (89.9% vs. 82.2%).
Three-quarters (76.1%) of patients assigned cilta-cel developed CRS, with 1.1% experiencing grade 3/grade 4 CRS events. Investigators reported no grade 5 CRS events.
Eight study participants (4.5%) experienced grade 1 or grade 2 ICANS.
Cilta-cel provided “uniform benefits” across patient subgroups, Dhakal said.
The CAR-T outperformed standard-care regimens among study participants with high-risk disease or soft plasma tumors, and regardless of the line of therapy in which it was received, he added.
“We continue to see deep and durable efficacy responses with cilta-cel that have significantly delayed disease progression, and with a manageable safety profile,” Dhakal told Healio. “Cilta-cel has the potential to be a new standard of care for patients with lenalidomide-refractory myeloma after first relapse.”
Clinicians interested in offering patients cilta-cel as an earlier line of therapy must consider the required manufacturing period, according to Samer Al Hadidi, MD, MS, FACP, assistant professor of medicine at University of Arkansas for Medical Sciences, associate member of the myeloma center at Winthrop P. Rockefeller Cancer Institute and Healio | Cell Therapy Next Peer Perspective Board Member.
Despite the potential of the agent to provide substantial benefits, many patients with aggressive disease may not survive a long turnaround time, he added.
“With excitement building about the potential benefit of earlier use of CAR-T in multiple myeloma — as evidenced by improved responses and PFS in this clinical trial — we need to ensure equitable access to such therapies and improve manufacturing capabilities to better match the expected incremental demand,” Al Hadidi told Healio | “Efforts need to be focused on providing these therapies for patients in most need.”
References:
- San-Miguel J, et al. N Engl J Med. 2023;doi:10.1056/NEJMoa2303379.
- Westin J, et al. N Engl J Med. 2023;doi:10.1056/NEJMoa2301665.
- Dhakal B, et al. Abstract LBA106. Presented at: ASCO Annual Meeting; June 2-6, 2023; Chicago.
- Roddie C, et al. Abstract 7000. Presented at: ASCO Annual Meeting; June 2-6, 2023; Chicago.
- Westin J, et al. Abstract LBA107. Presented at: ASCO Annual Meeting; June 2-6, 2023; Chicago.
For more information:
Samer Al Hadidi, MD, MS, FACP, can be reached at salhadidi@uams.edu.
Binod Dhakal, MD, MS, can be reached at bdhakal@mcw.edu.
Lee Greenberger, PhD, can be reached at lee.greenberger@lls.org.
Claire Roddie, PhD, FRCPath, MBChB, MRCP, can be reached at c.roddie@ucl.ac.uk.
Saad Z. Usmani, MD, MBA, FACP, can be reached at usmanis@mskcc.org.
Jason Westin, MD, MS, can be reached at jwestin@mdanderson.org.
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