Results presented Saturday at the annual meeting of the American Society of Hematology show significant benefits in event-free survival, progression-free survival, and complete response over standard of care.
This article has been updated.
The anti-CD therapy lisocabtagene maraleucel (liso-cel) offered significant benefits over standard of care when given to patients whose large B-cell lymphoma (LBCL) returned or failed to respond (R/R) to the first treatment after 12 months, according to interim findings of the randomized phase 3 TRANSFORM study.1
“This is a breakthrough therapy which has shown superiority over standard of care in terms of efficacy with an extremely favorable safety profile,” said Manali Kamdar, MD, of the University of Colorado, who presented the TRANSFORM results Saturday during the 63rd Annual American Society of Hematology Meeting and Exposition in Atlanta. “We are excited about the potential of this study to change the existing standard of care in these high-risk patients.”
All signs point to liso-cel and another chimeric antigen receptor (CAR) T-cell therapy, axicabtagene cilocleucel (axi-cel), becoming the new standard of care for second-line treatment of patients with LBCL, given the results for liso-cel and those for the phase 3 ZUMA-7 trial, which were highlighted in a press conference and will be formally presented in Sunday’s plenary session.
Press briefing moderator Laurie Sehn, MD, a hematologist-oncologist at the British Columbia Cancer Centre for Lymphoid Cancer at the University of British Columbia, called both sets of results “remarkable,” and said they would be welcomed by clinicians who feel limited by the current standard of care.
“I think it's inevitable that this will become the standard of care,” she said.
Liso-cel, sold as Breyzani by Bristol Myers Squibb, was approved earlier this year for adults who have failed on 2 prior treatments for LBCL based on results of the TRANSCEND-NHL study.2 Investigators have reported that its manufacturing process, which results in an equal balance of CD8+ and CD4+ CAR T-cells, makes the product more consistent and less toxic for patients than the first CAR T-cell therapies approved for R/R LBCL.
Use of CAR T-cell therapy earlier in a patient’s course of care is a major theme of this year’s ASH meeting. Kamdar’s press briefing just ahead of her presentation outlined how liso-cel offered significantly improved measures of survival over salvage chemotherapy followed by autologous stem cell transplant—with less toxicity than seen with axi-cel, which was approved back in 2017.
In TRANSFORM, 184 patients were randomized to receive liso-cel or standard of care (SOC). Patients ranged in age from 20 to 75; the median age of the SOC arm was 58, while the median age of the liso-cel arm was 60. Two-thirds of the SOC arm was male; the liso-cel arm was 52% female. Patients were well-matched by type of non-Hodgkin lymphoma; no racial or ethnic breakdown was reported.
Median event-free survival (EFS), the study’s primary end point, was 2.3 months for SOC vs 10.1 months for liso-cel, for a risk reduction of 65% (HR, 0.349; P <.0001). Secondary end points all favored liso-cel:
“Despite a relatively short follow-up period of just over 6 months, the positive results of this study suggest that CAR T-cell therapy has the potential to become the new standard of care for patients who do not respond to initial chemotherapy or who relapse within 12 months,” Kamdar said.
She pointed out that the in the patients in the study were very high risk; under current standard of care, many do not make it to stem cell transplant—by contrast, in second-line most did get to liso-cel infusion. This is in contrast to the situation when patients are at later stages of treatment—a major challenge is that patients may be too ill to wait for the CAR T-cell manufacturing process to be complete.
“Of the patients were randomized to standard of care, only 46% were able to proceed to transplantation,” Kamdar said. “On the other hand…97% of patients are able to successfully receive liso-cel infusion.”
Adverse events. From a safety standpoint, liso-cel was comparable to SOC, and some patients were able to receive the CAR T-cell therapy in an outpatient setting. Although the well-known effects associated with CAR T-cell therapy of cytokine release syndrome (CRS) and neurological toxicity were seen, there were no grade 4 or 5 neurological events. No deaths were attributable to liso-cel treatment.
Investigators reported no new liso-cel safety signals when giving the treatment in the second-line setting. Roughly half (49%) of those receiving liso-cel had some level of CRS, with 37% reporting grade 1 and 11% grade 2; 1 patient reported grade 3 effects that started on day 9 after treatment and resolved in 2 days. Patients were treated with tocilizumab (24%) and corticosteroids (17%). The most common treatment-emergent AEs were cytopenias, which were reported in 43% of patients.
Findings are logical. “For somebody who has to treat patients with large B cell lymphoma like I do, it's incredibly frustrating when patients [have] failed frontline therapy,” she said. For patients in TRANSFORM and ZUMA-7, who are especially high risk—Sehn called them “the worst of the worst”—the current approach calls for doubling down with higher doses of chemotherapy. Patients continue to fail, she said.
So, “it's not surprising that coming in with a novel approach and a cellular therapy that has proven curative capacity [in the] third line setting, you may have outperformed coming in with more chemotherapy,” Sehn said.
The word that comes to mind, she said, is that the findings are “logical.”
1. Kamdar M, Solomon SR, Arnason JE, et al. Lisocabtagene maraleucel, a CD19-directed chimeric antigen reception T cell therapy, versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma: results from the randomized phase 3 transform study. Presented at: 63rd ASH Annual Meeting; December 11, 2021; Atlanta, GA. Accessed December 11, 2021. https://bit.ly/30KxmfW
2. Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020;396(10254):839-852. doi:10.1016/S0140-6736(20)31366-0