Lisocabtagene maraleucel active, safe, ‘worth considering’ in outpatient setting for lymphoma subset
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ORLANDO — Nearly three-quarters of a cohort of patients with relapsed or refractory large B-cell lymphoma responded to treatment with lisocabtagene maraleucel, according to results of the phase 1 multicenter TRANSCEND-NHL-001 trial presented at TCT | Transplantation & Cellular Therapy Meetings.
In addition, more than half of patients who received the investigational chimeric antigen receptor T-cell therapy had a complete response to treatment.
Lisocabtagene maraleucel (JCAR017, Bristol-Myers Squibb), often referred to as liso-cel, is an autologous anti-CD19 CAR T-cell therapy. As Healio previously reported, the FDA granted the agent priority review last month for treatment of adults with relapsed or refractory large B-cell lymphoma.
“TRANSCEND-NHL-001 is the largest clinical study to date using CD19-directed CAR T cells in patients with relapsed or refractory large B-cell lymphoma,” researcher Matthew A. Lunning, DO, assistant professor of internal medicine in the division of oncology and hematology at University of Nebraska Medical Center, said during a presentation.
“Treatment with lisocabtagene maraleucel resulted in rapid, highly durable complete response rates with the absence of severe [cytokine release syndrome] and neurological events [among] patients with advanced, high-risk and aggressive large B-cell lymphoma. It produced clinically meaningful activity ... [and it is] worth considering the use of liso-cel in the outpatient setting,” Lunning added.
In the study, 269 patients (median age 63 years; range, 18-86) received lisocabtagene maraleucel after lymphodepletion chemotherapy with fludarabine and cyclophosphamide. Patients had received a median three (range, 1-8) previous therapies, with 35% having undergone previous hematopoietic stem cell transplantation. Patients in the dose-confirmation stage of the study (n = 126) received 100 × 106 CAR T cells.
Treatment-emergent adverse events and overall response rate as determined by an independent review committee served as the study’s primary endpoints. Secondary endpoints included complete response rate as assessed by an independent review committee, duration of response, PFS, OS and pharmacokinetics.
Median follow-up was 12 months (95% CI, 11.2-16.7).
Results showed an overall response rate of 73% (95% CI, 67-78) among 256 patients evaluable for efficacy. The complete response rate was 53% (95% CI, 47-59), with more than half of patients remaining in response at 6 months (60.4%) and 12 months (54.7%).
Researchers reported PFS rates of 51.4% (95% CI, 44.6-57.7) at 6 months and 44.1% (37.3-50.7) at 12 months, and OS rates of 74.7% (95% CI, 68.9-79.6) at 6 months and 57.9% (95% CI, 51.3-63.8) at 12 months. Median OS was 21.1 months (95% CI, 13.3 to not reached).
Nearly all patients (99%) experienced treatment-related adverse events, the most common of which were neutropenia (any grade, 63%; grade 3 or higher, 60%), anemia (any grade, 48%; grade 3 or higher, 38%) and fatigue (any grade, 44%; grade 3 or higher, 1%). Seven patients experienced grade 5 adverse events, including four events linked to liso-cel.
Researchers observed no incidence of grade 5 cytokine release syndrome or neurotoxicity. Forty-two percent of patients developed cytokine release syndrome (CRS), but only 2% (n = 6) experienced grade 3 or grade 4 cases.
Thirty percent of patients experienced some level of neurotoxicity, with 10% being grade 3 or grade 4. – by Drew Amorosi
Reference:
Abramson JS, et al. Abstract LBA4. Presented at: TCT | Transplantation & Cellular Therapy Meetings; Feb. 19-23, 2020; Orlando.Disclosures: Lunning reports research funding from ADC Therapeutics, Celgene, Curis, Janssen Scientific, Juno Therapeutics, miRagen Therapeutics and TG Therapeutics, and consultant roles with AbbVie, Bayer, Celgene, DAVA Oncology, Gilead Sciences, Juno Therapeutics, Kite, Novartis and OncLive. Please see the abstract for all other researchers’ relevant financial disclosures.
Perspective
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Dennis Cooper, MD
The results of the TRANSCEND-NHL-001 trial suggest that liso-cel is poised to become the next CAR T-cell product approved for the treatment of refractory diffuse large B-cell lymphoma. Beyond the excellent efficacy — which seems to be similar to that of the two FDA-approved products, tisagenlecleucel (Kymriah, Novartis) and axicabtagene ciloleucel (Yescarta; Kite, Gilead) — the most outstanding finding is the very low frequency of severe CRS and neurotoxicity. This appears to be a game-changing development for converting CAR T-cell therapy primarily to an outpatient setting.
Although it is difficult to compare toxicity across different evaluation scales and intervention algorithms, it is notable that less than half of the patients in this study had even grade 1 CRS (fever), whereas grade 3 CRS was rare. In addition, there was infrequent use of tocilizumab (Actemra, Genentech) and/or dexamethasone, indicating the low incidence of grade 3 CRS was not due to earlier use of tocilizumab or steroids — a strategy being employed far more frequently as information suggests these treatments do not impair the CAR T cells.
The low toxicity appears to be at least partly due to the use of the 4-1BB costimulatory molecule — a feature shared by tisagenlecleucel but with an unknown but possibly important contribution of the equal proportion of CD4 and CD8 cells in the liso-cel product.
In contrast to the potential outpatient use of liso-cel, there are no studies in which axicabtagene ciloleucel has been used in the outpatient setting, and the average duration of hospitalization is 12 to 14 days.
Tisagenlecleucel can be started in the outpatient setting, and approximately 75% of patients will experience their first fever 3 days or later after administration, a key time period for Medicare reimbursement. However, more than half of patients who receive tisagenlecleucel will experience CRS; 10% to 20% will experience grade 3 CRS, and the average duration of hospitalization for patients treated with tisagenlecleucel is unclear. Thus, liso-cel may have the potential to substantially lower the costs of therapy by reducing the duration of hospitalization, as well as by decreasing the need to treat severe CRS. Accordingly, the approval of liso-cel is eagerly awaited.
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