Lisocabtagene maraleucel effective as second-line therapy for R/R large B-cell lymphoma in patients not intended for transplantation
The phase II PILOT study evaluated lisocabtagene maraleucel (liso-cel), an autologous, CD19-directed chimeric antigen receptor T-cell product, as second-line treatment in patients with relapsed or refractory large B-cell lymphoma not intended for haematopoietic stem cell transplantation. In this population of frail patients, liso-cel demonstrated substantial and durable overall and complete responses, with no new safety concerns.
After failure of chemo-immunotherapy as first-line treatment of large B-cell lymphoma (LBCL), approximately half of patients are considered suitable for potentially curative high-dose chemotherapy (HDCT) and haematopoietic stem cell transplantation (HSCT). For patients not intended for HDCT/HSCT, there is no effective established standard of care (SOC), and outcomes are historically poor. Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed chimeric antigen receptor (CAR) T-cell product that has recently demonstrated superiority over SOC as second-line therapy in patients intended for transplant in the phase III TRANSFORM study. The objective of the open-label, phase II PILOT study was to evaluate the efficacy and safety of liso-cel in patients with relapsed or refractory (R/R) LBCL after one prior line of therapy, not intended for HSCT owing to age or comorbidities.
Study design
Eligible patients were adults with R/R LBCL after first-line treatment who were not deemed candidates for HDCT and HSCT by investigator and met ≥ 1 of the following frailty criteria: age ≥ 70 years, Eastern Cooperative Oncology Group performance status (ECOG PS) of 2, diffusing capacity for carbon monoxide ≤ 60%, left ventricular ejection fraction < 50%, creatinine clearance < 60 mL/min, or alanine aminotransferase/aspartate aminotransferase > 2 × the upper limit of normal (ULN). Bridging therapy was allowed. Patients received lymphodepletion with cyclophosphamide and fludarabine, followed 2–7 days later by liso-cel infusion at a target dose of 100 × 106 CAR-T cells. The primary endpoint was objective response rate (ORR) per independent review committee (IRC). All patients had ≥ 6 months of follow-up from first response.
Results
Of the 74 patients who underwent leukapheresis, 62 received liso-cel. The main reasons for not receiving CAR-T cells were death or no longer meeting the eligibility criteria. Among the 62 treated patients, one patient received a nonconforming product and was excluded from the safety and efficacy analysis set. For liso-cel–treated patients, median age was 74 years (79% ≥ 70 years), 52% received bridging therapy, 61% had an LDH above the ULN, 54% had refractory disease and 21% relapsed within 12 months.
The primary endpoint of ORR was 80% in the efficacy analysis set, with a complete response (CR) rate of 54%. Responses were durable, with a median duration of response of 21.65 months in patients with CR and 12.09 months in patients with complete or partial response. CR rates were similar across multiple subgroups. The median progression-free survival (PFS) was 9.03 months and the median event-free survival (EFS) was 7.23 months. Among patients who achieved CR, both the median PFS and median EFS increased to 22.60 months. Median overall survival has not been reached.
The most common grade ≥3 treatment-emergent adverse events (TEAEs) were neutropenia (48%), leukopenia (21%) and thrombocytopenia (20%). Cytokine release syndrome (CRS) of any grade occurred in 23 patients (38%), of which only one was of grade 3. Of the 16 patients who received tocilizumab for CRS, 15 received only one tocilizumab dose. There was no prophylactic use of corticosteroids and none of the patients needed vasopressors. Any grade neurologic events occurred in 31% of patients, of which 5% were of grade 3. No grade 4 or 5 CRS or neurotoxicity occurred. Grade ≥3 prolonged cytopenias occurred in 18 patients (30%) and grade ≥3 infections were reported in 4 patients (7%), with 2 COVID-19-related deaths. There were no reports of second primary malignancies, macrophage activation syndrome or tumour lysis syndrome in the treatment-emergent period (< 90 days after liso-cel infusion).
Conclusion
Liso-cel as second-line treatment in patients with R/R LBCL for whom HSCT was not intended demonstrated high response rates, with durable responses in patients who achieved a CR. Responses were observed across all pre-specified subgroups. Despite the age and comorbidities of the population, there were no new safety signals. Incidences of grade 3 CRS and neurological events were low, with no grade 4 or 5 events. These results support liso-cel as a second-line treatment in patients with LBCL in whom HSCT is not intended and complement the results of the TRANSFORM study in patients with R/R LBCL intended for HSCT, demonstrating the efficacy and safety of liso-cel across a broad population of patients with R/R LBCL.
Reference
Sehgal A, et al. Lisocabtagene maraleucel (liso-cel) as second-line therapy for R/R large B-cell lymphoma (LBCL) in patients not intended for HSCT: primary analysis from the phase 2 PILOT study. Presented at EHA 2022, Abstract S258.
