Liso-cel as a second-line treatment for patients with R/R LBCL not intended for HSCT

Introduction

Only 50% of patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL), in whom first-line treatment did not yield a response, are eligible for high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT). This highlights an unmet need in patients not intended for HSCT, given the historically poor prognosis and limited treatment options in this population.

Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, defined composition, 4-1BB chimeric antigen receptor (CAR) T-cell product administered at equal target doses of CD8+ and CD4+ CAR+ T cells. The Lymphoma Hub has previously reported the phase II TRANSFORM study results, recently published in The Lancet,¹ which demonstrated the superiority of liso-cel over standard of care as second-line therapy for patients with R/R LBCL eligible for HSCT.

During the European Hematology Association (EHA) 2022 Congress, Nilanjan Ghosh presented the complimentary results of the phase II PILOT study evaluating the efficacy and safety of liso-cel in patients with R/R LBCL not intended for HSCT.² Below we summarize the results, which have also recently been published in The Lancet Oncology.³

Study design

This is a multicenter, open-label, phase II study conducted in 18 clinical sites within the US. Eligible patients were:

• ≥18 years of age with R/R LBCL who had experienced disease progression after frontline chemotherapy, consisting of an anthracycline and CD20 targeted agent;
• not deemed eligible for transplant by their treating healthcare professional, based on age and comorbidities; and
• met one or more of the six transplant non-intended criteria as follows: age ≥70 years, Eastern Cooperative Oncology Group Performance Status 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.

Patients received lymphodepletion with cyclophosphamide (300 mg/m²) and fludarabine (30 mg/m²), followed 2–7 days later by liso-cel infusion at a dose of 100 × 10⁶ CAR+ T cells (Figure 1).

*Adapted from Ghosh.¹
CY, cyclophosphamide; FLU, fludarabine; liso-cel, lisocabtagene maraleucel.

The primary endpoint was overall response rate determined by an independent review committee. Secondary endpoints included duration of response (DOR), complete response (CR) assessed by an independent review committee, progression-free survival (PFS), event-free survival (EFS), overall survival, adverse events, and laboratory abnormalities.

Results

Baseline characteristics

In total, 61 patients were treated with Liso-cel (Table 1).

Table 1. Selected baseline characteristics*

CR, complete response; DLBCL, diffuse large B-cell lymphoma; Fl3b, follicular lymphoma Grade 3b; HGBCL, high grade B-cell lymphoma; LBCL, large B cell lymphoma; LDC, lymphodepleting chemotherapy; LDH, lactate dehydrogenase; NOS, not otherwise specified; PD, progressive disease; PR, partial response; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CHP, rituximab, cyclophosphamide, doxorubicin, and prednisone; R-EPOCH, rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin; R-ICE, rituximab, ifosfamide, carboplatin, and etoposide; SD, stable disease; tFL, transformed follicular lymphoma; ULN, upper limit of normal. *Data from Ghosh.1
Characteristic, % (unless otherwise stated)	Liso-cel treated patients (n = 61)
Median age (range), years	74 (53–84)
Pre-LDC LDH
<500/≥500 unit/L	82/18
≤ULN/>ULN	39/61
Histology
DLBCL NOS	54
tFL	15
HGBCL with DLBCL histology	30
FL3b	2
Double or triple hit	33
Bone marrow involvement at baseline	11
Relapsed or refractory
Refractory	54
Relapsed ≤12 months	21
Relapsed >12 months	25
Best response to first-line therapy for LBCL
CR/PR	46/25
SD/PD	8/21
First-line treatment for LBCL
Radiotherapy	11
Systemic treatment	100
R-CHOP	84
R-EPOCH	16
R-ICE, R-CHP, and/or other	13

Efficacy

• Overall response rate was 80% for all responders (partial response + CR) and CR rate was 54% (Figure 2).
• Median DOR for patients achieving CR was 21.7 months, compared with 12.1 months for all responders.
• Median PFS and EFS was 9.0 and 7.2 months, respectively, and both were 22.6 months in patients who achieved CR.
• Median overall survival was not reached.

CR, complete response; ORR, overall response rate.
*Adapted from Ghosh.¹

Safety

The most frequent treatment-emergent adverse events across all grades were neutropenia (51%), fatigue (39%), and cytokine-release syndrome (CRS; 38%). The most common Grade ≥3 treatment-emergent adverse events were neutropenia (48%), leukopenia (21%), and thrombocytopenia (20%; Figure 3).

Overall, CRS incidence was 38% (n = 23) and neurological events (NEs) occurred in 31% of patients (n = 19). There was a low incidence of Grade 3 CRS and NEs (n = 1 and n = 3, respectively) and no Grade 4/5 CRS and NEs were reported. Only one of 16 patients required more than one dose of tocilizumab to manage CRS. There were no treatment-related deaths reported and there was no prophylactic use of corticosteroids and vasopressors.

CRS, cytokine release syndrome.
*Adapted from Ghosh.¹

Conclusion

The results demonstrated the effectiveness of liso-cel as a second-line treatment for patients with R/R LBCL who are not intended for HSCT, with a median DOR of 12.1 months and overall response rate of 80%. These findings complement the TRANSFORM phase II study results, which reported liso-cel was superior to standard of care for those intended for HSCT. Given there were no new safety signals, a low incidence of Grade 3 CRS and NEs, and no Grade 4/5 CRS and NEs, liso-cel could offer a potential new treatment for patients with R/R LBCL not intended for HSCT.