Lisocabtagene maraleucel as a second-line treatment | Interim results of phase II PILOT trial

The ongoing, open-label phase II PILOT trial (NCT03483103) is the first study to assess the efficacy and safety of lisocabtagene maraleucel (liso-cel), as a second-line treatment option in patients with relapsed/refractory (R/R) aggressive large B-cell non-Hodgkin lymphoma (NHL) following the first-line immunotherapy, who are not eligible for high-dose chemotherapy and hematopoietic stem cell transplant (HSCT) because of their age, performance status or comorbidities¹. There is an unmet need for an established standard of care in the treatment of this patient population who have a poor prognosis. Liso-cel, is a 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 interim results of this phase II trial were published by Alison R. Sehgal, University of Pittsburgh Medical Center, US, and colleagues, and presented during the 2020 American Society of Clinical Oncology (ASCO) Virtual Meeting².

Preliminary data of this trial were presented during the 61st American Society of Hematology (ASH) Annual Meeting & Exposition.

Study design²

The ongoing PILOT study is investigating the safety, antitumor activity, and pharmacokinetics of liso-cel in transplant noneligible (TNE) patients with R/R large B-cell lymphoma (LBCL). Key eligibility criteria include:

• Large B-cell NHL:

• • Diffuse LBCL (not otherwise specified, de novo or transformed from indolent NHL)
  • High-grade B-cell lymphoma (MYC and/or BCL2 and/or BCL6 rearrangements with diffuse LBCL histology)
  • Follicular lymphoma Grade 3B

• One line of prior therapy containing an anthracycline and anti-CD20 agent
• TNE status by meeting one or more of the following: age ≥ 70 years, Eastern Cooperative Oncology Group (ECOG) Performance Status 2, impaired pulmonary, cardiac, renal or hepatic function

Endpoints

Primary endpoint: Objective response rate

Secondary endpoints: Adverse events, complete response rate, duration of response, pharmacokinetic profile, estimated progression-free survival, event-free survival, overall survival, laboratory abnormalities, and health-related quality of life

Methods

• Follow-up duration during the study is 24 months and patients will be followed up to 15 years after the last liso-cel therapy
• Lymphodepletion chemotherapy with fludarabine 30 mg/m² and cyclophosphamide 300 mg/m² for 3 days
• Bridging therapy was allowed
• Liso-cel intravenous dose of 100 × 10⁶ CAR+ T cells, 2–7 days following lymphodepletion chemotherapy

Patient characteristics

• From a total of 41 patients leukapheresed, 29 patients received liso-cel treatment by the cutoff date
  • Seven patients were waiting for lymphodepleting chemotherapy, two patients died, two patients no longer met the eligibility criteria, and one patient received a non-conforming product
• Efficacy population: n = 27
• Safety population: n = 29

Baseline characteristics are presented in Table 1. The median age was 72 years (range 53–85), and the vast majority of patients were 65 years and older (86%). Being aged 70 years and above was the most common reason for ineligibility for transplantation (76%), followed by an ECOG PS of 2 (31%) and creatinine clearance < 60 mL/min (28%). A high proportion of patients (79%) had adverse prognostic features. 59% of patients were treated in an inpatient setting and 41% treated as outpatients.

Table 1. Patient characteristics²

ABC, activated B-cell; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; FL3B, follicular lymphoma Grade 3B; GCB, germinal center B-cell; HCT-CI, Hematopoietic Cell Transplantation-specific Comorbidity Index; LDH, lactate dehydrogenase; NHL, non-Hodgkin lymphoma; NOS, not otherwise specified; SPD, sum of the product of perpendicular diameters; TNE, transplant noneligible
Characteristic, n (%)	Patients receiving liso-cel (n = 29)
Male sex	18 (62)
B-cell NHL subtypes DLBCL NOS Transformed FL High-grade B-cell lymphoma FL3B	14 (48) 5 (17) 9 (31) 1 (3)
LDH ≥ 500 U/L	4 (14)
SPD ≥ 50 cm2, n = 27	10 (37)
HCT-CI score, median (range), n = 27	3 (0-9)
Prognostic factors Double-/triple-hit lymphoma Refractory Relapsed within < 1 year ≥ 1 prognostic factor ≥ 1 TNE criteria and ≥ 1 prognostic factor	9 (31) 15 (52) 6 (21) 23 (79) 23 (79)
Cell of origin ABC, non-GCB GCB Unknown/unreported	7 (24) 10 (34.5) 12 (41)

Efficacy²

The objective response rate was 89% (95% confidence interval [CI], 71–98) at a median follow-up of 5 months, and 15 responses were ongoing as of the cutoff date. An objective response was achieved in all patients with ≥ partial response within 30 days of treatment. The complete response rate was 56%, and the partial response rate was 33%. Three patients had disease progression and were treated with pembrolizumab (n = 2) and rituximab plus chemotherapy (n = 1). The probability of durable response at 3 months and 6 months was estimated to be 63% (95% CI, 37–81) and 53% (95% CI, 25–75), respectively.

The median time to peak CAR T-cell levels of liso-cel was Day 11 (Day 11, Day 15).

Safety analysis

The most common treatment-emergent adverse events (TEAEs) were cytopenias. In total, 69% of patients experienced grade 3–4 TEAEs (Table 2). One patient experienced a Grade 5 TEAE of infection on Day 81, which was not considered to be related to the treatment with liso-cel.

Table 2. Grade 3–4 TEAEs in ≥ 15% of patients²

TEAEs, treatment-emergent adverse events *Neutropenia, thrombocytopenia, or anemia not resolved at Day 29
TEAEs, n (%)	Grade 3–4 (N = 29)
Any TEAEs	20 (69)
Neutropenia	10 (34.5)
Leukopenia	6 (21)
Lymphopenia	6 (21)
Thrombocytopenia	5 (17)
Prolonged cytopenia*	8 (28)

Six patients experienced Grade 1–2 cytokine release syndrome (CRS) and no CRS events of Grade 3–5 occurred. Median time to onset of CRS was 5 days (range, 3–12) with a median resolution in 2.5 days (range, 1–4).  Neurological events (NE) occurred in only three patients (Grade 1–2, n = 1; Grade 3, n = 2). Median time to onset of NE was 8 days (range, 7–8) with a median resolution in 4 days (range, 1–5).  Three (10%) patients required tocilizumab and a corticosteroid for CRS, while two patients (7%) required a corticosteroid for NE. The number of death events was 3.

Conclusion

The interim results indicate that second-line treatment with liso-cel in this elderly, high-risk patient population who were ineligible for HSCT was associated with durable responses, including CRs with a high overall response rate. The benefit-risk profile was similar to previously reported in later-line settings.

Liso-cel therapy may be an appropriate second-line treatment option in patients with R/R aggressive large B-cell NHL following first-line immunotherapy who are not eligible for high-dose chemotherapy and transplantation; however, further evaluation and data are warranted.