Liso-cel updates from TRANSCEND-CLL-004 and TRANCEND-NHL-001 trials

Lisocabtagene maraleucel (liso-cel), is an investigational, CD19-directed, defined composition, 4-1BB chimeric antigen receptor (CAR) T-cell product administered at equal doses of CD8⁺ and CD4⁺ CAR T cells, and it is currently under evaluation in several subtypes of relapsed or refractory (R/R) lymphoma.

TRANSCEND-CLL-004 (NCT03331198) is a phase I/II trial investigating the safety and efficacy of liso-cel as monotherapy or in combination with ibrutinib in patients with R/R chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Initial phase I results of the combination cohort were presented by William Wierda during the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition.¹

TRANSCEND-NHL-001 (NCT02631044) is a phase I seamless design study evaluating the safety and efficacy of liso-cel in B-cell non-Hodgkin lymphoma. During ASH 2020, Maria Lia Palomba presented the initial results from the R/R mantle cell lymphoma (MCL) cohort receiving liso-cel.² Liso-cel has been recently approved by the U.S. Food and Drug Administration (FDA) for the treatment of adults with R/R diffuse large B-cell lymphoma (DLBCL), Grade 3B follicular lymphoma (FL), or primary mediastinal large B-cell lymphoma (PMBCL), based on favorable results from TRANSCEND-NHL-001. European Medicines Agency approval is currently being sought.

Here, we are pleased to summarize these two talks.

Update from the TRANSCEND-CLL-004 trial¹

In this study, patients with R/R CLL/SLL received lymphodepleting chemotherapy followed by liso-cel infusion. Results from the phase I combination cohort (outlined in red in Figure 1) were presented. The results of the phase I monotherapy arm (n = 23) were previously summarized here.

CAR, chimeric antigen receptor; Cy, cyclophosphamide; DL, dose level; Flu, fludarabine; liso-cel, lisocabtagene maraleucel.

The phase I combination cohort included patients:

• With R/R CLL/SLL who progressed on ibrutinib at the time of enrolment; or
• With high-risk features and received ibrutinib for ≥ 6 months but achieved less than a complete response (CR); or
• With ibrutinib-resistant mutations including BTK or PLCɣ2 mutations; or
• Who had prior ibrutinib exposure without contraindications to reinitiating ibrutinib

Patients continued or restarted ibrutinib up to a target dose of 420 mg at enrolment, for up to 90 days following liso-cel infusion, or longer in case of clinical benefit. Bridging therapy was allowed.

Primary objectives were safety and determination of recommended dose for the dose expansion part of the study. Dose-limiting toxicities (DLTs) were evaluated in the first 28 days after liso-cel infusion.

Results

Table 1 provides baseline characteristics among dose levels. Most patients (95%) had high-risk disease, were heavily pretreated, and were all R/R to ibrutinib.

Table 1. Patient characteristics¹

BTKi, Bruton tyrosine kinase inhibitor; DL, dose level; R/R, relapsed or refractory; Ven, venetoclax.
Characteristic	Combination cohort (DL1/DL2 + ibrutinib; N = 19)	DL1 + ibrutinib (n = 4)	DL2 + ibrutinib (n = 15)
Median age, years (range)	61 (50–77)	58 (50–70)	61 (51–77)
Median time since diagnosis, months (range)	121 (21–252)	84 (31–176)	127 (21–252)
Bulky disease ≥ 5 cm, n (%)	6 (32)	0 (0)	6 (40)
Received bridging therapy, n (%)	8 (42)	2 (50)	6 (40)
Stage, n (%)               Rai stage III/IV               Binet stage C	9 (47) 9 (47)	2 (50) 2 (50)	7 (47) 7 (47)
High-risk feature (any), n (%)               Del(17p)               TP53 mutated               Complex karyotype	18 (95) 8 (42) 6 (32) 8 (42)	4 (100) 2 (50) 1 (25) 3 (75)	14 (93) 6 (40) 5 (33) 5 (33)
Median prior lines, n (range)               Prior ibrutinib, n (%)               Ibrutinib R/R, n (%)               Prior BTKi and Ven, n (%)	4.0 (1–10) 19 (100) 19 (100) 11 (58)	4.5 (1–5) 4 (100) 4 (100) 2 (50)	3.0 (2–10) 15 (100) 15 (100) 9 (60)

Safety

Liso-cel plus ibrutinib combination was well tolerated with no DLTs observed.

• Any grade cytokine release syndrome (CRS) occurred in 14 patients (74%) with a median time to onset of 6.5 days (range, 1–13) and a median duration of 6 days (range, 3–13)
• Any grade neurological events (NEs) occurred in 6 patients (32%) with a median time to onset of 8 days (range, 5–12) and a median duration of 6.5 days (range, 1–8)
• Tocilizumab and/or corticosteroids were used to manage these events
• No Grade 4 CRS or NEs were reported

Table 2 summarizes Grade ≥ 3 adverse events (AEs) at both dose levels. No Grade 5 AEs were reported. Dose reductions or treatment discontinuation due to ibrutinib-related treatment-emergent AEs (TEAEs) were uncommon.

Table 2. Safety outcomes¹

AE, adverse events; CRS, cytokine release syndrome; DL, dose level; NE, neurological event; TEAE, treatment-emergent AE. *Included anemia (n = 4), neutropenia (n = 4), atrial fibrillation, hypertension, lung infection, staphylococcal infection, and thrombocytopenia (n = 1 each).
AE, n (%)	Combination cohort (DL1/DL2 + ibrutinib; N = 19)	DL1 + ibrutinib (n = 4)	DL2 + ibrutinib (n = 15)
Grade 3/4 TEAEs               Neutropenia               Anemia               Febrile neutropenia	18 (95) 17 (89) 9 (47) 5 (26)	4 (100) 3 (75) 3 (75) 1 (25)	14 (93) 14 (93) 6 (40) 4 (27)
Grade 3 CRS	1 (5)	1 (25)	0 (0)
Grade 3 NEs	3 (16)	0 (0)	3 (20)
Grade 3/4 ibrutinib-related TEAEs*	7 (37)	2 (50)	5 (33)
Ibrutinib dose reduction due to TEAE	2 (11)	0 (0)	2 (13)
Ibrutinib discontinuation due to TEAE	4 (21)	1 (25)	3 (20)

Response

Best overall response and rates of undetectable minimal residual disease (uMRD; sensitivity of ≤ 10^–4) are shown in Figure 2.

A Best overall response; B uMRD at any time point.
CI, confidence interval; CR, complete response; CRi, CR with incomplete hematologic recovery; DL, dose level; PR, partial response; uMRD, undetectable minimal residual disease (≤ 10^-4).

Most patients remained in remission at 10-month follow-up. Patients who responded achieved an early response by Day 30 after liso-cel infusion.

The two liso-cel dose levels did not affect CAR⁺ T-cell expansion differently, while median peak CAR⁺ T-cell expansion occurred by Day 11 in the combination cohort.

Conclusion

In summary, these initial findings suggest a favorable tolerability with low rates of Grade 3 CRS or NEs. This heavily pretreated patient cohort with R/R CLL/SLL achieved rapid and high response rates and uMRD when liso-cel was combined with ibrutinib. The safety profile was similar among dose levels, and DL2 (100 × 10⁶ CAR⁺ T cells) was identified as the recommended dose for the expansion cohort. Further evaluation of the combination of liso-cel and ibrutinib is currently ongoing.

Update from the TRANSCEND-NHL-001 trial²

The TRANSCEND-NHL-001 trial included two patient cohorts: (i) large B-cell lymphoma (LBCL), and (ii) MCL. In the LBCL cohort, 269 patients received liso-cel; study design and patient characteristics can be found here. This update focuses on the dose finding and expansion parts of the MCL cohort, where the safety and initial antitumor activity of liso-cel was assessed.

The MCL cohort included patients with MCL who had received ≥ 2 lines of therapy, and who had previous exposure to BTK inhibitors, alkylating agents, and an anti-CD20 agent. Prior stem cell transplantation and secondary central nervous system lymphoma were allowed. The primary endpoints included AEs, DLTs, and overall response rate (ORR).

A total of 32 patients (Table 3) treated with liso-cel in two dose levels (DLs) following a 3-day lymphodepletion (30 mg/m² fludarabine and 300 mg/m² cyclophosphamide for 3 days):

• DL1: 50 × 10⁶ CAR⁺ T cells (n = 6)
• DL2: 100 × 10⁶ CAR⁺ T cells (n = 26)

Table 3. Patient characteristics²

ECOG PS, Eastern Cooperative Oncology Group Performance Status; BTKi, Bruton tyrosine kinase inhibitor; CNS, central nervous system; HSCT, hematopoietic stem cell transplantation; MCL, mantle cell lymphoma.
Characteristic	MCL cohort (N = 32)
Age               Median, years (range)               ≥ 65 years, n (%)	67 (36–80) 21 (66)
ECOG PS, n (%)               0               1	16 (50) 16 (50)
Blastoid morphology, n (%)	13 (41)
Ki67 ≥ 30%, n (%)	23 (72)
TP53 mutations, n (%)	7 (22)
Secondary CNS lymphoma, n (%)	1 (3)
Bridging therapy, n (%)	17 (53)
Prior therapies
Median number (range)               ≥ 3 therapies, n (%)	3 (1–7) 22 (69)
HSCT, n (%)	11 (34)
BTKi, n (%)               Prior ibrutinib               Refractory to ibrutinib	28 (88) 24 (75) 10 (31)
Venetoclax, n (%)               Refractory to venetoclax	8 (25) 5 (16)

Safety

All patients treated with liso-cel experienced at least one TEAE of any grade, and 84% experienced Grade ≥ 3 TEAEs (Table 4). Two patients who received DL2 experienced Grade 5 TEAEs which were considered related to liso-cel (n = 1, tumor lysis syndrome; n = 1, cryptococcal meningoencephalitis leading to death). Two DLTs were recorded, both at DL2, and included tumor lysis syndrome, and neutropenia/thrombocytopenia.

Table 4. Grade ≥ 3 AEs²

AE, adverse event; CRS, cytokine release syndrome; NE, neurological event; TEAE, treatment-emergent AE; TLS, tumor lysis syndrome. *Neutropenia, anemia, or thrombocytopenia not resolved on Day 29.
Grade ≥ 3 AEs, n (%)	N = 32
TEAEs               Neutropenia               Anemia               Thrombocytopenia	27 (84) 14 (44) 12 (38) 10 (31)
CRS               Median time to onset, days (range)               Median time to resolution, days (range)	1 (3) 6 (2–10) 4 (2–9)
NEs               Median time to onset, days (range)               Median time to resolution, days (range)	4 (12.5) 8 (2–25) 4 (1–27)
Prolonged cytopenia*	11 (34)
Infections               Bacterial               Viral               Fungal               Unspecified	5 (16) 2 (6) 1 (3) 1 (3) 1 (3)
TLS	1 (3)

Response rates

Median on-study follow-up was 5.9 months (range, 0.4–24.8), and median time to first CR or PR was 0.95 months (range, 0.9–2.0). Figure 3 presents best overall responses in all patients and those with high-risk features.

A Best overall response in all patients (N = 31); B Response rates in patients with high-risk features.
CI, confidence interval; CR, complete response; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease.

Median duration of response was not reached at a median follow-up of 3.9 months. Six patients had durable responses over 1 year, and responses were mostly similar in patients with blastoid morphology and those resistant to ibrutinib.

The median time of maximal liso-cel expansion was achieved 10 days following infusion. Long-term liso-cel persistence at 1 year and 2 years was recorded in 67% and 33% of patients, respectively.

Conclusion

These findings indicate promising results in terms of safety and clinical activity of liso-cel in patients with R/R MCL. The rate of Grade ≥ 3 TEAEs was low, with Grade ≥ 3 CRS and NE rates at 3% and 12.5%, respectively. Response rates were encouraging, with an ORR of 84%, CR of 66%, and median duration of response was not reached. Enrolment in the MCL cohort is ongoing with DL2.

Related: The FDA recently granted approval to brexucabtagene autoleucel for the treatment of R/R MCL.