Rapid Readouts: Phase 1 Cohort of TRANSCEND-CLL-004 Study

William G. Wierda, MD, discusses data from the following presentation:

• TRANSCEND-CLL-004 phase 1 cohort of lisocabtagene maraleucel combined with ibrutinib for patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic leukemia (R/R CLL/SLL). (Wierda EG, et al. iwCLL 2021; September 17-20, 2021)
  • Recent studies in patients with R/R CLL suggest that CD19-directed CAR (chimeric antigen receptor) T-cell therapy combined with ibrutinib improves response rates with CTL119 and JCAR014 (Gill SI, et al. Blood. 2018;132:298; Gauthier J, et al. Blood. 2020;135:1650-60). This study reports initial safety and preliminary efficacy from the phase 1 lisocabtagene-maraleucel and ibrutinib combination cohort of the ongoing phase 1/2 TRANSCEND-CLL-004 study (NCT03331198) in patients with R/R CLL/SLL.
  • Eligible patients with CLL/SLL met ≥1 of the following: 1) received ibrutinib and progressed at time of study enrollment; 2) had high-risk features and received ibrutinib for ≥6 months with less than a complete response (CR); 3) had a Bruton tyrosine kinase (BTK) or PLCγ2 gene mutation, with or without progression on ibrutinib; 4) had received prior ibrutinib with no contraindication to reinitiating ibrutinib.
  • Primary end points were safety and to determine the recommended dose of lisocabtagene-maraleucel in combination with ibrutinib for R/R CLL/SLL; overall response rate (CR + CR with incomplete blood count recovery [CRi] + partial response (PR) and pharmacokinetics were exploratory end points.
  • Efficacy results:
    • At data cutoff, 23 patients received lisocabtagene-maraleucel (DL1, n = 4; DL2, n = 19) with ibrutinib. Median age was 61 (range, 50-77) years, and 22 patients (96%) had high-risk cytogenetics (del[17p], n = 9; TP53 mutation, n = 8; complex karyotype, n = 10).
    • Patients had a median of 4 (range, 1-10) prior therapies. All patients were R/R to prior ibrutinib; 12 patients (53%) had prior BTK inhibitor and venetoclax therapy.
    • Patients received lisocabtagene-maraleucel infusion at 50 × 106 (dose level [DL]1) or 100 × 106 (DL2) CAR + T cells.
    • 21 patients (95%) responded to therapy, including 13 (59%) who achieved CR/CRi and 8 (36%) who achieved PR
    • Deepening of response was observed in 4 patients who initially had a PR and improved to a CR at a later assessment.
    • No patients had PD during the first month after lisocabtagene-maraleucel
    • All responders (n = 21/22) achieved a response by Day 30 after lisocabtagene-maraleucel.
    • Among 18 patients with ≥6 months of follow-up, 83.3% (n = 15/18) maintained or improved response from Day 30.
    • Median progression-free survival was not reached (NR) (95% CI, 12.62—NR).
    • Median duration of response was NR (95% CI, NR—NR).
  • Safety results:
    • The combination of lisocabtagene-maraleucel and ibrutinib was well tolerated, with no reported dose-limiting toxicities.
    • No grade 5 adverse events or grade 4 or 5 cytokine release syndrome or neurological events were reported.
    • Grade 3/4 ibrutinib-related treatment-emergent adverse events included neutropenia/neutrophil count decrease (n = 6), anemia (n = 4), thrombocytopenia (n = 2), atrial fibrillation (n = 1), hypertension (n = 1), lung infection (n = 1), and staphylococcal infection (n = 1).
  • No clear difference in safety was observed between dose levels, and DL2 was selected as the recommended dose expansion of lisocabtagene-maraleucel and ibrutinib in patients with R/R CLL/SLL. Heavily pretreated, refractory patients with R/R CLL/SLL had rapid, high overall response rates and achieved undetectable minimal residual disease with lisocabtagene-maraleucel and ibrutinib treatment. Because of encouraging preliminary results, we continue to evaluate the impact of lisocabtagene-maraleucel combined with ibrutinib on efficacy and safety in this actively enrolling clinical trial.