TARMAC trial: Time-limited ibrutinib plus CAR T-cell therapy for the treatment of R/R MCL

Patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) experience high response rates with CD19-directed chimeric antigen receptor (CAR) T cells; however, there is a risk of relapse and often considerable toxicity.

Here, we summarize the outcomes of the phase II TARMAC (NCT04234061) trial, published by Minson et al.¹ in Blood, of the combination of time-limited ibrutinib and CTL019 CAR T-cells in patients with relapsed/refractory mantle cell lymphoma (MCL).

Study methods¹

• This ongoing phase II study included patients with R/R MCL after ≥1 prior line of therapy.
• Ibrutinib was started at least 7 days before leukapheresis and continued through CAR T-cell production for at least 6 months after CAR T-cell administration.
• The primary endpoint was complete response (CR) rate at Month 4 after CAR T-cell infusion.
• Secondary endpoints included safety, overall response rate, measurable residual disease (MRD) negativity at Months 1, 4, 6, 9, and 12, progression-free survival (PFS), and overall survival; responses were also analyzed based on TP53 mutation status.

Key findings¹

• Overall, 20 patients were included in the study:
  • 75% were male;
  • the median age was 66 years;
  • The median time from study enrollment to CAR T-cell infusion and CAR T-cell manufacture was 60 days and 49 days, respectively; and
  • 50% of patients had prior Bruton’s tyrosine kinase inhibitor (BTKi) exposure and 45% were BTKi refractory, with 15% receiving >1 BTKi.
• After infusion, the 4-month endpoint of CR rate was high, with a similar overall response rate, and an MRD-negativity rate of 70% (Figure 1).

CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.
*Adapted from Minson, et al.^1
†14 patients were MRD negative by flow cytometry.

• At the median follow-up of 13 months, median PFS was not reached; however, the estimated 12-month PFS and overall survival were 75% and 100%, respectively.
• Deep and durable responses were seen in high-risk subgroups, including in patients with prior BTKi exposure or TP53 mutation.
  • Deep responses were associated with robust CAR T-cell expansion and a less exhausted baseline T-cell phenotype.
• All patients reported an adverse event of any grade:
  • 15 patients developed CRS (Grade 1–2, n = 12; Grade 3, n = 3).

Two patients developed reversible Grade 1–2 neurotoxicity.

Key learnings

The combination of CAR T cells and time-limited ibrutinib demonstrated high CR and molecular MRD negativity rates in patients with R/R MCL, irrespective of prior BTKi exposure and TP53 mutation status. A less exhausted baseline T-cell phenotype led to robust CAR T-cell expansion, which led to positive responses. Further study is needed to guide strategies that will improve the safety and efficacy of BTKi and CAR T-cell combination treatment efficacy in this patient population.