TARMAC trial—a new path for chimeric antigen receptor (CAR) T in relapsed mantle cell lymphoma (MCL)?

Minson et al. present compelling results from the TARMAC trial, a phase II single-arm multicenter study utilizing time-limited ibrutinib to enhance the efficacy and safety profile of CTL019, a CD19-directed chimeric antigen receptor (CAR) T-cell therapy in relapsed mantle cell lymphoma (MCL) (1). By combining ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor, with CTL019, the authors report results of 20 patients who received a median of 2 prior lines of therapy with a four-month post-infusion complete response rate (CRR) of 80%, estimated 12-month progression-free survival (PFS) of 75%, and an undetectable measurable residual disease (uMRD) rate of 70% by flow cytometry measured at the time of investigator-determined CRR at month 4 after CTL019 infusion. They also report a favorable safety profile with a low grade ≥3 cytokine release syndrome (CRS) rate of 20% and no grade ≥3 immune effector cell associated neurotoxicity syndrome (ICANS), providing evidence of a promising approach in relapsed MCL.

Advances in frontline treatment for MCL have improved outcomes; however, relapse is inevitable, requiring multiple lines of treatment (2). Small molecule kinase inhibitors such as BTK inhibitors are currently accepted as the preferred second-line treatment option for MCL. Despite having high response rates with BTKi, all but a few patients will eventually relapse after 24 months of treatment (3). Treatment is until disease progression and a small proportion of patients achieve a complete response (CR). Moreover, in biologically aggressive subtypes such as those with TP53 aberrancy, the median overall survival (OS) is short at 12 months with BTKi. A new category of therapies, such as CAR T-cell, have been revolutionary in lymphoid malignancies. Brexucabtagene autoleucel (Brexu-cel), which is a CD19-directed CAR T-cell with a CD28 costimulatory domain when administered to MCL patients with a median of 5 prior lines of therapy including BTKi, had a CRR of 59% (4). The responses were consistent across high-risk disease features, including the presence of blastoid variant MCL, TP53 mutation, high MCL international prognostic index (MIPI) score, and a Ki-67 index of ≥50. However, 40% of patients will still not have a CR to CAR T-cell therapy with a poor outcome. To improve the efficacy of CAR T-cell therapy, the proportion of exhausted T-cells at apheresis needs to be lower, and the infused T-cells need to persist longer (5).

The TARMAC study builds on the growing evidence suggesting combining BTK inhibitors with CAR T-cell therapy may offer a synergistic effect. Preclinical models demonstrate that ibrutinib can enhance CAR T-cell expansion and persistence, potentially leading to improved anti-tumor activity (6-10). While the overall impact of ibrutinib on T-cell functioning is not fully understood, the combination of ibrutinib and CAR T-cell therapy has increased anti-tumor activity compared to individual therapy, possibly from additive effects of two different treatment modalities. The findings are supported in an observational study of 7 patients who received a second CD19 CAR T-cell therapy with concurrent ibrutinib; 6 patients achieved a CR, and one achieved a partial response with higher peak CAR T-cell levels compared to the first CAR T-cell infusion but with a higher grade CRS and hematological toxicity profile (11). In the ZUMA-2 trial of Brexu-cel, 19 of the 57 BTKi-exposed patients continued BTKi during bridging therapy (4). There was no difference in objective response rates (ORR) compared to BTKi-naive patients, suggesting that BTKi exposure might not improve T-cell fitness during apheresis. However, no patients in the ZUMA-2 trial continued BTKi after receiving CAR T-cell infusion, a critical period where BTKi exposure could potentially improve CAR T-cell persistence and enhance efficacy. Also, limiting the duration of BTKi to six months post CAR T-cell infusion could potentially mitigate certain long-term side effects such as increases in infection rates, cardiovascular comorbidities, and the development of BTKi resistance mutations. To address this gap, the prospective TARMAC trial was designed to investigate the influence of BTKi exposure on the efficacy and safety of CAR T-cell therapy.

With a robust preclinical rationale and preliminary clinical evidence of augmenting CAR T-cell efficacy with BTKi exposure, the TARMAC study planned to study the concurrent combination of ibrutinib and CTL019 with ibrutinib exposure seven days before apheresis, bridging and post-CAR T-cell infusion. Ibrutinib was ceased for those who achieved a CR and without measurable residual disease (MRD) by flow cytometry in peripheral blood (PB) 6 months after infusion. The population enrolled in the study had a median of 2 prior lines of therapy, was biologically a high-risk group, with 71% patients with Ki-67 index >30%, 63% with intermediate or high-risk MIPI score, 45% with TP53 gene aberrancy, and 15% with blastoid variant MCL. In terms of treatment, 65% required treatment for progressive disease within 24 months of initial therapy, of which 50% were refractory to the most recent line of therapy consistent with a therapeutically aggressive variant of MCL. In this high-risk and aggressive population, the CR rate at four months was 80% and 14 of the 16 patients who achieved CR also had uMRD with the cessation of ibrutinib at six months. The remaining two patients with MRD+ continued ibrutinib and remained progression-free at 13 months follow-up. On discontinuing ibrutinib at six months post CAR T-cell therapy, the 12-month estimated PFS and OS rates were numerically higher at 75% and 100% compared to that observed with indefinite treatment with ibrutinib (median PFS of 14.6 months) with a similar number of prior lines of therapy (12). Therefore, with this approach, an adaptive treatment method can be considered where indefinite BTKi exposure in the second line could be limited to 6–9 months with the addition of CAR T-cell therapy. Non-responders or those with MRD+ can continue BTKi indefinitely. Cautious cross trial comparisons show numerically lower rates of CRS (any grade; 75% vs. 91%, grade ≥3; 20% vs. 15%) and ICANS (any grade; 10% vs. 63%, grade ≥3; 0% vs. 22%) with the combination compared to Brexu-cel possibly from different constructs of CAR T-cell therapy (4-1BB for CTL019 and CD28 for Brexu-cel). Ibrutinib’s inhibition of interleukin-2-inducible T-cell kinase (ITK) and other CRS-inducing cytokines may also provide a rationale for lower rates of high-grade CRS with the ibrutinib combination.

One of the hypotheses of the study was ibrutinib improved CAR T-cell persistence. Exploratory analysis in this CAR T-cell cellular kinetics study showed BTKi exposed patients had a delayed time to CAR T-cell level peak but no difference in peak levels compared to BTKi naïve patients. The lower rate of CAR T-cell expansion in this study was also observed in the study by Gauthier et al. and has been attributed to ibrutinib’s effect on ITK (8). However, as described in these studies, the final peak levels of CAR T-cells are unaffected. The peak levels of CAR T-cells correlated with depth of response, and patients with MRD+ or progressors had lower peak CAR T-cell levels, which is consistent with other prior CAR T-cell therapy clinical trials (13). Another hypothesis of the study was ibrutinib improved T-cell subsets at the time of apheresis, improving fitness and overcoming senescence. Analysis of T-cell subsets during apheresis showed patients with shorter exposure to BTKi before apheresis had lower naïve T-cells and higher CD8⁺/HLA-DR^–/PD-1⁺ terminally differentiated effector memory subsets compared to healthy controls, which correlated with a lack of deep response to treatment post-CAR T-cell infusion. Also observed in this study were patients with prior bendamustine exposure who had lower absolute lymphocyte and NK cell count at the time of apheresis despite BTKi exposure and lower peak CAR T-cell levels.

Despite the promising results of this study, it does have a few limitations. The trial was single-arm and not randomized, limiting the ability to compare this combination to CAR T-cell therapy alone directly. With high and durable response rates observed in the ZUMA-2 trial with Brexu-cel in patients with five prior lines of therapy, whether the benefit of combination therapy persists when compared to sequential treatment needs to be evaluated. The study’s premise relies on the effect of ibrutinib on T-cell fitness. The exploratory analysis does not show an improvement in T-cell subsets in all patients with seven days of BTKi exposure prior to apheresis. Longer exposure with BTKi treatment had a higher fraction of naïve T-cells; however, the optimal duration of this period of BTKi exposure prior to apheresis is not known with at least one study in CLL suggesting five months or greater of pretreatment with ibrutinib improves CAR T-cell expansion (10). Furthermore, lack of exploratory studies evaluating the tumor immune contexture as biomarkers to delineate responders from non responders is a missed opportunity (14). The optimal duration of ibrutinib treatment after CAR T-cell infusion is also uncertain, as many patients achieved deep MRD-negative remissions at 1 month, suggesting that earlier cessation of BTK inhibition may have been sufficient. Lastly, ibrutinib is no longer available in the US for use in MCL. Therefore, would the findings from the TARMAC study also extrapolate to second-generation, more selective BTKi such as acalabrutinib and zanubrutinib?

Nonetheless, the TARMAC trial represents a significant step forward. It paves the way for larger, randomized trials to confirm these findings and explore the broader applicability of this approach. If validated, this combination therapy could transform the treatment landscape for relapsed MCL patients by utilizing an adaptive combination approach, enhancing the efficacy of CAR T-cell therapy and limiting the long term use of BTKi only in those patients with a sub-optimal response to CAR T-cell therapy. In conclusion, the TARMAC trial’s results are promising for patients with relapsed MCL, suggesting that combining ibrutinib and CAR T-cell therapy may offer a more effective and potentially safer treatment option.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

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Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-95/coif). S.K. received payment or honoraria for speakers bureaus from Eli Lilly. M.N. received institutional research funding from ADC Therapeutics, EUSA/Recordati Rare Diseases, American Cancer Society, Genentech/Roche, Beigene, Genmab, Cullinan Oncology; consulting fees to individual from Abbvie, Pharmacyclics, ADC, Kite/gilead; payment or honoraria to individual from Genentech/Roche, Adaptive Technologies, Lilly Oncology, Abbvie; and was on the Data Safety Monitoring Board or Advisory Board of ADC, Kite/gilead. The authors have no other conflicts of interest to declare.

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