Novartis's CAR-T Tisagenlecleucel Continues to Show Efficacy for R/R Follicular Lymphoma in Long-Term Follow-Up

This article originally appeared on our sister site, OncLive®.

Novartis' tisagenlecleucel (marketed as Kymriah), and FDA-approved chimeric antigen receptor T-cell (CAR-T) therapy, maintained efficacy and safety in 4-year follow-up data patients with relapsed/refractory (r/r) follicular lymphoma (FL) treated in the pivotal phase 2 ELARA clinical trial (NCT03568461).¹ The data were presented by Catherine Thieblemont, MD, PhD, Service Hémato-Oncologie, Hôpital Saint- Louis, Paris, France, at the 66th American Society of Hematology (ASH) Annual Meeting, held December 7-10, 2024, in San Diego, California.

The 94 efficacy-evaluable patients had follow-up ranging from 46 to 62 months (median, 53). The complete response (CR ) rate was 69.1%. The median overall survival (OS) was not reached and the 4-year OS rate was 79.3%. Furthermore, the median progression-free survival (PFS) was 53.3 months (95% CI, 18.2–not evaluable) and the 4-year PFS rates were 50.2% overall and 66.1% in patients who achieved a CR. Thieblemont pointed out that these efficacy benefits extended to high-risk patient subgroups.

“Correlative analyses suggest that most baseline high-risk disease characteristics (double-refractory disease, bulky disease, POD24, and high FLIPI) are not associated with inferior efficacy following tisagenlecleucel infusion in patients with r/r FL,” Thieblemont said.

Specifically, among patient subgroups at high-risk, the 4-year OS rates were 80.8% in patients with disease progression within 2 years of frontline systemic therapy (POD24), 73.2% in patients with a high Follicular Lymphoma International Prognostic Index (FLIPI) score, 73.0% in patients with bulky disease, 83.7% in patients who were double refractory, and 65.5% in patients with high tumor burden. The 4-year PFS rates were 45.5% (POD24), 45.5% (high FLIPI), 45.2% (bulky disease), 52.8% (double refractory), and 23.2% (high tumor burden). The CR rates reported for 4 of these subgroups were 60.7% (POD24), 63.2% (high FLIPI), 66.1% (bulky disease), and 67.7% (double refractory).

Among the 97 total patients enrolled in the trial, 32 (33%) had minimal residual disease (MRD) data. Twenty-eight of these patients (87.5%) achieved MRD-negative status at any time point. In addition, MRD negativity was held by 24 of 29 (82.8%) evaluable patients at 28 days posttreatment, 14 of 18 evaluable patients (77.8%) at 3 months posttreatment, 16 of 22 evaluable patients (72.7%) at 6 months posttreatment, and 14 of 17 evaluable patients (82.4%) at 12 months posttreatment.

“High frequencies of MRD-negative status were achieved among MRD-evaluable patients, showing that tisagenlecleucel therapy can achieve deep response in treated patients,” Thieblemont added.

Thieblemont noted that there were no new safety signals for the CAR-T reported since the previous analysis. All 97 treated patients were included in the safety set. Twenty-four (28.6%) patients experienced an adverse event (AE) of grade 3 or greater and 16 (19.0%) patients had at least 1 infection at 1 year or later after induction. About half (48.5%) of patients experienced grade 1 or grade 2 cases of cytokine release syndrome during the 8 weeks following infusion. Although, only 1 patient had a case of CRS (grade ≥3) at more than 1 year after receiving tisagenlecleucel.

Second primary malignancies were reported in 6 patients. Cases included basal cell carcinoma in 2 patients, squamous cell carcinoma in 2 patients, acute myeloid leukemia in 1 patient, bladder transitional cell carcinoma in 1 patient, Bowen's disease in 1 patient, malignant melanoma in 1 patient, metastatic squamous cell carcinoma in 1 patient, and myelodysplastic syndrome in 1 patient.

There were 19 on-study deaths as of the data cutoff: 8 due to progressive disease, 1 from euthanasia, and 10 from adverse events—1 each for acute myeloid leukemia, bladder transitional cell carcinoma, cardiac arrest, CRS, encephalitis, gastrointestinal hemorrhage, infection, metastatic squamous cell carcinoma, pneumonia, and sepsis.

The study included 97 patients with r/r FL (grades I-IIIa) who had received at least 2 lines of systemic therapy (including an alkylating agent and antiCD20 monoclonal antibody). Patients received a single infusion of tisagenlecleucel (0.6-6×10⁸ CAR+ viable T cells). The study design allowed for bridging therapy.

The median patient age at baseline was 57.0 years (range, 29-73) and 43% of patients had an Eastern Cooperative Oncology Group performance status of 1 or higher. Overall, 86% of patients had stage III-IV disease at study entry, 38% had bone marrow involvement, 65% had bulky disease, and 60% were FLIPI high (≥3). The median number of prior therapies was 4 (range, 2-13), 63% had POD24, and 78% were refractory to their last line of therapy. Further, 71% were refractory to at least 2 regimens, 68% were double refractory (anti-CD 20 monoclonal antibody and alkylating agent), and 14% were refractory to PI3K inhibitors. A little over one-third (36%) of patients had prior autologous hematopoietic stem cell transplant.

Based on previously reported results from the ELARA trial, the FDA approved tisagenlecleucel in May 2022 for the treatment of adult patients with r/r FL after 2 or more lines of systemic therapy.²

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REFERENCES
1. Thieblemont C, Dreyling M, Dickinson MJ, et al. Clinical Outcomes of Patients with High-Risk Relapsed/Refractory Follicular Lymphoma Treated with Tisagenlecleucel: Phase 2 ELARA 4-Year Update. Blood. 2024; 144 (suppl 1): 3034. doi:10.1182/blood-2024-201730
2. FDA approves tisagenlecleucel for relapsed or refractory follicular lymphoma. FDA. May 27, 2022. Accessed December 9, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tisagenlecleucel-relapsed-or-refractory-follicular-lymphoma