4-YEAR UPDATE OF PHASE 2 ELARA TRIAL: CLINICAL OUTCOMES OF TISAGENLECLEUCEL IN PATIENTS (PTS) WITH HIGH-RISK RELAPSED/REFRACTORY FOLLICULAR LYMPHOMA (R/R FL)

Tisagenlecleucel, a CD19-directed CAR-T cell therapy, is approved in the United States and Europe for adults with r/r FL after ≥2 lines of therapy. Primary analysis of the phase 2 ELARA trial reported high response rates and favourable safety profile of tisagenlecleucel in pts with high-risk r/r FL (Dreyling M et al, 2024). The aim of this study is to report the 4-year follow-up (FU) of efficacy, safety and pharmacokinetics findings. Eligible pts with r/r FL (grades 1-3A) previously treated with ≥2 lines of systemic therapy (including an anti-CD20 monoclonal antibody and alkylating agent) received a single tisagenlecleucel infusion (0.6-6×108 cells). Bridging therapy was permitted. Baseline clinical characteristics and circulating blood naive T cells were correlated with progression-free survival (PFS) and overall survival (OS). Cellular kinetics were determined by measuring transgene levels using quantitative polymerase chain reaction.

Minimal residual disease (MRD) levels were determined via clonoSEQ® Next Generation Sequencing assay performed at Adaptive Biotechnologies (Seattle, WA, USA): pre-infusion tissue samples were used for clonotype identification; MRD tracking was performed in post-infusion plasma (ctDNA) samples. As of March 27, 2024 (median FU: 53 months; range: 46-62), 97 pts were infused; of which, 94 were evaluable for efficacy. At baseline, high-risk disease characteristic was identified among these pts (Figure 1a).

The estimated 45-month PFS was 52.9% (95% CI: 42.0, 62.6) and median OS was not reached as assessed by independent review committee, long-term FU data of PFS and OS are presented in Figure 1b, patients with high-risk characteristics also experienced durable responses. MRD data were available for 31/94 pts (33%); 28/31 pts (90%) achieved MRD negativity at any time point. MRD-negative status was achieved in 82% (22/27) of evaluable pts at day 28, 75% (12/16) at month 3, 69% (11/16) at month 6, and 76% (13/17) at month 12, respectively. CAR transgene persistence (Tlast; time to last quantifiable transgene level) was observed for up to 1680 days; median Tlast was 210 days (range: 13-1680). No new safety signals have been reported since the last data cut. Second primary malignancies (defined as any new cancer occurring post infusion regardless of tisagenlecleucel relationship) were reported in 6 (6.2%) pts: basal cell carcinoma (n=2), squamous cell carcinoma (n=2), acute myeloid leukaemia (n=1), bladder transitional cell carcinoma (n=1), Bowen's disease (n=1), malignant melanoma (n=1), metastatic squamous cell carcinoma (n=1), and myelodysplastic syndrome (n=1). As of the data cutoff, 19 pts have died during the study — progressive disease (n=8), adverse events (n=10; 1 pt each of acute myeloid leukaemia, bladder transitional cell carcinoma, cardiac arrest, cytokine release syndrome, encephalitis, gastrointestinal haemorrhage, infection, metastatic squamous cell carcinoma, pneumonia, sepsis), and euthanasia (n=1). Tisagenlecleucel continues to demonstrate robust durable responses >4 years post infusion, alongside a favourable safety profile in this long-term follow-up analysis from the ELARA trial.

Correlative analyses suggest that most baseline high-risk disease characteristics are not associated with inferior efficacy following tisagenlecleucel infusion in pts with r/r FL. Furthermore, high frequencies of MRD-negative status were achieved in a subset of evaluable patients.

TISAGENLECLEUCEL VERSUS MOSUNETUZUMAB IN RELAPSED/REFRACTORY FOLLICULAR LYMPHOMA: AN UPDATED MATCHING-ADJUSTED INDIRECT COMPARISON (MAIC) ANALYSIS AFTER 3-YEAR FOLLOW-UP DATA

In the absence of head-to-head trials, a MAIC has been conducted to compare efficacy and safety of tisagenlecleucel and mosunetuzumab among patients with relapsed/refractory follicular lymphoma (r/r FL) after ≥2 lines of systemic therapies.  In a prior analysis using 2-year follow-up, tisagenlecleucel was associated with improved overall response rate (ORR) and progression-free survival (PFS) and comparable overall survival (OS) and safety outcomes, compared to mosunetuzumab (Fowler et al, 2023). The current update presents MAIC results using 3-year follow-up data from the ELARA trial. Individual patient data of tisagenlecleucel from ELARA trial (NCT03568461; March 29, 2023 data cut; Efficacy set: N=98; Safety set: N=97) were matched to the aggregate published data of mosunetuzumab from the GO29781 trial (NCT02500407; May 02, 2023 data cut; N=90).

The baseline characteristics adjusted in MAIC are selected based on clinical input and include prognostic factors available from both studies: age, sex, race, Eastern Cooperative Oncology Group performance status, Ann Arbor disease stage at enrollment, FL International Prognostic Index score, number of prior lines of therapy, refractory status to the most recent regimen, double refractory status, progression of disease within 24 months from the first anti-CD20 monoclonal antibody-containing therapy, and prior autologous stem cell transplant. Efficacy outcomes (per investigator assessment), i.e., PFS, OS, ORR, and complete response (CR) rate, and safety outcomes, i.e., cytokine release syndrome (CRS), tocilizumab and corticosteroid use for CRS management, and immune effector cell-associated neurotoxicity syndrome (ICANS) were compared between tisagenlecleucel and mosunetuzumab after adjustment of baseline characteristics. Due to the limited follow-up of published mosunetuzumab data, a sensitivity analysis for PFS was conducted based on PFS through month 36 of both treatments.

After adjustment for baseline differences, compared with mosunetuzumab, tisagenlecleucel was associated with significantly lower hazard of disease progression or death (PFS hazard ratio [HR]=0.34; 95% CI, 0.20-0.58; p<0.001), however, the proportional hazard assumption (PHA) was violated. In the sensitivity analysis through month 36, tisagenlecleucel remained having a significantly lower hazard of disease progression or death after matching (PFS HR=0.57; 95% CI, 0.34-0.93; p<0.05) with no violation of PHA (similar to the prior MAIC analysis: PFS HR=0.54; 95% CI, 0.32-0.90; p<0.05).  Compared with mosunetuzumab, tisagenlecleucel had numerically lower hazard of death, though not statistically significant (OS HR=0.81, 95% CI, 0.37-1.74; p=0.58).

Response rates and safety outcomes including CRS and ICANS stayed the same as the previous data cut. Hence, same as the prior results, tisagenlecleucel had significantly higher ORR (92.86% vs 77.78%; p<0.01) and CR (80.52% vs 60.00%; p<0.01) compared with mosunetuzumab. In this updated MAIC analysis using 3-year follow up data, tisagenlecleucel continued to demonstrate more favorable PFS, ORR, and CR than mosunetuzumab in patients with r/r FL after adjustment for baseline characteristics. Despite a numerical benefit in hazard of death for tisagenlecleucel, OS was not mature enough to demonstrate significance and a longer follow-up is needed. Safety comparison remained unchanged with the extended follow-up, showing comparable CRS and ICANS rates between the two treatments.

RAPCABTAGENE AUTOLEUCEL (YTB323) IN PATIENTS WITH RELAPSED/REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA: A PHASE II TRIAL CLINICAL UPDATE

Rapcabtagene autoleucel is a CD19-directed chimeric antigen receptor (CAR) T-cell therapy that utilizes the T-Charge™ platform to preserve T-cell stemness by rapidly manufacturing product (<2 days; Barba P, et al., 2022). Here the authors report an interim descriptive analysis of the ongoing phase II trial (NCT03960840) in patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL). Eligible patients received a single dose of rapcabtagene autoleucel (12.5×106 cells). Bridging therapy before infusion was permitted. Primary endpoint was complete response rate (CRR; best overall response [BOR] of complete response [CR]). Secondary endpoints included cellular kinetics, overall response rate (ORR), progression-free survival (PFS), and duration of response (DOR).

As of February 1, 2024, 63 patients had received rapcabtagene autoleucel with a median follow-up of 16.4 months (range: 0.1-44.1; Table 1). Among the 60 infused patients with r/r DLBCL who had ≥1 month follow-up, ORR was 88% and CRR was 65%. CRR at 3, 6, and 12 months were 55% (30/55), 57% (25/44), and 47% (18/38), respectively. Median DOR was 15.2 months (5.1-not estimable [NE]); in patients with a BOR of CR, the median DOR was not reached (10.4-NE) and the 12-month DOR was 69%. Median PFS was 11.9 months; among patients in CR at 3 months, the median PFS was not reached. PFS rates at 12 months were 48% for all patients and 79% for patients in CR at 3 months. High CR rates at 3 months were observed across most patient subgroups including high-risk populations; 64% for patients age ≥65 years, 53% for patients with ≥3 prior therapies, 46% for patients with an International Prognostic Index ≥3; a lower CR rate of 29% was reported for patients with elevated lactate dehydrogenase before infusion. Among the 63 infused patients, adverse events (AEs) were reported in 98% (grade ≥3, 84%) including infections (all grade, 49%; grade ≥3, 27%), cytokine release syndrome (CRS; all grade, 43%; grade ≥3, 6%), and immune effector cell-associated neurotoxicity syndrome (ICANS; all grade, 6%; grade ≥3, 3%). Grade ≥3 infections were reported in 27% (17/63), 15% (8/55), and 19% (6/32) of patients any time, between 12 weeks and 1 year, and >1 year post infusion, respectively. Median time to onset of CRS and ICANS were 8 days (range: 1-20) and 13 days (range: 10-28), respectively. Grade ≥3 cytopenias included neutropenia (62%), anemia (33%), thrombocytopenia (25%), and lymphopenia (16%). Probability of resolution by 3 months for neutropenia and anemia was 100%; for thrombocytopenia and lymphopenia 3 and 6 months resolution was 92%/100% and 65%/74%, respectively.

As of data cutoff, 12 deaths had occurred, all unrelated to rapcabtagene autoleucel; 6 each due to disease progression and AEs. Four deaths reported were non-relapse mortalities; 2 deaths due to AEs were reported post progression. Cellular kinetics showed robust in vivo expansion by quantitative polymerase chain reaction with a median maximum observed drug concentration (Cmax) of 41,800 copies/µg DNA. At the 12.5×106 CAR positive cell dose, rapcabtagene autoleucel showed promising efficacy and a favorable safety profile. Although patient numbers were limited, risk-benefit analysis supports use of the lower-dose lymphodepletion regimen before infusion; continued assessment of long-term efficacy and safety outcomes is needed.