Pooled analysis of early-Phase trials highlights robust activity of CD3-CD20 T-cell engagers in follicular lymphoma

Abstract Background: Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma. It's characterized by slow disease course but frequent relapses and refractoriness to standard therapy. Bispecific CD3-CD20 T-cell engagers (TCEs) have emerged as a promising class in FL treatment. Several agents have been studied in the frontline and relapsed settings over the last 5 years. We conducted a pooled analysis of the overall response rate (ORR), complete response rate (CR), and cytokine release syndrome (CRS) / Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) rates of the recent early-phase trials. To our knowledge, this is the first pooled analysis for TCE therapy in follicular lymphoma. Methods: We systematically reviewed published phase I–II (no results from Phase III trials as of now) trials of TCE therapy in FL, including monotherapy and combination regimens. We performed a single-arm pooled analysis (random-effects) of the included trials, combining ORR and CR rates across studies. Meta-analyses were performed using the metaprop function (R meta package) with inverse-variance weighting and Freeman–Tukey double-arcsine transformation to stabilize variances. Random-effects models account for between-study heterogeneity. We defined two main cohorts: Frontline (previously untreated) and Relapsed/Refractory (R/R) disease. Results: A total of 14 trials (7 frontline, 7 R/R) met our inclusion criteria. Overall, these trials represented 911 patients. Epcoritamab was evaluated in 5 trials, Mosunetuzumab in 6 trials, Glofitamab in 1 trial, and Odronextamab in 1 trial.Frontline FL: In the front-line setting, Epcoritamab and Mosunetuzumab were investigated. Epcoritamab was investigated in 2 trials as combination therapy, while Mosunetuzumab was in 5 trials, 2 of which were combination therapy. Pooled ORR was 93% [95% CI: 89–95%], with CR 81% [95% CI: 72–86%]. Combination regimens demonstrated high response rates ORR 93% [95% CI: 87-97%], CR 86% [95% CI: 79-91%]. Monotherapy trials also showed high response rates with ORR 92% [95% CI: 86-96%], CR 75% [95% CI: 62-84%]. It was not feasible to compare monotherapy with combination therapy trials due to limitations in the reported risk categories of patients enrolled.R/R FL: In the relapsed setting, Epcoritamab was included in 3 trials (one of which was in combination with lenalidomide and rituximab (R2)), Mosunetuzumab in 2, Glofitamab in 1, and Odronextamab in 1. Pooled ORR for Monotherapy trials were 81% [95% CI: 77–84%] and CR 67% [95% CI: 61-72%]. Subgroup analysis showed ORR for Epcoritamab (monotherapy trials only) 87% [95% CI 65–96%] and Mosunetuzumab 79% [95% CI 70–86%]. Notably, the combination of Epcoritamab with R2 had an ORR of 96% and a CR of 87% in that single trial.CRS / ICANS rates: All 14 trials were included in this pooled analysis. CRS rate (any grade) was at 60.7% [95% CI: 43.3–75.8%]. After excluding one trial with atypically high CRS incidence (90%), the pooled rate for CRS (any grade) decreased to 55.1% [95% CI: 36.8–72.2%]. CRS grade 3 or higher rate was at 1.9% [95% CI: 1.1-3.2%]. ICANS (any grade) rate was at 3.1% [95% CI: 2-4.7%]. Only 1 patient out of all included studies was reported to have a Grade 3 ICANS. Conclusions: This pooled analysis confirms that CD3-CD20 TCE therapies achieve high overall and complete response rates in FL. This is particularly seen in the frontline setting. Responses in R/R were also clinically meaningful and durable, especially given that most trials enrolled patients with at least 2 or more previous lines of therapy. Although CRS incidence was high, most cases were low grade and medically manageable. Indirect comparisons between different TCEs were hard to make and interpret due to the lack of enough data for adjustments. These findings underscore the huge potential and relative similarity in efficacy in terms of ORR and CR rates that these agents have supporting the continuation of phase III trials and earlier lines of use.