7006 Background: Patients (pts) with advanced R/R MCL have poor outcomes, especially pts with high-risk features or those progressing after BTKi therapies. Glofitamab is a CD20xCD3 2:1 bispecific antibody that redirects T cells to eliminate malignant B cells. A Phase 1/2 trial (NCT03075696) evaluated glofitamab monotherapy, given with step-up dosing (SUD) after obinutuzumab pretreatment (Gpt), in pts with R/R MCL. Prior analyses showed high response rates and manageable safety, regardless of prior BTKi exposure (Phillips, et al. ASCO 2024). We report longer follow-up data from this MCL cohort. Methods: Pts with R/R MCL after ≥1 prior line of systemic therapy received Gpt (single 1000 mg dose or 2000 mg split over 2 days, as needed) on cycle (C)1 day (D)1. Glofitamab SUD was given on C1D8 (2.5 mg) and C1D15 (10 mg), then the target dose of 16 or 30 mg every 3 weeks on D1 of C2–12. Efficacy endpoints included investigator-assessed complete response (CR) rate, overall response rate (ORR), duration of CR (DoCR), duration of response (DoR), progression free survival (PFS), and overall survival (OS). Results: As of Sept 8, 2025, 61 pts with R/R MCL were enrolled (Gpt: 1000 mg, n=17; 2000 mg, n=44); 60 pts were treated. The median number of prior lines of therapy was 2 (range 1–5), median age was 72.0 years (range 41–86), 86.9% of pts had Ann Arbor stage III/IV, and 26.3% had a simplified MCL International Prognostic Index score of ≥6. Pts had high-risk disease features such as Ki-67 proliferation index ≥30% (62.3%), blastoid/pleomorphic variants (9.8%), and TP53 mutation (19.7%). The median number of glofitamab cycles received was 12 (range 1–13). With a median OS follow-up of 41.5 months (mo; 95% CI: 37.4–48.7), the ORR and CR rate were 82% and 77%, respectively. Median DoCR was 40.8 mo (95% CI: 14.1–NE); 48.9% of pts had ongoing CRs at the data cut-off. Estimated 33-mo DoCR and DoR rates were 50.5% and 47.4%, respectively. Median (95% CI) PFS was 18 mo (11.3–42.8) and OS was NE (26.9–NE). For pts who received prior BTKi therapy (n=34 [55.7%]), the ORR and CR rate were 73.5% and 70.6%, respectively. Median (95% CI) DoCR was 15.4 mo (8.3–NE), PFS was 11.3 mo (5.1–32.6), and OS was 29.9 mo (11.3–NE). Estimated 33-mo DoCR and DoR rates were 42.7% and 41.0%, respectively. No new safety signals were observed. Cytokine release syndrome remained the most common adverse event (n=42/60, 70%; Grade 1–2, 58.3%; Grade 3–4, 11.6%), with lower rates in the 2000 mg (n=28/44, 63.6%) vs 1000 mg (n=14/16, 87.5%) Gpt cohorts. Conclusions: Updated data on fixed-duration glofitamab monotherapy in heavily pretreated pts with R/R MCL show robust efficacy and manageable safety, including in BTKi-exposed pts. Glofitamab monotherapy is a suitable treatment for pts with R/R MCL in need of rapid disease control and is under investigation in the Phase 3 GLOBRYTE trial. Clinical trial information: NCT03075696 .

Background and Significance: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of aggressive non-Hodgkin lymphoma. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) is a standard first line (1L) therapy for DLBCL but only ~60% of patients (pts) achieve durable remissions. Recently, Pola-R-CHP became the first therapy to be approved by the FDA for 1L treatment of DLBCL in ~20 years, and demonstrated a significant progression-free survival (PFS) benefit (hazard ratio: 0.73; 95% confidence interval 0.57-0.95; p=0.02) over R-CHOP (Tilly, et al. NEJM 2022). Glofitamab is a CD20xCD3 T-cell-engaging bispecific antibody that redirects T-cells to eliminate B-cells and has shown durable responses in pts with relapsed/refractory (R/R) DLBCL (Dickinson, et al. NEJM 2022). Glofitamab is approved in pts with R/R LBCL after ≥2 prior lines of therapy based on data from study NCT03075696. In an ongoing Phase Ib trial (NP40126; NCT03467373), treatment with glofitamab in combination with Pola-R-CHP demonstrated promising efficacy in untreated pts with DLBCL, with a complete metabolic response rate of 91.7%. The safety profile was manageable, and dose intensity was maintained for all glofitamab and Pola-R-CHP components (Topp, et al. ASH 2023. Poster 3085). Glofitamab plus Pola-R-CHP also demonstrated promising efficacy and safety in the Phase I/II COALITION study in pts with high-risk 1L DLBCL (Minson, et al. Hemasphere 2023). Here, we describe the study design of SKYGLO (GO44145; NCT06047080), a Phase III, multicenter, randomized, open-label trial evaluating the efficacy and safety profile of glofitamab plus Pola-R-CHP versus Pola-R-CHP alone in pts with previously untreated CD20-positive LBCL. Study Design and Methods: Eligible pts are those with previously untreated CD20-positive LBCL according to the 2022 World Health Organization classification of lymphoid neoplasms. Other key eligibility criteria include age 18-80 years, ≥1 bi-dimensionally measurable lesion (>1.5cm in its longest dimension), an International Prognostic Index score of 2-5 and an Eastern Cooperative Oncology Group performance status of 0-2. Key exclusion criteria include current diagnosis of follicular lymphoma grade 3B; transformations of indolent B-cell lymphomas; or active viral infections (including SARS-CoV-2). Approximately 1130 pts will be randomized 1:1 to receive glofitamab plus Pola-R-CHP or Pola-R-CHP alone. Treatment will be administered over 8 cycles of 21 days each. Pts in the glofitamab plus Pola-R-CHP group will receive glofitamab during Cycles (C) 2-8, using a step up-dosing schedule, and Pola-R-CHP in C1-6. Pts in the Pola-R-CHP group will receive Pola-R-CHP during C1-6 and rituximab in C7-8. The primary endpoint is PFS as determined by Independent Review Facility, defined as the time from randomization to the first occurrence of disease progression or relapse, or death due to any cause, whichever occurs first. Treatment comparisons for the primary endpoint, performed in all randomized pts, will be made using a two-sided level 0.05 stratified log-rank test. Secondary endpoints include PFS as determined by the investigator; event-free survival (time from randomization to disease progression, death, initiation of new treatment or positive biopsy for residual disease); objective and complete response (CR) rate at the end of treatment or discontinuation; duration of response; duration of CR; overall survival (OS); disease-free survival; PFS and OS in pts classified as high-risk according to ctDNA; glofitamab pharmacokinetic profile; immunogenicity; and safety. All responses and time-to-event outcomes will be determined according to Lugano criteria (Cheson, et al. J Clin Oncol 2014). Safety endpoints include incidence and severity of adverse events (AEs) as defined by the National Cancer Institute Common Toxicity Criteria for Adverse Events v5.0 (including cytokine release syndrome graded per the American Society for Transplantation and Cellular Therapy [Lee, et al. Biol Blood Marrow Transplant 2019]), and tolerability as assessed by dose interruptions, reductions, study discontinuation and dose intensity. Pts will be enrolled from approximately 260 sites globally. Enrollment began in September 2023.

Background: Glofitamab is a CD20xCD3 bispecific antibody that engages and redirects T cells to eliminate B cells. In this Phase II study (NCT03075696) of patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL), fixed-duration glofitamab monotherapy induced high complete response (CR) rates and durable responses with manageable toxicity (Dickinson, et al. N Engl J Med 2022). As a result, glofitamab monotherapy was approved by the FDA and EMA for use in patients with R/R LBCL after ≥2 prior lines of therapy. Here, we present updated data with an extended follow-up of over 3 years, a landmark analysis assessing outcomes of patients in CR, and exploratory biomarker analyses after end of treatment (EOT) evaluating the risk and benefit of fixed-duration treatment. Methods: Patients with LBCL and ≥2 prior therapies received obinutuzumab pretreatment (1000mg) on Day (D)1 of Cycle (C)1. Intravenous glofitamab was then given as step-up doses during C1 (2.5mg on D8; 10mg on D15), followed by the target dose (30mg) on D1 of C2-12 (21-day cycles). The primary endpoint was independent review committee (IRC)-assessed CR rate using Lugano criteria (Cheson, et al. J Clin Oncol 2014). Progression-free survival (PFS) and overall survival (OS) post-hoc analyses were performed in responders (landmark for CR at EOT). A modified AVENIO circulating tumor (ct)DNA analysis workflow (Roche; Research Use Only) was used for next-generation sequencing based on personalized cancer profiling; ctDNA was quantified as mutant molecules per milliliter of plasma (MMPM). CD19-positive B-cell count was measured centrally with the T, B, and natural killer cell (TBNK) assay. Results: As of May 17, 2024, 155 patients were enrolled; 154 patients had received ≥1 dose of study treatment. Baseline characteristics have been previously published (Dickinson, et al. N Engl J Med 2022). Median number of prior therapies was 3 (range: 2-7); 33% had received prior chimeric antigen receptor T-cells and 84% were refractory to their most recent regimen. Median time on study was 41.0 months (range: 0-52), with all patients with ongoing remission being treatment-free for ≥2 years following EOT. The IRC-assessed CR rate was 40% and overall response rate was 52%. After a median follow-up of 37.7 months (range: 0-51) in patients with a CR, median duration of CR was 29.8 months (95% CI: 22.0-not estimable [NE]). In patients with a CR at EOT, the PFS and OS rates 2 years after EOT were 57% and 77%, respectively. The incidence of adverse events (AEs) and serious AEs was stable compared with earlier analyses; two new Grade ≥3 AEs (neutropenia [Grade 3] and adenocarcinoma pancreas [Grade 4]) were reported. No new cytokine release syndrome events, infections, other cytopenia, or fatal AEs were reported since the previous analysis. Baseline ctDNA levels were previously shown to be prognostic in patients treated with glofitamab monotherapy. Patients with a CR at EOT and evaluable for ctDNA at baseline (27/45; 60%) showed a rapid and sustained decrease of ctDNA levels on treatment, maintained 12 months after EOT in patients with ongoing remission (baseline [n=27]: median MMPM 37.48 [range 3.13-23544.37]; C3 [n=27]: median MMPM 0.55 [range 0.00-471.18]; EOT [n=27]: median MMPM 0.29 [range 0.00-49.59]; 12 months follow-up [n=18]: median MMPM 0.04 [range 0.00-95.08]. B-cell depletion occurred in all patients during treatment; recovery of B cells and immunoglobulins was observed starting around 18 months after glofitamab treatment in patients with a sustained response after EOT. Conclusions: With this extended follow-up of over 3 years, durable responses continued to be observed with fixed-duration glofitamab in patients with R/R LBCL. The safety profile remains manageable and consistent with previous analyses. ctDNA kinetics showed that molecular response to glofitamab was rapid and sustained after EOT. Evidence of B cell and immunoglobulin recovery after EOT was observed in patients in remission. These data support the potential for long-lasting remissions and a beneficial effect on immune system recovery in patients with R/R LBCL treated with fixed-duration glofitamab.

Background: Glofitamab, a CD20xCD3 T-cell engaging bispecific antibody with a novel 2:1 (CD20:CD3) format, induced frequent and durable complete responses (CRs) with a manageable safety profile in pivotal expansion cohorts of an ongoing Phase I/II study (NCT03075696) in patients (pts) with R/R LBCL (Dickinson et al. NEJM 2022, Falchi et al. ASCO 2023). Cytokine release syndrome (CRS) is a potentially life-threatening toxicity caused by immune activation that can be triggered non-specifically by T-cell engaging therapies. As previously reported, corticosteroid (steroid) premedication was required to prevent or mitigate CRS in pts treated with glofitamab. Dexamethasone (Dex) was mandated in one expansion cohort to assess if this could reduce the rate and severity of CRS versus other steroids. Here, we report data from the dose-escalation and expansion cohorts in pts with R/R LBCL who received Dex only versus non-Dex premedication. Methods: Pts with R/R LBCL (diffuse LBCL not otherwise specified [DLBCL NOS], high-grade B-cell lymphoma [HGBCL], primary mediastinal LBCL [PMBCL], or LBCL arising from follicular lymphoma [trFL]) and ≥2 prior therapies received 1000mg obinutuzumab pretreatment (Gpt) 7 days prior to the first glofitamab dose. IV glofitamab was administered with step-up dosing during Cycle (C) 1 (Day 8, 2.5mg; Day 15, 10mg) followed by the target dose (30mg) on Day 1 of C2-12 (21-day cycles; 8.4 months). Steroid premedication (80mg IV methylprednisolone, or equivalent dose of prednisone [100mg] or prednisolone [100mg], or 20mg IV Dex) was given at least 60 minutes prior to Gpt and each glofitamab dose. Responses were assessed using Lugano criteria (Cheson et al. JCO 2014). CRS events were graded by ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Results: As of May 1, 2023, 145 pts with R/R LBCL had received glofitamab, including 33 (22.8%) pts (DLBCL NOS, n=24 [72.7%]; HGBCL, n=2 [6.1%]; trFL, n=7 [21.2%]) who received Dex premedication before each glofitamab dose (Dex only cohort) and 112 (77.2%) pts (DLBCL NOS, n=81 [72.3%]; HGBCL, n=5 [4.5%]; PMBCL, n=6 [5.4%]; trFL, n=20 [17.9%]) who had not received Dex premedication before each glofitamab dose (non-Dex cohort). In the Dex only and non-Dex cohorts, median age was 73.0 years (range: 27-86) and 66.0 years (range: 21-90), and 26/33 (78.8%) pts and 83/112 (74.1%) pts had Ann Arbor stage III/IV disease, respectively. Median number of prior therapies was 3.0 for both cohorts. Ten (30.3%) and 37 (33.0%) pts had previously received chimeric antigen receptor T-cell therapy, and 6 (18.3%) and 22 (19.6%) pts had received autologous stem cell transplant in the Dex only and non-Dex cohorts, respectively. Median number of glofitamab cycles was 5.0 in both cohorts. CRS of any grade occurred in 48.5% of pts in the Dex only cohort and 73.2% of pts in the non-Dex cohort, and CRS leading to serious adverse events occurred in 5 (15.2%) and 27 (24.1%) pts, respectively. In both cohorts, CRS events were mostly low grade and primarily occurred during C1 (Table; Figure). Recurring Grade (Gr) ≥2 CRS was not observed in the Dex only cohort and 6 (5.4%) pts had recurring Gr ≥2 CRS in the non-Dex cohort. Median time to CRS onset and median time to resolution were similar in the two cohorts. Treatment discontinuation rate was lower in the Dex only cohort (n=21, 63.6%) versus the non-Dex cohort (n=80, 71.4%), mainly due to progressive disease (Dex only cohort, n=12 [36.4%]; non-Dex cohort, n=52 [46.4%]). In the DLBCL NOS and trFL population, the best overall response assessed by Independent Review Committee was similar between the Dex only (n=31) and non-Dex (n=101) cohorts, with CR reported in 14 (45.2%) and 44 (43.6%) pts, and 12 (38.7%) and 34 (33.7%) pts remaining in CR at data cutoff, respectively. The estimated event-free rate among complete responders at 12 months after the first CR was 83.1% (95% CI: 61.5-100.0) in the Dex only cohort and 77% (95% CI: 63.8-90.2) in the non-Dex cohort. Conclusions: The incidence, severity, and seriousness of CRS after glofitamab administration in pts with R/R LBCL were numerically lower with Dex premedication versus premedication with other steroid regimens. Response rates in the Dex only cohort were similar to those reported in the non-Dex cohort. We therefore propose Dex as the steroid of choice for premedication to prevent or mitigate CRS in pts with LBCL treated with glofitamab monotherapy, considering its half-life and potency.

Rituximab plus fludarabine and cyclophosphamide (RFC) is the standard of care for fit patients with untreated chronic lymphocytic leukemia (CLL); however, its use is limited in ‘unfit’ (co-morbid and/or full-dose F-ineligible) patients due to its toxicity profile. We conducted a systematic review and Bayesian network meta-analysis (NMA) to determine the relative efficacy of commercially available interventions for the first-line treatment of unfit CLL patients.