Glofitamab in Combination with Rituximab Plus Ifosfamide, Carboplatin, and Etoposide Shows Favorable Efficacy and Manageable Safety in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma, Eligible for Stem Cell Transplant or Chimeric Antigen Receptor T-Cell Therapy: Results from a Phase Ib Study
Authors: Diefenbach Catherine S. , Caimi Paolo F. , Saba Nakhle S , Vargas Madueno Fernando , Hamadani Mehdi , Fayad Luis E. , Riedell Peter A. , Gillis-Smith Andrew , Simko Stephen , Orellana-Noia Victor , Filippou-Frye Maria , Kapp Amy V. , Relf James , Lundberg Linda , Pinter-Brown Lauren C. 
Published: December 2024

Background: Glofitamab, a CD20xCD3 bispecific antibody, is approved as monotherapy for the treatment of patients (pts) with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL), after two or more lines of systemic therapy. In the Phase III STARGLO study, glofitamab in combination with gemcitabine and oxaliplatin (GemOx) showed statistically significant and clinically meaningful benefit in overall and progression-free survival over rituximab (R)-GemOx, in pts with R/R DLBCL ineligible for autologous stem cell transplant (ASCT; Abramson et al. EHA 2024). However, for pts with R/R DLBCL eligible for ASCT or CD19-directed chimeric antigen receptor (CAR) T-cell therapy, several cycles of salvage chemoimmunotherapy (e.g., R plus ifosfamide, carboplatin, and etoposide; R-ICE) may be required to achieve disease control prior to receiving these therapies. In pts with R/R DLBCL treated with R-ICE prior to ASCT, the overall response rate (ORR) was 63.5% and complete response rate was 38.0% (Gisselbrecht C, et al. J Clin Oncol 2010). As approximately 50% of pts with large B-cell lymphoma are refractory to salvage chemoimmunotherapy, an unmet need remains for optimizing pre-transplant salvage or CAR T-cell bridging therapies. Glofitamab has potential as a salvage treatment prior to CAR T-cell therapy as it targets different molecular antigens. Here, we present preliminary efficacy and safety data for glofitamab in combination with R-ICE (Glofit-R-ICE) in pts with R/R DLBCL eligible for ASCT or CAR T-cell therapy from a Phase Ib study (GO43693; NCT05364424).

Methods: Enrolled pts had DLBCL not otherwise specified (NOS) or high-grade B-cell lymphoma (HGBCL), had received one prior line of therapy, had an Eastern Cooperative Oncology Group performance status of 0-1, had no CNS lymphoma involvement, and were eligible for ASCT or CAR T-cell therapy. Pts received obinutuzumab pretreatment (1000mg) on Cycle (C) 1 Day (D) 1, followed by ICE (standard dose; C1D1─3) and R-ICE (R 375mg/m2 C2D1; ICE C2D1─3) in 21-day cycles. Glofitamab was administered with step-up dosing in C1 (D8, 2.5mg; D15, 10mg) and at target dose (30mg) on C2D8. Pts could receive two or three cycles of Glofit-R-ICE at target dose, at the discretion of the investigator. The primary endpoint was investigator-assessed ORR by 2014 Lugano criteria, defined as the proportion of pts that achieved complete or partial metabolic response (CMR; PMR) within three cycles of Glofit-R-ICE. The interim efficacy-evaluable population was defined as all pts who received their first dose of study treatment at least 77 days before May 31, 2024. The safety-evaluable population was defined as all pts who had ≥1 dose of any study treatment.

Results: As of May 31, 2024, 41 pts provided informed consent and received study treatment. At baseline, median age was 66 years (range: 41-78) and 71.1% of pts were male. Most pts were White (65.9%; Asian: 7.3%; Black/African American: 7.3%; Native Hawaiian: 2.4%; unknown: 12.2%; and 4.9% not reported). Histological subtypes were confirmed as DLBCL NOS (70.7%), HGBCL with MYC and BCL-2/6 rearrangements (12.2%), HGBCL NOS (4.9%), and DLBCL activated B cell (2.4%); 9.8% were unknown. Extranodal disease was reported in 39.0% of pts. Median duration of glofitamab treatment was 28.0 days (range: 1-65). At the time of this interim analysis, the best ORR (CMR or PMR) was 78.1% (95% confidence interval [CI]: 60.0─90.7) and the CMR rate was 68.8% (95% CI: 50.0─83.9) in the interim efficacy-evaluable population (n=32). In the safety-evaluable population (n=41), the most common adverse event (AE) was cytokine release syndrome (CRS; 48.8%; Grade [Gr] 1, 29.3%; Gr 2, 19.5%); no Gr ≥3 CRS events were reported and all events resolved. No immune effector cell-associated neurotoxicity syndrome events were reported. Infections occurred in 19.5% of pts (Gr 1, 4.9%; Gr 2, 7.3%; Gr 3, 7.3%). Gr 3/4 AEs occurred in 61.0% of pts; platelet count decreased/thrombocytopenia was the most common (26.8%). Serious AEs were reported in 41.5% of pts. No Gr 5 AEs were reported. In total, one pt discontinued glofitamab treatment due to AEs. This pt had transformed Waldenstrom's macroglobulinemia with Gr 2 CRS and Gr 3 tumor lysis syndrome.

Conclusions: Glofit-R-ICE demonstrated high response rates in pts with R/R DLBCL eligible for ASCT or CAR T-cell therapy. The safety profile was manageable with a low treatment discontinuation rate. Updated data will be presented.