Glofitamab, an investigational CD20xCD3 T-cell engaging bispecific antibody, elicited encouraging response rates in patients with relapsed/refractory diffuse large B-cell lymphoma in a phase 1/2 study.
Patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who had received at least 2 prior lines of therapy achieved promising responses with glofitamab, an investigational CD20xCD3 T-cell engaging bispecific antibody, according to part 2 findings from a phase 1/2 study (NCT03075696).1
A total of 155 patients were assigned to glofitamab monotherapy at step-up doses of 2.5 mg and 10 mg, followed by 30 mg on day 1 of cycles 2 through 12 from January 2020 through September 2021. All patients received pretreatment with obinutuzumab (Gazyva) to mitigate cytokine release syndrome (CRS).
At a median follow-up of 12.6 months (range, 0.1-22.1) the complete response (CR) rate was 39% (95% CI, 32%-48%) as assessed by the independent review committee. The median time to CR was 42 days (95% CI, 42-44).
The objective response rate (ORR) was 52% (95% CI, 43%-60%). Concordance between results according to independent review assessment and investigator assessment was 93% for CR and 86% for ORR.
In comparison, axicabtagene ciloleucel (Yescarta) induced CR rates of 54% in patients who failed on at least 2 previous treatments in phase 1 findings from the ZUMA-1 trial (NCT02348216).2 In results from the multicenter, phase 2 JULIET trial (NCT02445248) in adults with relapsed or refractory DLBCL and DLBCL after transformation from follicular lymphoma, tisagenlecleucel (Kymriah) induced a CR rate of 32% (95% CI, 21.5%-44.8%) in 68 evaluable patients. The FDA approved tisagenlecleucel based on these results in 2018.3
CAR T-cell therapies such as axicabtagene ciloleucel and tisagenlecleucel appear to be more effective in the relapsed/refractory patient population than approved antibody-drug conjugates such as tafasitamab-cxix (Monjuvi) with lenalidomide (Revlimid), pixantrone (Pixuvri), and selinexor (Xpovio). However, investigators noted that CAR T-cell therapies are not consistently available due to logistic, geographic, or resourcing constraints.
Many patients with DLBCL who are selected for CAR T-cell infusion do not receive the treatment because of disease progression or death while awaiting therapy. Furthermore, approximately 40% of patients have durable remission with third-line CAR T-cell therapy, so there is an unmet need for effective and immediately available treatments.
To address that need, investigators evaluated glofitamab. The bispecific monoclonal antibody has a novel 2:1 tumor–T-cell binding configuration that confers bivalency for CD20 B cells and monovalency for CD3 T cells. The agent engages and redirects patients’ existing T cells to eliminate malignant B cells.
Eligible adult patients were diagnosed with histologically confirmed DLBCL not otherwise specified (71%), transformed follicular lymphoma (18%), high-grade B-cell lymphoma (7%), or primary mediastinal LBCL (n = 4%).
The median patient age was 66 years (range, 21-90). Patients had received a median of 3 lines (range, 2-7) of previous therapy. Sixty percent of patients received at least 3 previous therapies, 33% of whom received CAR T-cell therapy previously. Among those who received CAR T-cell therapy, 71% did so as the therapy immediately preceding study enrollment and 89% were refractory.
The median duration between the receipt of CAR T-cell therapy and obinutuzumab pretreatment was 127 days (range, 46-912; interquartile range, 104-212). Most patients (75%) had Ann Arbor stage III or IV disease. Fifty-eight percent had disease that was primary refractory to previous treatment and 86% were refractory to last therapy.
All the patients had a dose intensity of at least 90%. The median duration of glofitamab treatment was 79 days (range, 1-326) and investigators administered a median of 5 (range, 1-13) cycles. Patients with a CR received a median of 12 cycles.
At the data-cutoff date, 66% of the objective responses and 80% of CRs were ongoing. The median duration of objective response was 18.4 months (95% CI, 13.7-not reached [NR]). Objective response was ongoing at 12 months in 64% (95% CI, 51%-76%) of the 80 patients with an objective response.
The median duration of CR was not reached (95% CI, 16.8-NR). CR was ongoing at 12 months in 78% (95% CI, 64%-91%) of the 61 patients who had CR. At the data-cutoff date, 87% of patients with a CR were alive, as were 74% of patients with an objective response.
The 12-month progression-free survival rate was 37% (95% CI, 28%-46%). The estimated 12-month overall survival rate among all 155 patients was 50% (95% CI, 41%-58%).
Just 14 of 154 of patients discontinued treatment because of adverse effects (AEs). Five patients (3%) had a glofitamab-related AE leading to treatment discontinuation (gastrointestinal hemorrhage, myelitis, and CRS in 1 patient each, and neutropenia in 2 patients).
Sixty-two percent of patients experienced grade 3 or higher AEs. Eight (5%) patients experienced fatal AEs (Covid-19–related pneumonia or Covid-19 in 5, sepsis in 2, and delirium in 1). Although 91% of patients experienced glofitamab-related AEs, no deaths were attributed to the therapy. Sixty-four (42%) patients had grade 3/4 glofitamab-related AEs.
The most common any-grade AEs included CRS per ASTCT criteria (63%), neutropenia (38%), anemia (31%), and thrombocytopenia (25%). CRS was primarily associated with the first 3 doses of glofitamab. Four percent of patients experienced grade 3/4 CRS.
Investigators recorded grade 3/4 AEs in 56% of patients, most commonly neutropenia (27%), anemia (6%), and thrombocytopenia (8%). CRS was the most common serious AE (21%) followed by sepsis (4%), tumor flare (3%), COVID-19 (3%), and COVID-19–related pneumonia (3%).
References
Autologous HCT Does Not Provide Added Survival Benefit in Patients With MCL in First CR
December 10th 2024Patients with mantle cell lymphoma in first complete response with undetectable MRD did not benefit from consolidative autologous transplant, according to results from the ECOG-ACRIN EA4151/BMT-CTN 1601 trial.
Liso-Cel Shows Comparable Real-World Outcomes in Relapsed/Refractory LBCL
December 9th 2024Real-world treatment with liso-cel showed a broad spectrum of outcomes that were comparable to those in the pivotal TRANSFORM and PILOT trials in patients with relapsed/refractory large B-cell lymphoma.