Updated findings from a phase Ib/II study (NCT03533283) presented at the 2024 ASH Annual Meeting reveal that fixed-duration glofitamab (Columvi) in combination with polatuzumab vedotin (Polivy) yields high response rates and durable remissions in patients with relapsed/refractory large B-cell lymphoma (LBCL). The study highlights the benefit of this regimen across various histologies, including high-grade B-cell lymphomas and cases where prior CAR T-cell therapy had failed.
Durable Remissions and High Response Rates
With a median follow-up of 28.2 months, the study involving 129 patients showed an overall response rate (ORR) of 80.6% (95% CI, 72.7%-87.1%) based on investigator assessment and 78.3% (95% CI, 70.2%-85.1%) by independent review committee (IRC) assessment. Complete response (CR) rates were 62.0% (95% CI, 53.1-70.4%) per investigators and 59.7% (95% CI, 50.7%-68.2%) per IRC.
"There's a high concordance between the investigator-based assessment of response and the assessment by the independent review committee, almost the same overall and complete response rates," noted Martin Hutchings, MD, PhD, of Rigshospitalet at the University of Copenhagen in Denmark, during the presentation.
Notably, in 44 patients with high-grade B-cell lymphoma, the ORR was 79.5%, with 65.9% achieving a complete response. Hutchings emphasized that these results are "pretty unparalleled from previous studies."
Patients previously treated with and failed on CAR T-cell therapy (n = 28) also showed promise, with an ORR of 75.0% and a complete response rate of 50.0%.
The median duration of complete response was 37.8 months (95% CI, 24.1-NE), with a 24-month duration of complete response event-free rate of 63.9% (95% CI, 51.4%-76.4%). The median progression-free survival (PFS) was 12.3 months (95% CI, 8.8-27.7) with a 24-month PFS event-free rate of 41.8% (95% CI, 32.2%-51.5%).
Safety Profile and Adverse Events
The safety signals were consistent with the known profiles of the individual treatments. Glofitamab is associated with cytokine release syndrome (CRS) and cytopenias, while polatuzumab vedotin can cause peripheral neuropathy. Hutchings stated, "We saw no signs of synergistic toxicity between these two drugs, but we did see the additive effects of the components."
Adverse events (AEs) occurred in 99.2% (n = 128) of patients, with 58.9% (n = 76) being grade 3-4. There were 12 (9.3%) grade 5 AEs. "Out of the 7 fatal infections, 5 of those were COVID," Hutchings noted, reminding the audience that the study was conducted during the height of the COVID pandemic.
CRS occurred in 44% of patients, which Hutchings indicated is consistent with glofitamab monotherapy after the introduction of compulsory dexamethasone pretreatment. These events were mainly low grade and resolved within approximately 2 days.
Study Design and Mechanism of Action
Glofitamab, a CD20xCD3 bispecific antibody, redirects T cells to eliminate B cells. Polatuzumab vedotin, an antibody-drug conjugate targeting CD79b on B cells, complements glofitamab's mechanism of action.
The study included patients with DLBCL, high-grade B-cell lymphoma, transformed follicular lymphoma, or primary mediastinal LBCL who had an ECOG performance status of 0-2 and had received at least one prior therapy, including an anti-CD20 antibody and CAR T-cell therapy.
To mitigate CRS risk, patients received 1000 mg of obinutuzumab pretreatment on Cycle 1 Day 1, seven days before the first glofitamab dose. Polatuzumab vedotin was administered at 1.8 mg/kg on Cycle 1 Day 2 and Day 1 of Cycles 2 through 6. Glofitamab was given as a step-up dose, with 2.5 mg on Cycle 1 Day 8 and 10 mg on Cycle 1 Day 15, followed by the target dose of 30 mg on Day 1 of Cycles 2 to 12. Treatment continued for six cycles of polatuzumab vedotin and 12 cycles of glofitamab unless discontinued due to toxicity, disease progression, or withdrawal.
The primary endpoint of the study was ORR, in addition to determining the optimal dose of glofitamab in this combination.
Glofitamab with salvage chemoimmunotherapy
Bispecific antibodies are a novel immunotherapy for patients diagnosed with R/R DLBCL. They act by bringing T-cells in proximity to the malignant B cells, leading to T-cell mediated cytotoxicity. The current phase 1b study, presented at the 2024 American Society of Hematology meeting, was aimed at evaluating the safety and response rates of the combination of glofitamab with chemoimmunotherapy, including rituximab, ifosfamide, carboplatin and etoposide (glofitamab-R-ICE).
Interim analysis showed ORR (CMR or PMR) of 78.1% (95% CI: 60.0 - 90.7) and a CMR rate of 68.8% (95% CI: 50.0 - 83.9) (N = 32). Among the patients who had one or more doses of any study treatment, the most common adverse event (AE) was cytokine release syndrome (CRS), grades 1 and 2, with no grade 3 CRS and no immune effector cell-associated neurotoxicity syndrome (ICANS) events reported. Grade 3 and 4 AEs occurred in 61.0% of patients, and no fatal AEs were reported.
