Glofitamab Plus Polatuzumab Vedotin Demonstrates High Early Efficacy in LBCL

The combination of glofitamab (Columvi) plus polatzumab vedotin (Polivy) demonstrated high efficacy and durable responses in patients with relapsed/refractory large B-cell lymphoma (LBCL), according to trial results published in the Journal of Clinical Oncology.¹

The phase 1b/2 trial (NCT03533282) produced an overall response rate (ORR) of 78.3% among the efficacy-evaluable patients (n = 129). A complete response (CR) rate of 59.7% was observed. The median duration of response (DOR) was 26.4 months (95% CI, 10.9–44.3). The median duration of CR was 37.8 months (95% CI, 24.1–not estimable [NE]). The median progression free-survival (PFS) was 12.3 months (95% CI, 8.8–27.7). The median overall survival (OS) was 33.8 months (95% CI, 20.6–NE). The 24-month OS rate was 54.3%.

In the subgroup of patients with high-grade B-cell lymphoma (n = 44), ORR was 79.5%, CR was 65.9%, median PFS was 16.3 months (95% CI, 9.1–NE), and the median duration of CR was NE.

In the subgroup of patients who had previous CAR T-cell therapy (n = 28), ORR was 75% and CR was 50%.

In the primary refractory disease subgroup (n = 80), the CR rate was 52.5% and the median DOR was 31.8 months (95% CI, 16.4–NE). In the second-line therapy subgroup (n = 53), the ORR was 79.2%, the CR rate was 66%, and the median PFS was 17.7 months (95% CI, 8.1–NE).

The safety profile of glofitamab plus polatzumab vedotin was manageable and consistent with the known profiles of its individual components. Any-grade adverse events (AEs) occurred in 128 (99.2%) patients. Grade 3 or 4 AEs occurred in 76 (58.9%) patients. Serious AEs occurred in 79 (61.2%) patients. Grade 5 AEs occurred in 12 (9.3%) patients. The most common AEs were cytokine release syndrome (CRS) (n = 56), neutropenia (n = 54), peripheral neuropathy (n = 34), diarrhea (n = 31), and SARS-CoV-2 infection (n = 30).

CRS occurred in 44.4% (n = 56/126) of patients who received glofitamab. Most events were low-grade, with 42.9% being grade 1 or 2. There was only 1 grade 3 and 1 grade 5 event reported. The 1 grade 5 CRS event occurred in a 73-year-old patient with advanced high-grade BCL, multiple risk factors, and an unresolved infection who declined further intensive management. CRS events were primarily managed with tocilizumab (Actemra) (33.9%) and supportive care; the median time to resolution was 2 days.

By the end of treatment, CD19+ B-cell depletion was observed in all patients. B-cell counts began to recover 6–12 months after the end of the fixed-duration treatment.

Glofitamab induced T-cell activation and expansion over the treatment course. This demonstrates that the regimen is not lymphodepleting, in contrast to therapies like CAR T-cells or bendamustine.

The phase 1b/2 trial is an open-label, multicenter study with primary end points of ORR and safety. Patients received a single 1000-mg dose of obinutuzumab (Gazyva) pretreatment to mitigate the risk of CRS. Patients received a 1.8-mg/kg dose of polatuzumab vedotin in 6 21-day cycles. Glofitamab was administered with step-up dosing in cycle 1 (2.5 mg, 10 mg) followed by a target dose of 30 mg for a total of 12 21-day cycles. The median age of patients was 67 years. Patients had received a median of 2 prior lines of therapy (range, 1–7).

The study authors note that its success supports the ongoing phase 3 SKYGLO (NCT06047080) trial, which is evaluating the glofitamab and polatuzumab combination in the first-line setting for untreated LBCL.

As noted by Journal of Clinical Oncology editor-in-chief Jonathan W. Friedberg, MD, "Future studies of this combination should focus on patients previously treated with polatuzumab and define molecular subtypes of lymphoma which are particularly sensitive to this regimen."

REFERENCE

1.Hutchings M, Sureda A, Bosch F, et al. Efficacy and safety of glofitamab plus polatuzumab vedotin in relapsed/refractory large B-cell lymphoma including high-grade B-cell lymphoma: Results from a phase Ib/II trial. J Clin Oncol 0, JCO-25-00992 doi:10.1200/JCO-25-00992