Glofitamab-Based Combo Confers High Response Rates in Heavily Pretreated Relapsed/Refractory LBCL

Large B-Cell Lymphoma
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Fixed duration glofitamab (Columvi) plus polatuzumab vedotin (Polivy) demonstrated high response rates and durable remissions in heavily pretreated patients with relapsed/refractory large B-cell lymphoma (LBCL), according to updates results from a phase Ib/II study (NCT03533283) presented at the 2024 ASH Annual Meeting.

Findings from the study also demonstrated a benefit with this treatment regimen across histologies, including patients with high-grade B-cell lymphomas and those who failed previous CAR T-cell therapy.

During a median follow-up of 28.2 months, in the 129 patients in the study, the overall response rate (ORR) was 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%) according to investigators and 59.7% (95% CI, 50.7%-68.2%) according to IRC.

“You can see 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,” Martin Hutchings, MD, PhD, of Rigshospitalet at the University of Copenhagen in Denmark, said during the presentation of the findings.

Although high response rates were observed across all histologies, Hutchings emphasized the findings in patients with high-grade B-cell lymphoma. In these 44 patients, the ORR of 79.5%, and 65.9% achieved a complete response from treatment.

“That is pretty unparalleled from previous studies,” Hutchings added.

He also noted that patients previously treated and failed on CAR T-cell therapy (n = 28) had an ORR of 75.0%, with 50.0% achieving a complete response.

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% (95A% 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%).

Duration of complete response and PFS benefits were notable across all histologies, including diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma, and high-grade B-cell lymphomas.

Regarding biomarkers, Hutchings noted that a reduction of circulating tumor DNA (ctDNA) was observed in patients with complete responses at the end of treatment, and was similar across all histologies. In addition, patients achieved an overall PFS rate of over 50% at 24 months, “something which is of clinical relevance to these patients,” Hutchings said.

During a median overall survival (OS) follow-up of 32.7 months (range, 0-55.0), the 24-month OS rate was 54.3% (95% CI, 45.3%-63.4%), with a median OS of 33.8 months (95% CI, 20.6-NE).

For safety, Hutchings said the signals were “quite consistent with the contributions of the individual components [of treatment].” In particular, glofitamab has a distinct safety profile with cytokine release syndrome (CRS) and cytopenias, whereas the toxicity profile of polatuzumab vedotin includes peripheral neuropathy.

“We saw no signs of synergistic toxicity between these two drugs, but we did see the additive effects of the components,” Hutchings said during the presentation.

Adverse effects (AEs) occurred in 99.2% (n = 128) of patients in the study, of which 58.9% (n = 76) were considered grade 3-4. There were 12 (9.3%) grade 5 AEs.

“Out of the 7 fatal infections, 5 of those were COVID,” Hutchings said. “And I should remind you in that context that this study was carried out during the height of the primary COVID pandemic.”

AEs leading to treatment discontinuation occurred in 12.4% (n = 16) related to glofitamab and in 8.5% (n = 11) related to polatuzumab vedotin.

Hutchings noted that the frequency of CRS was 44%, “which actually is in keeping with the numbers from glofitamab monotherapy after the introduction of compulsory dexamethasone pretreatment, as opposed to any steroid.” In addition, CRS events were mainly low grade and occurred early during step-up dosing. He noted that CRS events resolved within approximately 2 days.

Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 3.8% (n = 5) of patients, of whom 0.8% (n = 1) had an event considered grade 3 or higher. Other AEs of interest of any grade included peripheral neuropathy (24%), neutropenia (41.9%), febrile neutropenia (1.6%), serious infections (30.2%), and tumor flare (7.0%).

Study Design and Background

Glofitamab is a CD20xCD3 bispecific antibody that engages and redirects T cells to eliminate B cells. In addition, polatuzumab vedotin is an antibody drug conjugate that targets CD79b on B cells, and has a complementary mechanism of action to glofitamab, according to the presentation.

These updated results including a longer follow-up in 129 patients with DLBCL, high-grade B-cell lymphoma, transformed follicular lymphoma or primary mediastinal LBCL. Patients in the study also had an ECOG performance status of 0-2, and were treated with at least 1 prior therapy including an anti-CD20 antibody and CAR T-cell therapy.

To mitigate the risk for CRS, patients in the study received 1000 mg of obinutuzumab (Gazyva) pretreatment on Cycle 1 Day 1, 7 days before the first dose of glofitamab was given. Polatuzumab vedotin was given as a 1.8 mg/kg dose on Cycle 1 Day 2 and Day 1 of Cycles 2 through 6, of which the cycles consisted of 21 days each. Glofitamab was given as a step-up dose, with 2.5 mg on Cycle 1 Day 8 and 10 mg at Cycle 1 Day 15, followed by the target dose of 30 mg on Day 1 of Cycles 2 to 21, which were 21-day cycles. Fixed treatment of 6 cycles of polatuzumab vedotin and 12 cycles of glofitamab were given unless a patient discontinued treatment for unacceptable toxicities, disease progression, or content withdrawal.

The primary end point of the study was ORR, in addition to the optimal dose of glofitamab in this combination.

Hutchings noted that the baseline characteristics during this follow-up were similar to what had been previously presented. The median age of patients in the study was 67.0 years (range, 23-84) and 63.6% were male.

Some characteristics of note included the fact that there were 34.1% of patients with high-grade B-cell lymphoma, which included patients with double-hit and triple-hit lymphoma (22.5%). Sixty-two percent of patients had been primary refractory, and 71.3% were refractory to the most recent line of treatment.

The median number of treatment cycles received was 10.5 for glofitamab (range, 1-17) and 6 for polatuzumab vedotin (range, 1-12).

Reference

Hutchings M, Balari AS, Bosch F, et al. Glofitamab in combination with polatuzumab vedotin maintains durable responses and a manageable safety profile in patients with heavily pre-treated relapsed/refractory (R/R) large B-cell lymphoma (LBCL) including high-grade B-cell lymphoma (HGBCL): extended follow-up of a phase Ib/II study. Blood. 2024;144(suppl 1):988. doi:10.1182/blood-2024-194328