Glofitamab Plus Pirtobrutinib Yields High Activity, Tolerability in Covalent BTK Inhibitor–Exposed MCL

Glofitamab Plus Pirtobrutinib in Covalent

BTK Inhibitor–Exposed MCL | Image Credit:

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Both dosing strategies of glofitamab-gxbm (Columvi) in combination with pirtobrutinib (Jaypirca) were highly active and well tolerated when administered alongside enhanced steroid prophylaxis in patients with mantle cell lymphoma (MCL) who were previously exposed to a covalent BTK inhibitor, according to data from the phase 2 GoldiLox trial (NCT05833763).1

Results presented during the 2025 EHA Congress showed that the combination elicited an overall response rate (ORR) of 77% among evaluable patients (n = 13). This comprised a complete response (CR) rate of 69% and partial response (PR) rate of 8%. Of the 3 patients who did not meet the primary end point, 2 experienced disease progression and 1 died from infection and respiratory failure after receiving pre-treatment obinutuzumab (Gazyva).

Furthermore, minimal residual disease (MRD) negativity was achieved with the combination in all patients with available samples (n = 9), 8 of whom achieved a complete metabolic response and 1 of whom achieved a partial metabolic response. At a median follow-up of 5.6 months (range, 0.5-14), no responders experienced disease progression, and 81% of patients remained on study treatment.

“The high rates of ongoing CRs and MRD-negative responses justify further investigation of this combination in expansion cohorts,” Chan Cheah, MBBS (Hons), DMSc, FRACP, FRCPA, a specialist physician in hematology and pathology, as well as a clinical researcher at Hollywood Private Hospital and Sir Charles Gairdner Hospitals in Perth, Australia, and colleagues wrote in a poster presentation of the data. Cheah also serves as a clinical professor of internal medicine at the University of Western Australia Medical School.

Study Background and Design

Patients with relapsed/refractory MCL who progress following treatment with a covalent BTK inhibitor or CAR T-cell therapy have limited treatment options and a poor prognosis. Glofitamab, a bispecific CD20xCD3 T-cell engager, and pirtobrutinib, a highly selective, noncovalent BTK inhibitor, have each demonstrated clinical activity as monotherapies in heavily pretreated populations. Based on their complementary mechanisms of action, investigators hypothesized that combining glofitamab and pirtobrutinib would be safe and could lead to deeper and more durable responses in patients with prior covalent BTK inhibitor exposure.

The ongoing, investigator-initiated GoldiLox trial enrolled patients with MCL who had previously received a BTK inhibitor alone or as part of a combination regimen and had progressed on or failed to achieve a PR after 12 weeks of this prior treatment. An ECOG performance status of 0 to 2 and adequate organ function were also required. Key exclusion criteria included active central nervous system disease, receipt of autologous stem cell transplant (ASCT) or CAR T-cell therapy within 60 days, and inability to tolerate grade 3 or higher cytokine release syndrome (CRS), according to the investigator’s opinion.

Two dosing strategies were evaluated in this study: a pirtobrutinib lead-in (dosing strategy A) and delayed pirtobrutinib (dosing strategy B). Although the study was originally designed to assess these dosing strategies across 4 cohorts, cohort 4 was not used for this analysis.

Dosing strategy A consisted of a pre-phase dose of pirtobrutinib at 200 mg daily and intravenous obinutuzumab at 2 g in 2 to 3 divided doses over 1 week. This was followed by continuous pirtobrutinib for 14 to 21 days during cycle 1, and 21 days during cycles 2 through 12, and glofitamab at 2.5 mg on day 1 of cycle 1, 10 mg on day 8 of cycle 1, followed by 30 mg on day 1 of cycles 2 through 12 (cohort 1) or a 1.25 mg on cycle 1 day 1, 5 mg on cycle 1 day 8, and 10 my on cycle 1 day 15, followed by 30 mg on day 1 of cycles 2 through (cohort 2). Dosing strategy B comprised the same obinutuzumab pre-treatment strategy followed by standard step-up glofitamab, with the 200-mg daily dose of continuous pirtobrutinib being introduced 7 days after the target 30-mg dose of glofitamab in cycle 2 (cohort 3). Up to 6 patients each were planned for enrollment onto cohorts 1 and 3; 3 patients each were planned for enrollment onto cohorts 2 and 4.

The study’s primary end point was CR rate after 6 cycles of treatment per Lugano 2014 classification. Secondary end points included safety, progression-free survival, overall survival, and MRD status.

Baseline Characteristics

The median age among patients enrolled onto the study (n = 16) was 74 years (range, 67-77). Most patients were male (88%) and had an ECOG performance status of 0 (62%), a high score on the Simplified Mantle Cell Lymphoma Prognostic Index (56%), disease bulk greater than 5 cm (88%), and marrow involvement (56%). Patients had classical (38%), pleomorphic/blastoid (19%), or unknown/missing (44%) morphology.

Ki-67 score was less than 30% in 19% of patients, 30% or higher in 38% of patients, and unknown/missing in 44% of patients. TP53 mutations were absent, present, and unknown/missing in 6%, 12%, and 81% of patients, respectively. Similarly, 17p deletions were present in 31% of patients and unknown/missing in 69% of patients.

Other baseline characteristics of note included B symptoms (19%), elevated lactate dehydrogenase levels (44%), and circulating disease (31%).

Patients had received a median of 3 prior lines of therapy (range, 2-3). Previous exposure to ASCT and CAR T-cell therapy was reported by 37% and 31% of patients, respectively. Prior covalent BTK inhibitors included ibrutinib (Imbruvica; 50%), acalabrutinib (Calquence; 19%), zanubrutinib (Brukinsa; 31%), and TG-1701 (6%)

Enrollment onto this study is ongoing at 9 sites across Australia.

Safety Outcomes

Notably, dose-limiting toxicities (DLTs) of grade 4 tumor lysis syndrome and grade 3 CRS occurred in 2 of 5 patients in cohort 1. This spurred an exploration of alternative dosing strategies, such as enhanced steroid prophylaxis. Among the 8 evaluable patients in cohorts 2 and 3, no DLTs were observed. One death from multifactorial respiratory failure was reported in the trial but was deemed unrelated to the regimen. Temporary interruptions to treatment with pirtobrutinib and glofitamab due to adverse effects (AEs) occurred in 5 and 2 patients, respectively, with 1 patient ceasing all study treatment.

Any-grade CRS events were reported in 50% of patients, most of which were grade 1 (25%) or grade 2 (19%). Grade 3 CRS occurred in only 6% of patients. The median duration of CRS events was 3.5 hours (range, 0.7-134). Steroids and tocilizumab (Actemra) were utilized for CRS management in 38% and 6% of patients, respectively. All 11 CRS events were resolved.

Reference

Cheah C, Minson A, Falconer J, et al. GoldiLox: first experience of safety and activity of two dosing strategies of pirtobrutinib and glofitamab for mantle cell lymphoma in patients previously treated with covalent BTK inhibitors - an ALLG study. Presented at: European Hematology Association Congress; June 12-15, 2025; Milan, Italy. Abstract PS1874