Glofitamab-Pirtobrutinib Combination Shows 77% Response Rate in BTK Inhibitor-Exposed Mantle Cell Lymphoma
Key Insights
The phase 2 GoldiLox trial demonstrated that glofitamab plus pirtobrutinib achieved a 77% overall response rate with 69% complete responses in mantle cell lymphoma (search) patients previously exposed to covalent BTK (search) inhibitors.
All nine patients with available samples achieved minimal residual disease negativity, with no responders experiencing disease progression at median 5.6-month follow-up.
Enhanced steroid prophylaxis reduced dose-limiting toxicities, with cytokine release syndrome occurring in 50% of patients but mostly grade 1-2 severity.
The combination of glofitamab-gxbm (Columvi) and pirtobrutinib (Jaypirca) demonstrated high activity and tolerability in patients with mantle cell lymphoma (search) (MCL) previously exposed to covalent BTK (search) inhibitors, according to results from the phase 2 GoldiLox trial presented at the 2025 EHA Congress.
Among 13 evaluable patients, the combination achieved an overall response rate of 77%, comprising a complete response rate of 69% and partial response rate of 8%. Of the three patients who did not meet the primary endpoint, two experienced disease progression and one died from infection and respiratory failure after receiving pre-treatment obinutuzumab.
Deep Molecular Responses Achieved
The combination demonstrated particularly impressive depth of response, with minimal residual disease negativity achieved in all patients with available samples (n = 9). Eight of these patients achieved complete metabolic response, while one achieved 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," wrote Chan Cheah, MBBS (Hons), DMSc, FRACP, FRCPA, a specialist physician in hematology and pathology at Hollywood Private Hospital (search) and Sir Charles Gairdner Hospitals (search) in Perth, Australia, and colleagues.
Addressing Unmet Medical Need
Patients with relapsed/refractory MCL who progress following treatment with a covalent BTK (search) inhibitor or CAR T-cell therapy have limited treatment options and poor prognosis. The investigators hypothesized that combining glofitamab, a bispecific CD20xCD3 T-cell engager, with pirtobrutinib, a highly selective noncovalent BTK inhibitor, would be safe and could lead to deeper and more durable responses based on their complementary mechanisms of action.
Study Design and Patient Population
The ongoing investigator-initiated GoldiLox trial enrolled patients with MCL who had previously received a BTK (search) inhibitor and had progressed on or failed to achieve partial response after 12 weeks of prior treatment. The study evaluated two dosing strategies: pirtobrutinib lead-in (dosing strategy A) and delayed pirtobrutinib (dosing strategy B).
The median age among enrolled patients (n = 16) was 74 years (range, 67-77). Most patients were male (88%) and had ECOG performance status of 0 (62%). Notable baseline characteristics included high Simplified Mantle Cell Lymphoma (search) Prognostic Index scores (56%), disease bulk greater than 5 cm (88%), and marrow involvement (56%). Patients had received a median of 3 prior lines of therapy, with 37% having prior autologous stem cell transplant exposure and 31% having prior CAR T-cell therapy.
Prior covalent BTK (search) inhibitors included ibrutinib (50%), acalabrutinib (19%), zanubrutinib (31%), and TG-1701 (6%).
Safety Profile and Toxicity Management
Initial dose-limiting toxicities of grade 4 tumor lysis syndrome and grade 3 cytokine release syndrome occurred in 2 of 5 patients in the first cohort, prompting exploration of enhanced steroid prophylaxis. Among 8 evaluable patients in subsequent cohorts using enhanced steroid prophylaxis, no dose-limiting toxicities were observed.
Cytokine release syndrome events occurred in 50% of patients, with most being grade 1 (25%) or grade 2 (19%). Grade 3 cytokine release syndrome occurred in only 6% of patients. The median duration of cytokine release syndrome events was 3.5 hours (range, 0.7-134). Steroids and tocilizumab were utilized for management in 38% and 6% of patients, respectively, with all 11 events resolved.
Temporary treatment interruptions due to adverse effects occurred in 5 patients for pirtobrutinib and 2 patients for glofitamab, with 1 patient ceasing all study treatment. One death from multifactorial respiratory failure was reported but deemed unrelated to the regimen.
Treatment Regimens
Dosing strategy A consisted of pirtobrutinib at 200 mg daily with intravenous obinutuzumab at 2 g in divided doses, followed by continuous pirtobrutinib and step-up glofitamab dosing. Dosing strategy B used the same obinutuzumab pre-treatment with standard step-up glofitamab, introducing pirtobrutinib 7 days after the target 30-mg glofitamab dose.
The study's primary endpoint was complete response rate after 6 cycles per Lugano 2014 classification, with secondary endpoints including safety, progression-free survival, overall survival, and minimal residual disease status. Enrollment continues at 9 sites across Australia.