Magrolimab Plus Rituximab/Chemo Elicits Deep Responses in Relapsed/Refractory DLBCL

Article

The combination of magrolimab, rituximab, gemcitabine, and oxaliplatin produced deep, durable responses in patients with relapsed or refractory diffuse large B-cell lymphoma.

The combination of magrolimab, rituximab (Rituxan), gemcitabine, and oxaliplatin produced deep, durable responses in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), according to preliminary results from a cohort of a phase 1b trial (NCT02953509) presented at the 2022 ASH Annual Meeting.

At a median follow-up of 11.3 months (range, 0.1-33.4), patients with relapsed/refractory DLBCL (n = 33) achieved an overall response rate (ORR) of 51.5%, which included a complete response (CR) rate of 39.4% and a partial response (PR) rate of 12.1%. Additionally, 6.1% of patients achieved stable disease, 21.2% of patients experienced disease progression, and 21.7% of patients were not assessed. 

Among 17 patients who achieved a response, the median duration of response (DOR) was 18 months (95% CI, 4.7–not estimable [NE]), and the median time to response was 1.9 months (range, 1.8-3.4).

Moreover, the median progression-free survival (PFS) was 3.9 months (95% CI, 2.3-20.3), and the median overall survival (OS) was NE (95% CI, 9.4 months–NE). Additionally, the 1-year PFS and OS rates were 35.4% (95% CI, 17.5%-53.9%) and 67.1% (95% CI, 47.5%-80.8%), respectively.

“Responses were observed across multiple patient subgroups, regardless of number of prior lines of therapy or completed gemcitabine/oxaliplatin cycles,” wrote Joseph E. Maakaron, MD, who is the lead study author and an associate professor of Medicine at the University of Minnesota Medical School, and colleagues, in a poster of the data.

Patients with relapsed/refractory DLBCL have limited treatment options following up-front rituximab plus chemotherapy. Previous results from the study showed that magrolimab plus rituximab was active and safe when given to patients with relapsed/refractory DLBCL or indolent non-Hodgkin lymphoma.

Results from the cohort of patients with relapsed/refractory DLBCL who received magrolimab plus rituximab and chemotherapy were presented at the 2022 ASH Annual meeting.

Those enrolled to this cohort were required to have de novo or transformed DLBCL that was relapsed or refractory to 1 to 3 standard prior lines of treatment, including an anti-CD20 therapy. Patients also needed to be ineligible for intensive chemotherapy or autologous stem cell transplant (ASCT) or have relapsed after prior ASCT.

Patients were excluded if they relapsed following CAR T-cell therapy or were primary refractory, defined as failure to achieve a PR or CR to frontline treatment or experiencing disease progression within 3 months of completing treatment.

In the open-label, multicenter study, patients received either 30 mg/kg of intravenous (IV) magrolimab (n = 26) or 45 mg/kg of IV magrolimab (n = 7) in combination with rituximab and chemotherapy.

Magrolimab was given intravenously at an initial dose of 1 mg/kg to mitigate on-target anemia, followed by 30 mg/kg or 45 mg/kg weekly during cycles 1 and 2. Subsequently, maintenance doses of the drug were administered every 2 weeks in cycle 3 and beyond. All patients received IV rituximab at 375 mg/m2 weekly on days 8, 15, and 22 in cycle 1, then monthly on day 1 in cycles 2 to 6, and on day 1 of every other cycle thereafter. Moreover, IV gemcitabine was given at 1000 mg/m2 and IV oxaliplatin was given at 100 mg/m2 on days 11 and 23 in cycle 1, and days 2 and 15 for cycles 2 to 4. Additional dosing of gemcitabine/oxaliplatin was permitted beyond cycle 4 per investigator discretion, for a total of 8 doses.

The primary end points of the trial consisted of safety, tolerability, and ORR per Lugano criteria and investigator assessment. Key secondary end points included DOR, PFS, and OS.

The median duration of treatment with magrolimab, rituximab, and gemcitabine/oxaliplatin was 2.6 months (range, 0-23.2), 2.3 months (range, 0-19.5), and 1.8 months (range, 0-5.2), respectively. Patients received a median of 3 cycles of the combination.

The median patient age was 71.0 years (range, 31.0-86.0); 30.3% of patients were at least 75 years old and 63.6% were male. The median number of prior therapies received was 2 (range, 1-7). Patients had an ECOG performance status of 0 (36.4%), 1 (57.6%), or 2 (6.1%). Moreover, 78.8% of patients had de novo DLBCL, 21.2% had transformed DLBCL, and 3% had double-hit lymphoma.

Additionally, 9.1% of patients had stage I/II disease at initial diagnosis and 66.7% had stage III/IV disease; this was unknown for 24.2% of patients. Furthermore, 42.4% of patients were refractory to their last regimen, 21.2% were primary refractory, and 18.2% underwent prior ASCT. No patients previously received CAR T-cell therapy.

Patients who were refractory to their last treatment regimen (n = 14) experienced an ORR of 28.6%. In those who had 1 prior line of therapy (n = 14), 2 prior lines of therapy (n = 9), and more than 2 prior lines of therapy (n = 10), the ORRs were 57.1%, 55.6%, and 40.0%, respectively. In patients who completed 1 cycle of gemcitabine/oxaliplatin (n = 5), 2 cycles (n = 11), or more than 2 cycles (n = 14), the ORRs were 40.0%, 36.4%, and 78.6%, respectively.

Patients under 75 years of age (n = 23) achieved an ORR of 52.2%, and those aged 75 years and older (n = 10) experienced an ORR of 50.0%. In patients with a germinal center immunophenotype (n = 14), the ORR was 42.9% with the combination. Those with a non–germinal center immunophenotype (n = 8) experienced an ORR of 50.0%.

At a data cutoff date, 81.8% of patients discontinued magrolimab and rituximab due to disease progression (39.4% and 36.4% for magrolimab and rituximab, respectively), adverse effects (AEs; 15.2% and 18.2%), or physician decision (12.1% and 15.2%).

The most common any-grade treatment-emergent AEs (TEAEs) reported in at least 15% of patients included fatigue, anemia, diarrhea, nausea, infusion-related reactions, thrombocytopenia, dyspnea, pyrexia, decreased platelet counts, dizziness, headache, hypotension, vomiting, constipation, decreased appetite, chills, temperature intolerance, cough, hypokalemia, hypophosphatemia, asthenia, hypomagnesemia, back pain, pain in extremity, peripheral edema, neutropenia, abdominal pain, hyponatremia, increased aspartate transferase, increased alanine transaminase, and upper respiratory tract infection.

Grade 3 or higher TEAEs occurred in 93.9% of patients. Treatment-related TEAEs led to the discontinuation of magrolimab in 2 patients due to grade 4 ventricular fibrillation and grade 5 colitis in 1 patient each.

Notably, 84.7% of TEAEs occurred in the first 3 months of treatment, including anemia (82.3%), and most high-grade TEAEs were reported in the first 3 months. The median time to TEAE onset was 29 days (range, 1-700), and the median time to resolution was 7 days (range, 1-386). Notably, 79.2% of all TEAEs resolved.

“These results compare favorably with current standard-of-care regimens, with the potential added advantage of outpatient delivery, and support further evaluation of magrolimab combinations in patients with DLBCL,” the study authors concluded.

Reference

Maakaron JE, Asch A, Popplewell L, et. al. Magrolimab in combination with rituximab + chemotherapy in patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Blood. 2022;140(suppl 1):3728-3730. doi:10.1182/blood-2022-167772

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