Tafasitamab Plus Lenalidomide/Rituximab Improves PFS in Relapsed/Refractory Follicular Lymphoma

Tafasitamab-cxix (Monjuvi) plus lenalidomide (Revlimid) and rituximab (Rituxan) led to a 57% reduction in the risk of disease progression or death vs placebo plus lenalidomide and rituximab in patients with relapsed/refractory follicular lymphoma, according to primary findings from the phase 3 inMIND trial (NCT04680052) that were presented at the 2024 ASH Annual Meeting & Exposition.1

At a median follow-up of 14.1 months, the median investigator-assessed progression-free survival (PFS) was 22.4 months (95% CI, 19.2-not evaluable [NE]) with the triplet (n = 273) vs 13.9 months (95% CI, 11.5-16.4) with lenalidomide/rituximab alone (n = 275; HR, 0.43; 95% CI, 0.32-0.58; P < .0001).

According to independent review committee (IRC) assessment, the median PFS was not yet reached (NR; 95% CI, 19.3-NE) with the triplet vs 16.0 months (95% CI, 13.9-21.1) with the doublet (HR, 0.41; 95% CI, 0.29-0.56; P < .0001).

“The inMIND phase 3 study met its primary end point of prolonging PFS in relapsed/refractory follicular lymphoma,” Laurie H. Sehn, MD, MPH, lead study author of BC Cancer Centre for Lymphoid Cancer and The University of British Columbia, in Vancouver, Canada, said in a presentation of the data. “Benefit was observed in all prespecified subgroups, including patients with POD24 [progression of disease within 24 months of initial diagnosis], [those who were] refractory to prior anti-CD20 monoclonal antibodies, and [those] receiving multiple prior lines of therapy.”

Most patients with follicular lymphoma will require more than 1 line of therapy, and although immunotherapy is a preferred regimen for patients with relapsed or refractory disease, the duration of response (DOR) of these agents remains limited.

The combination of lenalidomide and rituximab has been an FDA-approved regimen for patients with previously treated follicular lymphoma since 2018. The approval was based on data from the phase 3 AUGMENT trial (NCT01938001), which showed an improvement in PFS vs rituximab alone.2 Tafasitamab is a CD19-directed monoclonal antibody that induces direct cytotoxic effects and improves NK cell and macrophage immune-mediated mechanisms.1

To evaluate the potential synergistic activity of adding tafasitamab to lenalidomide and rituximab investigators launched the double-blind, placebo-controlled, international, multicenter inMIND trial, which evaluated patients with follicular lymphoma and marginal zone lymphoma (MZL).

To be eligible for enrollment patients at least 18 years of age needed to have grade 1 to 3A follicular lymphoma or MZL and received at least 1 prior line of therapy, including an anti-CD20 monoclonal antibody. An ECOG performance status of 0 to 2 and no prior exposure to lenalidomide plus rituximab were also required.

Following confirmation of eligibility patients were randomly assigned 1:1 to the experimental or control arm. In the experimental arm patients received 12 mg/kg of intravenous (IV) tafasitamab every week for the first 3 cycles followed by every 2 weeks for cycles 4 through 12; plus 20 mg/day of oral lenalidomide on days 1 to 21 for 12 cycles; and 375 mg/m2 of IV rituximab once weekly for the first cycle and every 4 weeks for cycles 2 through 5. In the control arm patients received IV placebo in the same schedule as tafasitamab, plus lenalidomide and rituximab via the same dosing schedule as the experimental arm.

The primary end point was PFS. Key secondary end points included PET-complete response (CR) rate in the FDG-avid population and overall survival (OS). Other secondary end points included PFS by IRC, objective response rate (ORR), DOR, safety, quality of life, and minimal residual disease. Exploratory end points included assessments for time to next treatment (TTNT), B-cell recovery, Ig levels, and CD19 expression. All study end points were investigator-assessed unless stated otherwise.

The study was powered to assess PFS in the follicular lymphoma population and was initiated after 174 investigator-assessed events occurred.

A total of 548 patients were randomly assigned to treatment with tafasitamab (n = 273) or placebo (n = 275), and 51 (18.7%) and 42 (15.3%) remain on treatment, respectively. A total of 244 (89.4%) and 229 (83.3%) patients in the investigational and control arms, respectively, remain ongoing in the study. At the time of the analysis the median number of cycles received was 12 with tafasitamab vs 11 with placebo.

Baseline characteristics of the overall population indicated that the median age was 64.0 years (range, 31.0-88.0) and 19.7% of patients were at least 75 years of age. The median time since initial diagnosis was 5.3 years (range, 0.0-34.0) and most patients had an ECOG performance status of 0 (68.1%). Most patients also had Ann Arbor stage III or IV disease (81.4%), grade 1 or 2 disease (74.1%), and a Follicular Lymphoma International Prognostic Index score of 3 to 5 (52.4%). Diagnosis of follicular lymphoma had been confirmed by central pathology in 92.2% of cases.

With regard to treatment history, most patients had received 1 prior line of therapy (54.7%), were within 2 years of receiving their last anti-lymphoma therapy (55.5%), and had disease that had relapsed on the last therapy (56.9%).

Additional efficacy findings from the subgroup analysis also illustrated a PFS benefit favoring the investigational regimen regardless of POD24 status and refractoriness to anti-CD20 antibody therapy. In patients with POD24, the median PFS was 19.2 months (95% CI, 13.8-NE) with the triplet vs 11.3 months (95% CI, 8.3-13.6) with the doublet (HR, 0.43; 95% CI, 0.27-0.69). In patients without POD24, the median PFS was 23.6 months (95% CI, 22.3-NE) vs 16.0 months (95% CI, 13.3-21.4) with the triplet and doublet, respectively (HR, 0.45; 95% CI, 0.31-0.65).

In patients who were refractory to anti-CD20 antibody therapy the median PFS was 15.0 months (95% CI, 14.1-25.1) in the investigational arm vs 8.6 months (95% CI, 7.9-11.6) in the control arm (HR, 0.44; 95% CI, 0.30-0.65). In patients who were not refractory to anti-CD20 antibody therapy the median PFS was 24.0 months (95% CI, 22.3-NE) vs 18.2 months (95% CI, 14.4-NE) with the investigational and control regimens, respectively (HR, 0.44; 95% CI, 0.28-0.68).

With respect to response in the FDG-avid population the PET-CR rate was 49.4% (95% CI, 43.1%-55.8%) in the investigational arm (n = 251) vs 39.8% (95% CI, 33.7%-46.1%) in the control arm (n = 254; OR, 1.5; 95% CI, 1.04-2.13; P = .0286). In the intention-to-treat population, the ORR was 83.5% (95% CI, 78.6%-87.7%) in the triplet arm vs 72.4% (95% CI, 66.7%-77.6%) in the doublet arm (OR, 2.0; 95% CI, 1.30-3.02; P = .0014).

Additional efficacy findings demonstrated that the median DOR was 21.2 months (95% CI, 19.5-NE) with the triplet vs 13.6 months (95% CI, 12.4-18.6) with the doublet (HR, 0.47; 95% CI, 0.33-0.68; P < .0001).

The median TTNT was NR (95% CI, NE-NE) with the triplet vs 28.8 months (95% CI, 20.7-NE) with the doublet (HR, 0.45; 95% CI, 0.31-0.64; P < .0001).

Sehn stated that the OS analysis will be performed after the 5-year follow-up period, but to confirm the futility threshold was not crossed investigators conducted a preliminary survival analysis with a median follow-up of 15.3 months. The data indicated that the threshold had not been crossed, showcasing a positive trend with a median OS that was NR with either the triplet (95% CI, 27.9-NE) or the combination (95% CI, NE-NE; HR, 0.59; 95% CI, 0.31-1.13).

“The safety profile was manageable and consistent with expected toxicities with these agents,” Sehn said, turning to the regimen’s toxicity profile.

Some of the most common any-grade treatment-emergent adverse effects (TEAEs) in the tafasitamab and placebo arms, respectively, included neutropenia (48.5%; 45.2%), diarrhea (37.6%; 28.3%), COVID-19 (31.4%; 23.5%), constipation (29.2%; 24.6%), rash (21.9%; 21.3%), and fatigue (21.2%; 15.8%). The most common grade 3 or 4 TEAEs in the tafasitamab and placebo arms, respectively, included neutropenia (39.8%; 37.5%), pneumonia (8.4%; 5.1%), thrombocytopenia (6.2%; 7.4%), and decreased neutrophil count (5.8%; 6.6%), among others.

Sehn stated that tafasitamab and placebo dose interruptions or discontinuations because of TEAEs were similar between treatment arms, as were discontinuations for lenalidomide.

Deaths occurred in 5.5% (n = 15) of patients in the investigational arm vs 8.5% (n = 23) of those in the placebo arm.

“This study is the first to validate the approach of combining 2 antibodies for the treatment of patients with follicular lymphoma. Tafasitamab plus lenalidomide and rituximab can be administered in community as well as academic settings and represents a potential new standard of care for patients with relapsed/refractory follicular lymphoma,” Sehn said in conclusion.

Disclosures: Dr Sehn disclosed honoraria from AbbVie, Amgen, AstraZeneca, Beigene, Bristol Myers Squibb/Celgene, Genmab, Kite/Gilead, Incyte, Janssen, Merck, Seagen, F. Hoffmann-La Roche Ltd, and Genentech, Inc.; research funding from F. Hoffman-La Roche Ltd, Genentech, Inc., Teva; and consultancy for AbbVie, Amgen, AstraZeneca, Beigene, Bristol Myers Squibb/Celgene, Genmab, Kite/Gilead, Incyte, Janssen, Merck, Seagen, F. Hoffman-La Roche Ltd, and Genentech, Inc.

References

1. Sehn LH, Luminari S, Scholz CW, et al. Tafasitamab plus lenalidomide and rituximab for relapsed or refractory follicular lymphoma: results from a phase 3 study (inMIND). Blood. 2024;144(suppl 2):LBA-1. doi:10.1182/blood-2024-212970
2. FDA approves lenalidomide for follicular and marginal zone lymphoma. FDA. May 28, 2019. Accessed December 10, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lenalidomide-follicular-and-marginal-zone-lymphoma#:~:text=On%20May%2028%2C%202019%2C%20the,marginal%20zone%20lymphoma%20(MZL)