SUMMARY: The FDA on June 18, 2025, approved Tafasitamab-cxix (MONJUVI®) with Lenalidomide and Rituximab for adults with Relapsed or Refractory Follicular Lymphoma (FL).
The American Cancer Society estimates that in 2025, about 80,350 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 19,390 individuals will die of this disease. Indolent Non-Hodgkin Lymphomas are mature B cell lymphoproliferative disorders and include Follicular Lymphoma, Nodal Marginal Zone Lymphoma (NMZL), Extranodal Marginal Zone Lymphoma (ENMZL) of Mucosa-Associated Lymphoid Tissue (MALT), Splenic Marginal Zone Lymphoma (SMZL), LymphoPlasmacytic Lymphoma (LPL) and Small Lymphocytic Lymphoma (SLL).
Follicular Lymphoma is the most indolent form and second most common form of all NHLs, and they are a heterogeneous group of lymphoproliferative malignancies. Approximately 20% of all NHLs are Follicular Lymphomas and the average age of diagnosis is 65 years. Advanced stage indolent NHL is not curable and as such, prolonging Progression Free Survival (PFS) and Overall Survival (OS), while maintaining Quality of Life, have been the goals of treatment intervention. Asymptomatic patients with indolent NHL are generally considered candidates for “watch and wait” approach. Patients with advanced stage symptomatic Follicular Lymphoma are often treated with induction chemoimmunotherapy followed by maintenance Rituximab (RITUXAN®). This can result in a median Progression Free Survival (PFS) of 6-8 yrs and a median Overall Survival (OS) of 12-15 yrs. However, approximately 30% of the patients will relapse in 3 years, with prognosis worsening after each subsequent relapse. Immunotherapy-based approaches are increasingly favored, yet durable disease control remains elusive, particularly among patients with high-risk features such as progression within 24 months of initial therapy (POD24) or resistance to anti-CD20 monoclonal antibodies.
Lenalidomide in combination with Rituximab (R²) is an established option after at least one prior line of therapy. Tafasitamab, a humanized anti-CD19 monoclonal antibody with both direct cytotoxic and immune-mediated mechanisms of action, has previously demonstrated efficacy in Diffuse Large B-Cell Lymphoma in combination with Lenalidomide (L-MIND trial). The Phase III inMIND study (NCT04680052) was designed to evaluate whether adding Tafasitamab to the R² backbone could improve outcomes in patients with Relapsed or Refractory (R/R) FL. This study was powered to assess PFS in patients with FL only.
Study Design and Methods
inMIND was a randomized, double-blind, placebo-controlled, global Phase III trial that enrolled 548 patients with Grade 1–3A FL or Marginal Zone Lymphoma. All patients had received at least one prior systemic therapy, including an anti-CD20 monoclonal antibody, and required treatment for Relapsed or Refractory disease. Key eligibility criteria included age 18 years or older, CD19+/CD20+ disease, and ECOG performance status 2 or less. Patients were stratified by POD24 status, refractoriness to prior therapy, and number of prior treatment lines (1 vs >1).
Participants were randomized 1:1 to:
- Tafasitamab + Lenalidomide + Rituximab (Tafa arm)
- Placebo + Lenalidomide + Rituximab (control arm)
A total of 548 patients were randomized (Tafa, n=273; Placebo, n=275). Baseline characteristics were balanced between arms:
- Median age: 64 years
- 79% with intermediate/high-risk FLIPI scores
- 83% with high tumor burden (GELF criteria)
- 32% with POD24
- 43% refractory to prior anti-CD20 therapy
Tafasitamab (12 mg/kg IV) or placebo was administered on days 1, 8, 15, and 22 of cycles 1–3, and days 1 and 15 of cycles 4–12. All patients received standard dosing of Lenalidomide plus Rituximab for up to twelve 28-day cycles.
- Primary endpoint: investigator-assessed Progression-Free Survival (PFS) in patients with FL.
- Key secondary endpoints: Complete metabolic Response (PET-CR), Overall Response Rate (ORR), Duration of Response (DOR), Time To Next Treatment (TTNT), Overall Survival (OS), and safety.
At a median follow-up of 14.1 months:
- Primary endpoint met: Tafasitamab significantly reduced the risk of progression, relapse, or death by 57%.
- Median PFS: 22.4 months (Tafa) vs 13.9 months (placebo)
- Hazard ratio (HR) 0.43; 95% CI 0.32–0.58; P < 0.0001
- Independent Review Committee (IRC) confirmation: median PFS not reached with Tafasitamab vs 16.0 months with placebo (HR 0.41; P < 0.0001).
- Response outcomes:
- PET-CR rate: 49.4% vs 39.8% (P = 0.029)
- ORR: 83.5% vs 72.4% (P = 0.0014)
- DOR: 21.2 vs 13.6 months (HR 0.47; P < 0.0001)
- TTNT: not reached vs 28.8 months (HR 0.45; P < 0.0001)
- Overall Survival (immature): trend favoring Tafasitamab (HR 0.59; 95% CI 0.31–1.13).
Subgroup Analyses
PFS benefit with Tafasitamab was consistent across all prespecified groups, including POD24 patients, those refractory to prior anti-CD20 therapy and patients with ≥2 prior lines of therapy
Safety Profile
Adverse events were manageable and consistent with known profiles of the combination components.
- Grade 3/4 adverse events occurred in 71% (Tafa) vs 69.5% (placebo).
- Most common Grade 3/4 events: neutropenia (40% vs 38%), pneumonia (8% vs 5%), thrombocytopenia (6% vs 7%).
- COVID-19 infections were slightly more frequent in the Tafasitamab arm (6% vs 2%).
- Treatment discontinuation due to adverse events occurred in 11% (Tafa) vs 7% (placebo).
- On-study deaths were less frequent in the Tafasitamab arm (5.5% vs 8.5%).
Importantly, Tafasitamab did not interfere with the administration of Lenalidomide or Rituximab and dose reductions and treatment interruptions were comparable across arms.
Clinical Implications
The inMIND trial is the first phase III study to validate a dual-antibody approach targeting both CD19 and CD20 in FL. The addition of Tafasitamab to R² not only extended PFS by nearly nine months but also improved depth of response and delayed the need for subsequent therapy, without introducing unexpected toxicities.
For high-risk patients, including those with POD24 or anti-CD20–refractory disease, these results are particularly impactful, addressing a long-standing gap in treatment outcomes.
As novel immunotherapies such as bispecific antibodies and CAR T-cell therapies are integrated earlier in the treatment paradigm, questions about sequencing and immune fitness will become increasingly relevant. Nonetheless, Tafasitamab plus R² emerges from inMIND as a practical, chemotherapy-free regimen that can be delivered in both community and academic settings, representing a potential new standard of care for patients with R/R FL.
Key Takeaways
- inMIND met its primary endpoint, showing a 57% risk reduction in progression, relapse, or death with Tafasitamab + R² vs R² alone.
- Benefits were consistent across high-risk subgroups, including POD24 and anti-CD20–refractory patients.
- Secondary endpoints (ORR, CR, DOR, TTNT) also significantly favored Tafasitamab.
- Safety profile was manageable and aligned with expectations.
- Longer follow-up will clarify OS benefit, but current findings strongly support the role of Tafasitamab in improving outcomes for patients with Relapsed/Refractory Follicular Lymphoma.
Tafasitamab Plus Lenalidomide and Rituximab for Relapsed or Refractory Follicular Lymphoma: Results from a Phase 3 Study (inMIND). Sehn LH, Luminari S, Scholz CW, et al. Blood (2024), Volume 144, Supplement 2: LBA-1. https://doi.org/10.1182/blood-2024-212970
