Tafasitamab Plus Lenalidomide and Rituximab in Relapsed or Refractory Follicular Lymphoma

Although follicular lymphoma and marginal zone lymphoma often respond to initial therapy, relapse is common, and effective second-line or later-line treatments are crucial to improving long-term patient outcomes. The monoclonal antibody tafasitamab (brand name: Monjuvi), targeting the CD19 antigen on B-cells, has shown promising activity in combination with lenalidomide in diffuse large B-cell lymphoma (DLBCL). This has prompted the investigation into whether tafasitamab—when added to a backbone of lenalidomide plus rituximab—could similarly improve outcomes in patients with relapsed or refractory follicular lymphoma.

The inMIND Phase III trial addresses this question by evaluating the efficacy, safety, and potential superiority of adding tafasitamab to a standard salvage regimen (lenalidomide plus rituximab) versus lenalidomide plus rituximab with placebo. This study may define a new standard-of-care option for patients with these indolent B-cell lymphomas.

‘A Needed Additional Therapeutic Option’

At this year’s American Society of Hematology (ASH) meeting, Dr. Ann LaCasce, Director of Hematology/Oncology at Dana-Farber Cancer Institute, explained that the trial showed the addition of tafasitamab to lenalidomide plus rituximab resulted in improved progression free survival compared to lenalidomide plus rituximab, though the outcome of the control arm was less favorable compared to other studies of this combination.

“I do think tafasitamab, lenalidomide, and rituximab represents a needed additional therapeutic option in relapsed follicular lymphoma, though how the combinations will compare to bispecific antibody based regimens has yet to be seen in patients,” she explained.

InMIND is a randomized, double-blind, placebo-controlled, multicenter trial with two arms: experimental group (tafasitamab + lenalidomide + rituximab) and control group (placebo + lenalidomide + rituximab).

This approach isolates the effect of tafasitamab, as both arms receive lenalidomide and rituximab, which are accepted agents in the relapsed/refractory setting.

Inclusion criteria mandated patients be adults with histologically confirmed, relapsed or refractory follicular lymphoma (FL) or marginal zone lymphoma (MZL) who have previously received systemic therapy and now require further treatment.

Enrollment and Timeline:

-Estimated Enrollment: Approximately 450 participants
-Study Start: Began enrolling patients in early 2021
-Follow-up: Long-term follow-up is planned to adequately assess the durability of responses, overall survival, and long-term safety

According to ClinicalTrials.gov (NCT04680052), the primary completion date (when initial analyses of the primary endpoint are expected) is estimated to be around November 2025, with full study completion by mid-to-late 2027. These extended timelines reflect the need to capture robust data on progression, response depth, and survival in these indolent lymphoma subtypes. The primary endpoint lies in the analysis of Progression-Free Survival (PFS).

Top-Line Results (as of Late-Breaking Data at ASH 2024)

Superiority in PFS: Indications that tafasitamab + lenalidomide + rituximab improved PFS compared to the placebo arm, suggesting that the addition of tafasitamab delivers a more durable disease control.

Patients treated with tafasitamab achieved a median PFS by investigator assessment of 22.4 months compared to 13.9 months in the control arm (Hazard Ratio [HR]: 0.43; 95% Confidence Interval [CI] (0.32—0.58); P<0.0001), representing a 57% reduction in risk of progression, relapse, or death. 

Response Depth and Duration: Preliminary signals of higher overall response and complete response rates could suggest that tafasitamab intensifies the therapeutic effect of lenalidomide and rituximab. Longer follow-up will clarify whether these improvements translate into meaningful survival gains. Median overall survival was not reached in either group, but a positive trend was observed with the tafasitamab group versus the control arm (HR=0.59 [95% CI (0.31, 1.13)]).

Tolerability Profile: Early safety data are crucial. The most common treatment-emergent adverse events (TEAEs) in the tafasitamab and immunotherapy combination group were neutropenia (48.5%), diarrhea (37.6%), COVID-19 (31.4%) and constipation (29.2%).

As the trial progresses and more mature data become available, these initial findings may guide further regulatory review and potential label expansions for tafasitamab in combination with lenalidomide and rituximab, beyond its current approvals.

Potential Impact on Clinical Practice

If the inMIND trial’s positive preliminary findings are confirmed, it could impact treatment in several ways, including:

1. New Therapeutic Option: For patients with relapsed or refractory FL or MZL, tafasitamab in combination with lenalidomide and rituximab could become a valuable second-line or later-line option, potentially offering more extended disease control.
2. Enhanced Biological Synergy: Demonstrating that CD19 targeting (tafasitamab) enhances the immunomodulatory and anti-CD20 activity of lenalidomide and rituximab could reshape combination strategies in indolent lymphomas, potentially improving outcomes without significantly increasing toxicity.
3. Informed Treatment Sequencing: Positive results would give hematologists and oncologists a new evidence-based regimen to consider, altering current treatment algorithms and benefitting patients who are not well-served by existing options.

Who May Benefit the Most?

-Patients with Relapsed/Refractory FL or MZL: Particularly those who have exhausted first-line therapies and require effective regimens to extend remission and improve quality of life.
-Individuals Tolerant of Immunotherapies: Given the mechanism of action of tafasitamab and lenalidomide, patients suitable for immunomodulatory and targeted monoclonal antibody therapies stand to gain.

By offering significantly improved disease control, the inMIND trial’s findings may help clinicians target treatment choices, align therapy with patient goals, and ultimately contribute to better long-term management of indolent lymphomas.