FDA Approves MONJUVI® for Diffuse Large B-Cell Lymphoma

SUMMARY: The FDA on July 31, 2020, granted accelerated approval to MONJUVI® (Tafasitamab-cxix), a CD19-directed cytolytic antibody, in combination with REVLIMID® (Lenalidomide), for adult patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL) Not Otherwise Specified, including DLBCL arising from low grade lymphoma, and who are not eligible for Autologous Stem Cell Transplant.

The American Cancer Society estimates that in 2020, about 77,240 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 19,940 individuals will die of this disease. Diffuse Large B-Cell Lymphoma (DLBCL) is the most common of the aggressive Non-Hodgkin lymphoma’s in the United States, and the incidence has steadily increased 3-4% each year. More than half of patients are 65 or older at the time of diagnosis and the incidence is likely to increase with the aging of the American population. The etiology of Diffuse Large B-Cell Lymphoma is unknown. Contributing risk factors include immunosuppression (AIDS, transplantation setting, autoimmune diseases), UltraViolet radiation, pesticides, hair dyes, and diet. DLBCL is a neoplasm of large B cells and the most common chromosome abnormality involves alterations of the BCL-6 gene at the 3q27 locus, which is critical for germinal center formation. Two major molecular subtypes of DLBCL arising from different genetic mechanisms have been identified, using Gene Expression Profiling: Germinal Center B-cell-like (GCB) and Activated B-Cell-like (ABC). Patients in the GCB subgroup have a higher five year survival rate, independent of clinical IPI (International Prognostic Index) risk score, whereas patients in the ABC subgroup have a significantly worse outcome. Regardless, R-CHOP regimen (RITUXAN®-Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone), given every 21 days, for 6 cycles, delivered with curative intent, is the current standard of care for patients of all ages, with newly diagnosed DLBCL, regardless of molecular subtype. Approximately 30-40% of patients experience disease progression or relapse, during the first 2 years and attempts to improve on R-CHOP regimen have not been successful. Maintenance treatment strategy following R-CHOP, to better control the disease, delay disease progression and improve long term survival, have included Autologous Stem Cell Transplantation, maintenance treatment with agents such as oral protein kinase inhibitor Enzastaurin and Everolimus. Outcomes for transplant-ineligible patients with Relapsed/Refractory DLBCL patients remain poor.

REVLIMID® (Lenalidomide) is an oral immunomodulatory agent with activity in lymphoid malignancies, primarily through immune modulation (repair T-cell immune synapse dysfunction and Natural Killer cell/T-cell effector augmentation). It additionally has antiproliferative effects. REVLIMID® was shown to have significant activity in relapsed DLBCL when given alone or along with RITUXAN®. MONJUVI® is an investigational humanized Fc-engineered monoclonal antibody directed against CD19. MONJUVI® incorporates an XmAb(R) engineered Fc domain, which is intended to lead to a significant potentiation of Antibody-Dependent Cell-mediated Cytotoxicity (ADCC) and Antibody-Dependent Cellular Phagocytosis (ADCP), thus improving tumor cell kill. Preclinical data suggested that MONJUVI® might act synergistically with REVLIMID®.

L-MIND is an ongoing , multicenter, single arm, open-label, Phase II study, investigating the combination of MONJUVI® and REVLIMID® in patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (R/R DLBCL), after up to two prior lines of therapy, including an anti-CD20 targeting therapy (such as Rituximab), who are not eligible for high-dose chemotherapy and subsequent Autologous Stem Cell Transplantation. This study enrolled 81 patients and patients received 28-day cycles of MONJUVI® 12 mg/kg IV once weekly during Cycles 1-3 with a loading dose on Cycle 1 Day 4, then every 2 weeks during Cycles 4-12, along with REVLIMID® 25 mg orally daily on Days 1-21 of Cycles 1-12. After Cycle 12, progression-free patients received MONJUVI® every 2 weeks until disease progression. Eighty patients (N=80) received at least one dose of both MONJUVI® and REVLIMID®. The Primary endpoint was Objective Response Rate (ORR). Secondary endpoints included Duration of Response (DoR), Progression-Free Survival (PFS) and Overall Survival (OS).

In this long-term analysis after a minimum of two years follow-up, outcomes from the L-MIND study were consistent with the primary analysis. Assessment by an Independent Review Committee at data cut-off showed an ORR of 58.8% and a Complete Response (CR) rate of 41.3%. Median Duration of Response was 34.6 months. The median OS was 31.6 months and median PFS was 16.2 months. The safety profile was consistent with that observed in previously reported studies of MONJUVI® in combination with REVLIMID®. The most common Grade 3 or worse Adverse Events were cytopenias and febrile neutropenia.

To determine the the contribution of MONJUVI® in the combination with REVLIMID® and to prove its synergistic effect, an observational retrospective study was conducted (Re-MIND) to compare real-world response data of patients with Relapsed or Refractory DLBCL who received REVLIMID® monotherapy with the efficacy outcomes of the MONJUVI®- REVLIMID® combination, as investigated in the L-MIND trial. In this study, efficacy data was collected from 490 R/R DLBCL patients in the US and EU. Qualification criteria for matching patients of both studies were pre-specified. As a result, 76 eligible Re-MIND patients were identified and matched 1:1 to 76 of 80 L-MIND patients based on important baseline characteristics. Objective response rates (ORR) were validated based on this subset of 76 patients in Re-MIND and L-MIND, respectively. The Primary endpoint of Re-MIND was met and shows a statistically significant superior best ORR of the MONJUVI®/ REVLIMID® combination compared to REVLIMID® monotherapy. Further, there was a significant difference in OS as well as CR rates, favoring the L-MIND cohort over the observational cohort.

It was concluded that MONJUVI® in combination with REVLIMID® resulted high Complete Response rates, as well Durable Responses and improved survival, in a significant proportion of patients with relapsed or refractory Diffuse Large B-Cell Lymphoma, ineligible for Autologous Stem Cell Transplantation, and might represent a new therapeutic option in this clinical setting.

Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. Salles G, Duell J, Barca EG, et al. Lancet Oncol. 2020 Jul;21:978-988.