MINJUVI Powder for concentrate for solution for infusion Ref.[50430] Active ingredients: Tafasitamab

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies
ATC code: L01FX12

Mechanism of action

Tafasitamab is an Fc-enhanced monoclonal antibody that targets the CD19 antigen expressed on the surface of pre-B and mature B lymphocytes.

Upon binding to CD19, tafasitamab mediates B-cell lysis through:

• engagement of immune effector cells like natural killer cells, γδ T cells and phagocytes
• direct induction of cell death (apoptosis)

The Fc modification results in enhanced antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis.

Pharmacodynamic effects

Tafasitamab induced a rapid reduction in peripheral blood B-cell counts. In patients with relapsed or refractory DLBCL, the reduction relative to baseline B-cell count reached 97% after eight days of treatment in the L-MIND study. The maximum B-cell reduction at approximately 100% (median) was reached within 16 weeks of treatment.

In patients with relapsed or refractory follicular lymphoma, circulating B-cells decreased to undetectable levels by day 8 following administration of the recommended dosage of tafasitamab in patients who had detectable B-cells at treatment initiation. The depletion was sustained while patients remained on treatment.

Although the depletion of B-cells in the peripheral blood is a measurable pharmacodynamic effect, it is not directly correlated with the depletion of B-cells in solid organs or in malignant deposits.

Clinical efficacy

Relapsed or refractory DLBCL

Tafasitamab plus lenalidomide followed by tafasitamab monotherapy was studied in the L-MIND study, an open-label multicentre single-arm study. This study was conducted in adult patients with relapsed or refractory DLBCL after 1 to 3 prior systemic DLBCL therapies, who at the time of the trial were not candidates for high dose chemotherapy followed by ASCT or who had refused ASCT. One of the prior systemic therapies had to include a CD20 targeted therapy. The study excluded patients with severe hepatic impairment (total serum bilirubin >3 mg/dL) and patients with renal impairment (CrCL <60 mL/min.), as well as patients with history or evidence of clinically significant cardiovascular, CNS and/or other systemic disease. Patients with a known history of "double/triple-hit" genetics DLBCL were also excluded at study entry.

For the first three cycles, patients received 12 mg/kg tafasitamab via infusion on day 1, 8, 15 and 22 of each 28-day cycle, plus a loading dose on day 4 of cycle 1. Thereafter, tafasitamab was administered on days 1 and 15 of each cycle until disease progression. Premedication including antipyretics, histamine H1 and H2 receptor blockers and glucocorticosteroids was given 30 to 120 minutes prior to the first three tafasitamab infusions.

Patients self-administered 25 mg lenalidomide daily on days 1 to 21 of each 28-day cycle, up to 12 cycles.

A total of 81 patients were enrolled in the L-MIND study. The median age was 72 years (range 41 to 86 years), 89% were white and 54% were males. Out of 81 patients, 74 (91.4%) had ECOG performance score of 0 or 1 and 7 (8.6%) had ECOG score of 2. The median number of prior therapies was two (range: 1 to 4), with 40 patients (49.4%) receiving one prior therapy and 35 patients (43.2%) receiving 2 prior lines of treatment. Five patients (6.2%) had 3 prior lines of therapies and 1 (1.2%) had 4 prior lines of treatment. All patients had received a prior anti-CD20-containing therapy. Eight patients had a diagnosis of DLBCL transformed from low-grade lymphoma. Fifteen patients (18.5%) had primary refractory disease, 36 (44.4%) were refractory to their last prior therapy, and 34 (42.0%) were refractory to rituximab. Nine patients (11.1%) had received prior ASCT. The primary reasons for patients not being candidates for ASCT included age (45.7%), refractory to salvage chemotherapy (23.5%), comorbidities (13.6%) and refusal of high dose chemotherapy/ASCT (16.0%).

One patient received tafasitamab, but not lenalidomide. The remaining 80 patients received at least one dose of tafasitamab and lenalidomide. All patients enrolled in the L-MIND study had a diagnosis of DLBCL based on local pathology. However, as per central pathology review, 10 patients could not be classified as DLBCL.

The median duration of exposure to treatment was 9.2 months (range: 0.23, 54.67 months). Thirty-two (39.5%) patients completed 12 cycles of tafasitamab. Thirty (37.0%) patients completed 12 cycles of lenalidomide.

The primary efficacy endpoint was best objective response rate (ORR), defined as the proportion of complete and partial responders, as assessed by an independent review committee (IRC). Other efficacy endpoints included duration of response (DoR), progression-free survival (PFS) and overall survival (OS). The efficacy results are summarised in Table 4.

Table 4. Efficacy results in patients with relapsed or refractory diffuse large B-cell lymphoma in the MOR208C203 (L-MIND) study:

ITT = intention to treat; NR = not reached
^* One patient received only tafasitamab
CI: Binomial exact confidence interval using Clopper Pearson method
^a Kaplan Meier estimates

Overall survival (OS) was a secondary endpoint in the study. After a median follow up time of 42.7 months (95% CI: 38.0; 47.2), the median OS was 31.6 months (95% CI: 18.3; not reached). Amongst the eight patients who had a DLBCL transformed from a prior indolent lymphoma, seven patients had an objective response (three patients a CR, four patients a PR) and one patient had a stable disease as the best response to tafasitamab+ lenalidomide treatment.

Relapsed or refractory FL after at least one line of systemic therapy

The efficacy of tafasitamab in combination with lenalidomide and rituximab in patients with relapsed or refractory follicular lymphoma was evaluated in a randomised, double-blind, placebo-controlled phase 3 study (inMIND; INCMOR 0028-301).

Eligible patients were adults aged 18 years and above with histologically confirmed grade 1-3a follicular lymphoma (WHO 2016) whose disease relapsed or became refractory after at least 1 prior line of systemic therapy, including an anti-CD20 therapy. In addition, GELF criteria were recommended as guidance to the investigators, to identify the FL patients that were in need of treatment. As per inclusion criteria, all patients included in the study were required to have documented CD20+ and CD19+ expression based on local or central pathology review. The study excluded patients with CNS involvement or prior allogeneic HSCT.

A total of 548 patients with R/R follicular lymphoma were randomized in a 1:1 ratio to receive tafasitamab plus lenalidomide and rituximab or placebo plus R 2 for up to twelve 28-day cycles. Randomization was stratified by progression of disease within 24 months after initial diagnosis (POD24) (yes vs no), refractoriness to prior CD20-directed antibody therapy (yes vs no), and the number of prior lines of therapy (<2 vs ≥2).

Dosing in each treatment arm was as follows:

• Tafasitamab 12 mg/kg intravenously (Days 1, 8, 15 and 22 of Cycles 1 to 3 and on Days 1 and 15 of Cycles 4 to 12) and lenalidomide 20 mg orally once daily (Days 1 to 21 of Cycles 1 to 12) with rituximab 375 mg/m² intravenously (Days 1, 8, 15 and 22 of Cycle 1 and on Day 1 of Cycles 2 to 5).
• Placebo intravenously (Days 1, 8, 15, and 22 of Cycles 1 to 3 and on Days 1 and 15 of Cycles 4 to 12) and lenalidomide 20 mg orally once daily (Days 1 to 21 of Cycles 1 to 12) with rituximab 375 mg/m² intravenously (Days 1, 8, 15, and 22 of Cycle 1 and on Day 1 of Cycles 2 to 5).

The baseline demographics and disease characteristics were generally well balanced between the two treatment groups. Among the 548 patients with R/R FL enrolled in study inMIND, the median age was 64 years (range 31 to 88 years), 54.6% were male, and 79.9% were White. The median time since initial diagnosis was 5.3 years (range 0 to 34 years). Most participants (56.8%) had Ann Arbor Stage IV disease at study entry. Approximately half of participants had high-risk disease as per FLIPI score, and most participants met at least one GELF criterion for high tumour burden. Most participants had ECOG performance status of 0 (66.4%) and 37.8% of participants had a bulky disease (>7 cm).

The majority (54.7%) of participants had received 1 prior systemic anticancer line of therapy; the median number of prior therapies was 1 (range: 1 to 10), 209 patients (38.1%) were refractory to their last prior therapy. All participants in the FL Population had received prior anti-CD20 therapy; most participants had received 1 (61.3%) or 2 (24.8%) prior anti–CD20 therapies. Two participants, both in the placebo arm, received prior anti-CD 19 containing therapy. Prior treatments included R-CHOP (23.9% of participants), R-CHOP +R-maintenance (27.9% of participants), R-bendamustine (21.7% of participants), rituximab monotherapy (17.2% of participants), R-bendamustine +R-maintenance (12.2% of participants), R-CVP (6.8% of participants), and R-CVP +R-maintenance (5.8% of participants). Twenty-eight (5.1%) participants had received prior ASCT.

One third (34.3%) of participants were anti-CD20 refractory, and 31.6% had progression of disease within 24 months of initial diagnosis (POD24).

A total of 546 participants (99.6%) with R/R FL were treated, including 273 participants (100.0%) in the tafasitamab+R2 group and 273 participants (99.3%) in the placebo+R2 group.

The primary efficacy endpoint was investigator-assessed progression-free survival (PFS) in the FL population, defined as the time from randomization to first documented disease progression, or death from any cause, whichever occurs first. The key secondary endpoints included PET-CR rate by INV in the FDG-avid FL population, defined as a complete metabolic response at any time after start of treatment, as well as overall survival in the FL population. The median duration of PFS follow-up was 14.3 months (95% CI: 11.8, 15) in the tafasitamab group and 14.1 months (95% CI: 11.5, 15) in the placebo group.

The efficacy results are summarized in Table 5 and Figure 1.

Table 5. Efficacy Results from Study INCMOR 0208-301 (inMIND):

CI = confidence interval; NE = not evaluable.
^a Investigator-assessed
^b Per Cheson 2014 Response Criteria
^c Two-sided 95% CIs based on Brookmeyer and Crowley method.
^d Hazard ratio based on a stratified Cox proportional hazard model.
^e The PET-CR rate was defined as the proportion of patients in the FDG-avid FL population who achieved a complete metabolic response at any time after the start of treatment as per Lugano classification among the patients with a positive PET scan at baseline. Patients with no postbaseline assessment by PET or who did not achieve a CMR were classified as non-CR responders.
^f 95% CIs based on the Clopper-Pearson method.

Figure 1. Kaplan-Meier Curve for Progression-Free Survival by Investigator Assessment in inMIND:

At the interim analysis, the key secondary endpoint of OS was immature, and median OS was not reached in either treatment group (stratified hazard ratio of 0.587 (95% CI: 0.306, 1.128); p-value 0.1061).

Elderly

In the ITT set of L-MIND study, 36 of 81 patients were ≤70 years and 45 of 81 patients were >70 years.

Among the 273 patients with R/R follicular lymphoma treated with tafasitamab in inMIND study, 178 were ≤70 years and 95 were >70 years.

No overall differences in efficacy were observed for patients ≤70 years versus patients >70 years of age.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with MINJUVI in all subsets of the paediatric population in mature B-cell neoplasms (see section 4.2 for information on paediatric use).

This medicinal product has been authorised under a so-called 'conditional approval' scheme. This means that further evidence on this medicinal product is awaited.

The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.