Monjuvi (tafasitamab-cxix)

The anti-CD19 monoclonal antibody tafasitamab, paired with the immunomodulator lenalidomide, mediates antibody-dependent cellular toxicity and cellular phagocytosis; the antibody-drug conjugate loncastuximab tesirine delivers the DNA-cross-linking agent tesirine via CD19 binding and internalization; and CD19-directed chimeric antigen receptor T-cell therapy (CAR-T) products are engineered from autologous T cells. To date, clinical evidence on the effect of anti-CD19 therapy prior to CAR-T is restricted to small case series. Prospective studies and detailed analyses to understand how pre- and post-treatment CD19 expression correlates with clinical responses to subsequent CD19-directed therapy are needed to fully maximize treatment strategies.

The introduction of rituximab has improved the outcomes in CD20 positive cases. Other monoclonal antibodies, such as tafasitamab (anti-CD19), obinutuzumab (anti-CD20) and epratuzumab (anti-CD22) have been tested in trials (NCT05366218, NCT04920968, NCT00098839)...In contrast to ATP site inhibitors such as dasatinib and ponatinib, the novel first-in-class selective allosteric ABL myristoyl pocket (STAMP) inhibitor asciminib did not significantly impact ADCC in our settings. Our results suggest that asciminib should be considered in clinical trials.

P1, N=18, Recruiting, Canadian Cancer Trials Group | Trial completion date: Jul 2025 --> Jul 2026 | Trial primary completion date: Dec 2024 --> Dec 2025

P=N/A, N=200, Recruiting, Incyte Biosciences Italy S.r.l

P3, N=654, Active, not recruiting, Incyte Corporation | Trial primary completion date: Aug 2024 --> Feb 2024

P1, N=65, Recruiting, Incyte Biosciences Japan GK | Phase classification: P1b/2 --> P1

P1, N=27, Recruiting, City of Hope Medical Center | Initiation date: Jan 2024 --> Jun 2024

P1, N=18, Recruiting, Canadian Cancer Trials Group | Trial completion date: Jul 2024 --> Jul 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

P2, N=100, Recruiting, Academic and Community Cancer Research United | Not yet recruiting --> Recruiting

P1/2; Trial completion date: Apr 2023 --> Jun 2026 | Trial primary completion date: Apr 2023 --> Sep 2025

P1/2, N=54, Active, not recruiting, Incyte Corporation | Phase classification: P1b/2a --> P1/2 | Trial completion date: Oct 2023 --> Dec 2024 | Trial primary completion date: Oct 2023 --> Dec 2024

P2, N=70, Recruiting, Pfizer | Phase classification: P1b/2 --> P2

P=N/A, N=100, Recruiting, MorphoSys AG | N=1000 --> 100 | Trial completion date: Jul 2029 --> Aug 2026 | Trial primary completion date: Jul 2028 --> Oct 2025

P1, N=27, Recruiting, City of Hope Medical Center | Not yet recruiting --> Recruiting | Trial completion date: May 2027 --> May 2028 | Trial primary completion date: May 2027 --> May 2028

We performed an SLR to understand the efficacy and real-world (RW) effectiveness of non–CAR T-cell therapies for R/R LBCL including tafasitamab with lenalidomide (tafa/len), polatuzumab with bendamustine/rituximab (pola-BR), loncastuximab, selinexor, epcoritamab, and glofitamab. Currently, the evidence base, particularly RW studies, for non–CAR T-cell R/R LBCL therapies is still limited. In comparison, 78 RW CAR T-cell therapy studies were published (Jacobson et al. Tandem Meeting.

Comparators were axicabtagene ciloleucel (Axi-cel), lisocabtagene maraleucel (Liso-cel), tisagenlecleucel (Tisa-cel), loncastuximab tesirine (Lonca), polatuzumab vedotin + bendamustine + rituximab (Pola-BR), rituximab + gemcitabine + oxaliplatin (R-GemOx), tafasitamab + lenalidomide, and epcoritamab. Over 3 years, the estimated cumulative per-patient cost of glofitamab is projected to be the lowest when compared with per-patient costs of other available T-cell engaging therapies, resulting in cost savings after its formulary adoption for the treatment of R/R DLBCL after ≥2 lines of therapy.

A micro-costing analysis was developed to compare practice efficiency of treating patients with R/R DLBCL using epcoritamab versus comparator treatments (glofitamab, polatuzumab/bendamustine/rituximab [pola-BR], tafasitamab/lenalidomide [tafa-len], and axicabtagene ciloleucel [axi-cel]) over a time horizon of up to 1 year. Due to its unique SC administration, epcoritamab improves institutional practice efficiency despite more frequent dosing, saving personnel costs and inpatient costs. This could help to alleviate capacity constraints at infusion centers and ease patient scheduling. The resources saved (staff time, chair time, inpatient monitoring) can be redirected to other institutional needs, improving the availability and quality of healthcare services for patients.

Western blot analysis of splenocytes revealed that G1, 3, and 4 showed significantly lower expression of apoptosis-inducing protein gasdermin E on leukemic cells compared to G2, indicating reduced tumor pyroptosis in G2. In summary, application of the high affinity mAb tafasitamab prior to CART19 resulted in reduced CAR T apoptosis, diminished tumor cell pyroptosis, and reduction of CRS compared to lower affinity CD19 mAbs in preclinical models.

Study statusThe in-progress non-interventional realMIND study is expected to end by approximately December 2025, or earlier, when: ≥50 patients treated with tafasitamab + LEN have been recruited into each of Group 1 and Group 2 with either prospective or retrospective data collection; and all prospectively-followed patients have ≥6 months follow-up after starting tafasitamab treatment, or have discontinued from the study for any reason, whichever occurs earlier. The results are anticipated to describe the real-world safety and effectiveness of tafasitamab for R/R DLBCL in US patients, with a focus on underrepresented racial and ethnic minorities, to help optimize outcomes of treatment and identify opportunities for further studies.

Participants must provide a baseline tumor tissue sample (fresh or archival), for biomarker analysis. Exclusion criteria include previous treatment with anti-CD47, anti-CD19 (other than CAR-T) or immunomodulatory agents, prior allogeneic stem cell transplantation or autologous stem cell transplantation within 12 weeks prior to enrolment, and participants with active, uncontrolled viral, bacterial or fungal infections.

P1/2, N=51, Recruiting, MorphoSys AG | Phase classification: P1b/2 --> P1/2 | Trial completion date: Feb 2027 --> Oct 2027 | Trial primary completion date: May 2024 --> Nov 2024

Survivors of DLBCL have an increased risk of secondary primary malignancies; previous studies found that incidence of acute myeloid leukaemia (AML) nearly doubled in the post rituximab era...Due to severe chronic obstructive pulmonary disease, autologous transplant was excluded, thus request for Tafasitamablenalidomide under an extended access program was sent and approved in July 2022. After two cycles, lenalidomide was reduced because of grade 3-4 neutropenia poorly responsive to G-CSF...Patient started decitabine plus venetoclax protocol that is still ongoing...Patient has been candidated to allogenic transplant and azacitidine is now ongoing...Recently, the risk of SMN is also of particular concern in the CAR-T receivers. In conclusion a better comprehension of SPM/SMN pathology in DLBCL survivors is needed in order to guide the best “tailored” surveillance.

The current study highlights the importance of selecting appropriate CD19 detection tools and techniques for correct interpretation of CD19 expression. The findings presented herein can serve as a guideline to investigators and may help navigate treatment strategies in the clinical setting.

We also recently reported that tafasitamab plus lenalidomide induced brain parenchymal regressions in two consecutive CNS lymphoma patients with disease refractory to lenalidomide, pomalidomide and rituximab. Patients with HIV infection, CNS PTLD, and those who previously received a CD19-targeting CAR-T product are ineligible. The study is currently enrolling at the University of California San Francisco, with plans to expand enrollment to other institutions within the United States.

A prephase treatment with vincristine (1mg total dose) at D-7 and prednisone (60 mg/m2/d) from D-7 to D-4 is delivered prior study treatment. CONCLUSION VERLen trial is an innovative frontline trial for very elderly patients (≥80y.o) with newly diagnosed DLBCL, associating Tafasitamab; Lenalidomide and Rituximab, with a fixed duration of 12 cycles. Considering enrolling rates, we should provide the audience with results for ASH meeting 2024 (N+1).

R-CHOP remains the standard of care for newly diagnosed DLBCL patients...Tafasitamab was granted accelerated approval by the FDA in 2020 and conditional marketing authorization by the EMA in 2021 for the treatment of transplant-ineligible adult patients with relapsed or refractory (R/R) DLBCL in combination with the immunomodulatory drug lenalidomide...In addition, the combined treatment regimen appeared to be safe in mice as no side effects on both body weight loss and clinical score were recorded throughout the entire observation period. Our findings prove that the combination of tafasitamab and a CD20xCD3 T-cell engaging antibody significantly increases tumor cell eradication both in vitro and in vivo and lay the ground to potentially translate the results into improved outcome for patients with aggressive lymphoma in future clinical trials.

TALEN® gene editing technology is used to inactivate the TRAC and CD52 genes to minimize graft-versus-host disease (GvHD) and allow for the use of alemtuzumab (CLLS52, an anti-CD52 monoclonal antibody) in the lymphodepletion (LD) regimen, respectively...After LD with FCA (fludarabine 30 mg/m2 × 3d, cyclophosphamide 0.5g/m2 × 3d, CLLS52 12 mg on D1, 24 mg on D2, D3), a single infusion of UCART20x22 is administered at a flat dose level ([DL1] 50 x 106 cells; [DL2] 150 x 106 cells; and [DL3] 450 x 106 cells)...Pt 3 is an 18yo female with R/R DLBCL transformed from marginal zone lymphoma who previously received chemoimmunotherapy, venetoclax, ibrutinib, BR, CAR19, obinutuzumab, glofitamab, tafasitamab, lenalidomide, and an experimental epigenetic modifier...Pt 1 had G1 CRS and received tocilizumab (toci) x3 and dexamethasone (dex) x1... As of 01 July 2023, 3 pts were enrolled and treated at DL1. Pt 1 is a 76yo female with double-expressor diffuse large B-cell lymphoma (DLBCL) relapsed after R-CHOP, radiation therapy, and polatuzumab vedotin with bendamustine/rituximab (BR) and was considered ineligible for CAR19 due to recent high dose bendamustine. Pt 2 is a 65yo female with R/R triple-hit lymphoma transformed from follicular lymphoma who was previously treated with radiation therapy, BR, dose-adjusted R-EPOCH, and two separate CAR19 treatments.

Objectives Safety run-in: To determine the recommended Phase II dose of tafasitamab + lenalidomide + tazemetostat and of tafasitamab + lenalidomide + zanubrutinib. Interim analyses are planned for when approximately 50% of the expected events have occurred. Summary Statement For the current status of this study, please refer to the Lymphoma chapter.

P2; Not yet recruiting --> Recruiting | Trial completion date: Jul 2024 --> Oct 2025 | Trial primary completion date: Jul 2024 --> Oct 2025

P2, N=81, Completed, MorphoSys AG | Trial completion date: Nov 2022 --> Apr 2023 | Trial primary completion date: Nov 2018 --> Nov 2022

P1b/2, N=70, Recruiting, Pfizer | Trial completion date: Jul 2026 --> Mar 2029 | Trial primary completion date: Jan 2026 --> Mar 2027

P1; Not yet recruiting --> Recruiting

Based on ongoing randomized-controlled trials (RCTs), we considered four RCTs (n=150/arm) of the hypothetical treatment “Squirlitinib” vs bendamustine+rituximab (BR), rituximab+gemcitabine+oxaliplatin (R-GemOx), polatuzumab+bendamustine+rituximab (POLA-BR), and tafasitamab+lenalidomide (TAFA-LEN). Utilization of previously conducted ITCs may help with strategic HTA planning to ensure appropriate comparator use in pivotal trials and investigational drug effectiveness is sufficient to achieve HTA success.

In addition, the inhibitory receptor of CD47, signal regulatory protein alpha (SIRPα) is increased on macrophages from patients with follicular lymphoma who relapse or progress after frontline lenalidomide and rituximab. We show that CD47 and SIRPα were elevated in lymph node biopsies from DLBCL patients. Increased expression of SIRPα on macrophages correlated with decreased ADCP activity of tafasitamab, and CRISPR-mediated CD47 overexpression on lymphoma targets impaired tafasitamab-mediated phagocytosis, in vitro. Combination of tafasitamab and an anti-CD47 enhanced ADCP activity of in vitro generated macrophages.

In this real-world evaluation of tafasitamab-lenalidomide (TL) in relapsed/refractory LBCL, patients receiving TL had higher rates of comorbidities and high-risk disease characteristics, and substantially lower progression-free survival and overall survival, compared to the L-MIND registration clinical trial for TL.

Initial treatment consisted of DA-R-EPOCH (n=29), R-CHOP (n=24), R-CODOX-M/R-IVAC (n=3), Pola-R- CHP combination therapy (n=2), R-ICE (n=2), R-HyperCVAD (n=1), G-EPOCH (n=1), R-CHOP + tafasitamab (n=1), and steroids/cyclophosphamide (n=1). For patients with DHL, initial treatment with R-EPOCH is associated with higher CR rates and consolidative ASCT in CR1 with significantly better OS. CAR T-cell therapy may be an effective salvage option for patients with R/R DHL.

Tafasitamab, an anti-CD19 immunotherapy, is used with lenalidomide for patients with autologous stem cell transplant-ineligible relapsed/refractory diffuse large B-cell lymphoma (DLBCL) based on the results of the phase II L-MIND study (NCT02399085). Adverse events were consistent with previous reports and manageable, and their frequency decreased during tafasitamab monotherapy, with no new safety concerns. This final 5-year analysis of L-MIND demonstrates that this immunotherapy combination is well tolerated and has long-term clinical benefit with durable responses.

At last, the combination resulted in a synergistic survival benefit in a PBMC-humanized Ramos NOD/SCID mouse model. This study demonstrates that the combination of tafasitamab and rituximab improves efficacy compared to single-agent treatments in models of aggressive B-cell lymphoma in vitro and in vivo.

P2, N=100, Not yet recruiting, Academic and Community Cancer Research United | Initiation date: Jul 2023 --> Nov 2023

No modification of this scheme (increased chemotherapy dose intensity, new monoclonal antibodies, or the addition of immunomodulators or anti-target agents) has significatively improved the clinical outcomes, whereas therapy for recurrence or progression is evolving rapidly. The irruption of CART cells, polatuzumab vedotin, tafasitamab, and CD20/CD3 bispecific antibodies are changing the natural history of relapsed patients and will challenge R-CHOP as the benchmark for newly diagnosed patients.