Columvi (glofitamab-gxbm)

Historically, B and T cell (B-T cell) co-interaction was targeted through different pathways such as alemtuzumab, abatacept, and dapirolizumab with variable impact on B cell depletion (BCD), whereas the majority of patients with AID including rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis and organ transplantation benefit from targeted BCD with anti-CD20 monoclonal antibodies such as rituximab, ocrelizumab or ofatumumab...In the treatment of cancer, chimeric antigen receptor (CAR) T cell therapy and T cell engagers (TCE) that recruit T cells to induce B cell cytotoxicity have delivered promising results for anti-CD19 CAR T cell therapies, the CD19 TCE blinatumomab and CD20 TCE such as mosunetuzumab, glofitamab or epcoritamab. Limited evidence suggests that anti-CD19 CAR T cell therapy may be effective in managing refractory AID whereas we await evaluation of TCE for use in non-oncological indications. Therefore, here, we discuss the potential mechanistic advantages of novel therapies that rely on T cells as effector cells to disrupt B-T cell collaboration toward overcoming rituximab-resistant AID.

P2, N=40, Recruiting, French Innovative Leukemia Organisation | Not yet recruiting --> Recruiting

P2, N=40, Recruiting, City of Hope Medical Center | Not yet recruiting --> Recruiting

P1/2, N=27, Not yet recruiting, OHSU Knight Cancer Institute

P2, N=40, Not yet recruiting, City of Hope Medical Center | Initiation date: Mar 2024 --> Jun 2024

P2, N=99, Not yet recruiting, University College, London | Trial completion date: Jan 2028 --> Jul 2028 | Initiation date: Jan 2024 --> Apr 2024 | Trial primary completion date: Jan 2028 --> Jan 2027

P1/2, N=70, Recruiting, Pfizer | Phase classification: P2 --> P1/2

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

P2, N=40, Not yet recruiting, University Health Network, Toronto | Initiation date: Dec 2023 --> Aug 2024

We developed a bispecific CD19-targeted CD28 agonist (RG6333, CD19-CD28) to enhance the efficacy of glofitamab and similar TCBs by delivering signal 2 to tumor-infiltrating T cells. CD19-CD28 distinguishes itself from the superagonistic antibody TGN1412, as its activity requires the simultaneous presence of a TCR signal and CD19 target binding...Our findings highlight CD19-CD28 as a safe and highly efficacious off-the-shelf combination partner for glofitamab, similar TCBs, and other costimulatory agonists. CD19-CD28 is currently in a Phase 1 clinical trial in combination with glofitamab.

P1, N=40, Recruiting, Hoffmann-La Roche | Trial completion date: Jun 2024 --> Dec 2024 | Trial primary completion date: Jun 2024 --> Dec 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=50; Not yet recruiting; Sponsor:C. Babis Andreadis

Significant proportion of patients with diffuse large B-cell lymphoma (DLBCL) is refractory or relapse (R/R) after the treatment. Its side effects are similar to those of other T-cell-engaging agents and can be mitigated by pretreatment with obinutuzumab or step-up dosing. Its safety profile with manageable toxicities heads the clinical development toward combination strategies and its use in earlier therapeutic phases.

P2, N=40, Not yet recruiting, M.D. Anderson Cancer Center

P1, N=30, Completed, Hoffmann-La Roche | Active, not recruiting --> Completed

P1/2, N=280, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Nov 2024 --> Sep 2026 | Trial primary completion date: Nov 2024 --> Sep 2026 | Recruiting --> Active, not recruiting

P1, N=39, Recruiting, Memorial Sloan Kettering Cancer Center | Not yet recruiting --> Recruiting

P2, N=40, Not yet recruiting, City of Hope Medical Center | Initiation date: Dec 2023 --> Mar 2024

P1, N=39, Not yet recruiting, Memorial Sloan Kettering Cancer Center

P2, N=40, Not yet recruiting, French Innovative Leukemia Organisation

P2, N=66, Recruiting, Christine Ryan | Initiation date: Oct 2023 --> Apr 2024

P1, N=200, Recruiting, ADC Therapeutics S.A. | Phase classification: P1b --> P1

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

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.

P2, N=67, Active, not recruiting, The Lymphoma Academic Research Organisation | Trial primary completion date: Sep 2023 --> Jan 2023

It is recommended that there are no restrictions on concomitant treatment with any other drugs. Consideration may be given for potential DDI during the first cycle in patients who are receiving concomitant CYP substrates with a narrow therapeutic index via monitoring for toxicity or for drug concentrations.

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.

In subanalysis of CD20/CD3 products, pooled all-grade infections did not differ significantly between monotherapy epcoritimab (34% 95%CI: 21 - 47%) and glofitamab (39% 95%CI: 21 - 56%)...Mosunetuzumab was given with R-CHOP in a single study, but all-grade and severe infection rates were not reported...The higher rate of fatal viral and fungal infections highlights a potential need for increased clinical vigilance for infections classically associated with T-cell depletion. Although further data is needed, CD20-targeted BsAb may confer higher infection risk than CD19-directed products.

Background Maplirpacept (PF-07901801) is an anti-CD47 fusion protein constructed to enhance phagocytosis and antitumor activity via inhibition of CD47-mediated signaling. All patients should have adequate bone marrow, hepatic, and renal function (eGFR ≥45 mL/min) and ECOG performance status ≤2. Exclusion criteria include prior treatment with an anti-CD47 agent, prior anti-CD20xCD3 containing regimen, refractoriness to an obinutuzumab monotherapy containing regimen, prior allogeneic stem cell transplantation or autologous stem cell transplantation within 12 weeks prior to enrolment, high grade B-cell lymphoma with BCL2 and Myc rearrangement, active bacterial, viral, fungal, mycobacterial, parasitic, or other infection.

Eligible treatments included CAR T cell therapies (axicabtagene ciloleucel, lisocabtagene maraleucel, and tisagenlecleucel), T cell engagers (mosunetuzumab, glofitamab, epcoritamab, odronextamab), phosphatidylinositol 3-kinase (PI3K) inhibitors (copanlisib, duvelisib, idelalisib), HSCT, yttrium-90 (90Y) ibritumomab tiuxetan, tazemetostat, and conventional therapies (immunochemotherapies, single- or multiagent chemo- or immunotherapies, and alkylating agents). This SLR demonstrated an evolving FL treatment landscape, with new agents such as CAR T cell therapies and T cell engagers exhibiting potential for improving effectiveness of treatment for patients in 3L+, 4L+, and 2L+ POD24 populations.

P2, N=66, Recruiting, Matthew S. Davids, MD | Not yet recruiting --> Recruiting

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

P1/2, N=860, Recruiting, Hoffmann-La Roche | Active, not recruiting --> Recruiting

This might be due to the more heavily pretreated patients in our series with nearly all patients post CAR-T. Nevertheless, toxicity in our real-life analysis was better than reported in the pivotal study, supporting the role of glofitamab in R/R DLBCL patients.

Patients received obinutuzumab 1000mg on Cycle (C) 1 Day (D) 1 to mitigate the risk of severe cytokine release syndrome (CRS). Glofit+Pola demonstrated high response rates and durable responses in heavily pre-treated patients, the majority of whom were refractory to their last prior therapy, across all histologies, including in patients with HGBCL and those with prior CAR T-cell therapy. The safety profile was manageable and consistent with the individual drugs. The rates of CRS events and AEs potentially consistent with ICANS were low.

Glofitamab results in per-patient cost savings compared with epcoritamab at every cumulative administration cycle, particularly in the first few cycles when epcoritamab has more frequent dosing per cycle than glofitamab. Furthermore, glofitamab has lower total costs across all time horizons examined in this study (1-year, 5-year, 10-year, and lifetime). The lower total costs with glofitamab can be attributed to 1) lower annual drug acquisition costs, 2) fixed-duration treatment with a maximum of 12 cycles, and 3) less frequent dosing in earlier cycles.

CRS events occurred early and resolved at data cut-off; treatment (tocilizumab and dexamethasone) was administered for the Gr 2 CRS event only. Glofit + R-CHOP in 1L LBCL defined as high risk by ctDNA, had a manageable safety profile and induced high response rates at the interim analysis and at EOT. Dynamic on-treatment risk assessment using ctDNA offers potential to identify high-risk pts with LBCL, independent of baseline characteristics.

Background: Although rare, relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) in children, adolescents, and young adults is an area of high unmet need, with 1-year overall survival rates of <30% and complete remission (CR) rates of 27% after treatment with R-ICE (rituximab, ifosfamide, carboplatin, and etoposide) chemoimmunotherapy (Burke et al...Study treatment is administered with a single dose of obinutuzumab pretreatment followed by glofitamab step doses and repeated glofitamab full doses every 21 days as monotherapy or in combination with R-ICE...The first patient was enrolled in November 2022 and the study is ongoing. The study is planned at 23 sites in 9 countries (Europe, Australia, North America, South Korea, and China).

Pts with R/R LBCL (diffuse LBCL not otherwise specified [DLBCL NOS], high-grade B-cell lymphoma [HGBCL], primary mediastinal LBCL [PMBCL], or LBCL arising from follicular lymphoma [trFL]) and ≥2 prior therapies received 1000mg obinutuzumab pretreatment (Gpt) 7 days prior to the first glofitamab dose...Steroid premedication (80mg IV methylprednisolone, or equivalent dose of prednisone [100mg] or prednisolone [100mg], or 20mg IV Dex) was given at least 60 minutes prior to Gpt and each glofitamab dose... The incidence, severity, and seriousness of CRS after glofitamab administration in pts with R/R LBCL were numerically lower with Dex premedication versus premedication with other steroid regimens. Response rates in the Dex only cohort were similar to those reported in the non-Dex cohort. We therefore propose Dex as the steroid of choice for premedication to prevent or mitigate CRS in pts with LBCL treated with glofitamab monotherapy, considering its half-life and potency.

In this study, we demonstrated the MoA of englumafusp alfa in R/R NHL and key PD effects in combination versus glofitamab monotherapy that will support optimal biological dose finding. Furthermore, the observed association between expansion of TEM cells in PB and changes in ctDNA dynamics at EoT, albeit preliminary, supports ctDNA as a marker for depth and durability of response. Overall, our PD and biomarker observations so far strengthen the rationale of combining glofitamab with englumafusp alfa to drive long-term responses in this heavily pre-treated NHL patient population.