Zynlonta (loncastuximab tesirine-lpyl)

P2/3, N=210, Not yet recruiting, University of Birmingham | Trial completion date: Oct 2032 --> May 2033 | Initiation date: Oct 2023 --> May 2024 | Trial primary completion date: Oct 2030 --> May 2031

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.

We found Lonca is an effective treatment for R/R DLBCL regardless of CD19 expression by immunohistochemistry. These results provide the basis for future studies addressing CD19-targeted agent sequencing.

P1, N=33, Recruiting, Medical College of Wisconsin | Trial completion date: May 2028 --> May 2026 | Trial primary completion date: May 2027 --> May 2026

P2, N=41, Completed, ADC Therapeutics S.A. | Active, not recruiting --> Completed

P1, N=56, Recruiting, ADC Therapeutics S.A. | Phase classification: P1b --> P1

P1; Not yet recruiting --> Recruiting

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

"Foresight Diagnostics...announced multiple studies that consistently demonstrated higher clinical sensitivity and prognostic accuracy of Foresight Diagnostic's PhasED-Seq circulating tumor DNA (ctDNA) technology compared to that of standard-of-care imaging in patients with lymphoma...The new data have been presented across four podium presentations and two posters during this year's American Society of Hematology (ASH) annual meeting....'We are pleased to share our findings at ASH specific to the molecular response and mutational genotypes seen in DLBCL patients undergoing treatment with ZYNLONTA^® (loncastuximab tesirine-lpyl [Lonca]) to collectively improve our approaches to using ctDNA for drug development and clinical decision making.'"

All pts received axicabtagene ciloleucel. In this small, observational, real-world study, treatment of pts with lonca prior to CAR-T infusion did not preclude subsequent responses to CD19-directed CAR-T therapy. Studies in a large pt population are warranted to confirm the findings.

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.

In this real-world study, we examined the effectiveness of lonca for pts with R/R DLBCL following CAR-T. This is the first study to examine lonca at 3L following CAR-T at 2L and suggests that lonca can be a reasonable and effective treatment option for pts who are resistant/progressed after CAR-T. Data collection is still ongoing and final results (for the complete sample size) will be presented at the 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.

Similar results were obtained by combining Talazoparib and different PARP inhibitors with the alkylating agent cisplatin, indicating a class effect. Importantly, PBMC-derived T cells from healthy donors did not show any sign of DNA damage accumulation upon exposure to Lonca, Talazoparib and the combination. These data provide the rationale for future therapeutic strategies based on selective induction of DNA damage in neoplastic B cells in combination with DDR inhibition in aggressive MYC-positive B cell lymphoma.

P1b, N=56, Recruiting, ADC Therapeutics S.A. | Not yet recruiting --> Recruiting

"Foresight Diagnostics...announced today that six studies utilizing their patented PhasED-Seq technology will be presented at the 65th American Society of Hematology Annual Meeting and Exposition (ASH 2023) taking place December 9-12, 2023, in San Diego, California. Four of these studies have been accepted as oral presentations....Building upon these findings, Foresight and its partners will present new data at ASH 2023 that further supports the utility of Foresight's ultrasensitive PhasED-Seq MRD platform for accurate treatment response assessment."

ctDNA molecular response assessment using PhasED-Seq is prognostic for outcomes in pts receiving Lonca monotherapy. ctDNA levels as early as C2D1 can predict outcomes and are indicative of a fast response to Lonca. Furthermore, molecular responses can deepen with additional cycles.

IKS03 demonstrated greater activity than the clinical benchmark ADC loncastuximab tesirine. Secondary objectives include further evaluation of safety, tolerability, immunogenicity and PK profile of IKS03 as well as confirmation of the RP2D. Clinical trial information: NCT05365659.

Blood and tissue samples will be analyzed by multi-parameter flow cytometry and hiplex imaging assays (Phenocycler-Fusion/CODEX) to identify immune signatures of response and resistance to Lonca, and to assess CAR T-cell persistence; blood samples will be analyzed by CAPP-Seq to measure minimal residual disease. Finally, total metabolic tumor volume will be assessed on pre-treatment PET-CT scans, and association with response to consolidation therapy will be analyzed.

Loncastuximab teserine had a deleterious effect on several hematologic parameters, which was not observed with VIP924 or polatuzumab vedotin. The efficacy and tolerability observed in this study with VIP924 suggests further testing in human clinical trials is warranted.

IKS03 demonstrated greater in vivo efficacy than the clinical benchmark ADCs polatuzumab vedotin and loncastuximab tesirine approved for the treatment of patients with B-cell non-Hodgkin lymphomas. This is consistent with the proposed mechanism of action of CD19-mediated delivery of a PBD payload specifically to B-cell tumors. Clinical investigation in patients with advanced B-Cell Non-Hodgkin Lymphomas is being initiated (NCT05365659).

P2, N=0, Withdrawn, Barbara Ann Karmanos Cancer Institute | N=36 --> 0 | Recruiting --> Withdrawn

P1; Trial completion date: May 2025 --> Dec 2028 | Initiation date: Oct 2023 --> Feb 2024 | Trial primary completion date: Jan 2025 --> Dec 2026

P2, N=36, Recruiting, Barbara Ann Karmanos Cancer Institute | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

This study retrospectively evaluated the outcome of salvage therapy in 51 patients who failed axicabtagene ciloleucel or tisagenlecleucel for relapsed/refractory large B-cell lymphomas. Of these patients, 22 (43%) were enrolled in clinical trials (glofitamab or loncastuximab tesirine + ibrutinib), whereas 29 received standard therapies (lenalidomide [Len], checkpoint inhibitors [CPIs], ibrutinib [I], chemoimmunotherapy and radiotherapy) or supportive care...Factors adversely affecting the prognosis in the multivariable model were the absence of response to CAR T-cell therapy (HR: 3.08; p = 0.0109) and a diagnosis other than PMBCL and t-FL (HR: 4.54; p = 0.0069). The outcome of patients failing CAR T cells is poor and requires further investigation.

Patients: Part 1 enrolled 20 patients in a nonrandomized safety run-in; part 2 will randomly assign approximately 330 patients to receive Lonca-R or rituximab- gemcitabine-oxaliplatin. Lonca-R demonstrated no new safety signals and showed encouraging antitumor activity in patients with R/R DLBCL. Initial signs of durability are promising. Lonca-R has a fixed treatment duration, making it an appealing alternative to continuous therapies.

With additional follow-up, Lonca continued to demonstrate durable, long-term responses with manageable safety and tolerability in patients with CR. This trial is registered at ClinicalTrials.gov (NCT03589469).

P2, N=36, Recruiting, City of Hope Medical Center | Not yet recruiting --> Recruiting

P1; N=24; Not yet recruiting; Sponsor:Mayur Narkhede

P1, N=36, Recruiting, Brian Hill | Trial completion date: Mar 2023 --> Mar 2024 | Trial primary completion date: Jan 2023 --> Jan 2024

Baseline moderate to severe hepatic impairment has an unclear impact on the safety of loncastuximab tesirine-lpyl, and there is a lack of clear guidance on dose adjustment from the manufacturer. The authors present two cases of r/r DLBCL safely treated with full-dose loncastuximab tesirine-lpyl in the setting of severe hepatic dysfunction.

There is no proven benefit of CNS prophylaxis in older adults with DLBCL and it should be avoided due to increased risk of infections.6 R-CHOP remains the standard of care (SOC) for a majority of older adults with newly diagnosed DLBCL.7 In patients with high international prognostic index (IPI) score (2-5), R-CHP with polatuzumab should be preferred given its superiority over R-CHOP in terms of progression free survival without any increase in incidence of adverse events.8 Addition of targeted agents such as bortezomib,9 lenalidomide10,11 and ibrutinib12 to R-CHOP or intensification of therapy has not shown any benefit over R-CHOP alone. Similarly, maintenance strategies have not proven beneficial in improving outcomes.13–16 Ongoing clinical trials in older adults with DLBCL such as the SWOG 1918 study17 which is a phase II/III randomized study of R-miniCHOP with or without oral azacitidine (CC- 486), and the POLAR-BEAR study (NCT04332822), which is a randomized, multicenter, phase III trial comparing R-mini-CHOP with R-mini-CHP + polatuzumab have the potential to change the SOC in the next few years...The ZUMA-1 study showed an overall survival benefit of axi-cel over standard of care therapy in the 2L setting, hence all older adults eligible for CAR-T cell therapy must be offered this therapy.21 Both trial data and realworld data analyses have shown that the survival outcomes of older adults are similar to younger patients with CAR-T cell therapy with higher rates of cytokine release syndrome and neurotoxicity being offset by higher response rates.22,23 Data regarding the impact of GA on outcomes of older adults receiving CAR-T cell therapy is emerging and will help guide patient selection.24 The recent approval of epcoritamab for R/R DLBCL is a welcome advance that will greatly benefit older adults not eligible for CAR-T cell therapy.25 Other drugs available for patients ineligible for CAR-T cell therapy or for those who experience disease relapse post CAR-T cell therapy include polatuzumab-rituximab+/- bendamustine,26 tafasitamab-lenalidomide27 and loncastuximab28 or chemotherapy based approaches such as gemcitabine-oxaliplatin. Targeted drugs such as BTK inhibitors and lenalidomide are well tolerated and can lead to responses in patients with activated B-cell subtype of DLBCL. Exploration of aging biomarkers such as senescence associated secretory phenotype (SASP) and epigenetic clocks can inform appropriate patient and treatment selection in the future.

Several novel agents, polatuzumab vedotin, tafasitamab, loncastuximab tesirine, and selinexor, have been approved and offer new opportunities for this difficult to treat population. Additionally, advances in our understanding of DLBCL biology, genetics, and immune microenvironment have allowed for the identification of new therapeutic targets like Ikaros and Aiolos, IRAK4, MALT1, and CD47 with several agents in ongoing clinical trials. In this chapter we review updated data supporting the use of the approved agents and discuss other emerging novel therapies for patients with R/R DLBCL.

P2, N=24, Recruiting, Joseph Tuscano | Not yet recruiting --> Recruiting | Trial completion date: Aug 2027 --> Feb 2028 | Initiation date: Dec 2022 --> May 2023 | Trial primary completion date: Aug 2025 --> Feb 2026

PRACTICAL APPLICATIONS: Although most patients with diffuse large B-cell lymphoma will be cured with up-front chemoimmunotherapy, 30%-40% of patients will relapse. Although autologous stem-cell transplant offered a second chance at a durable remission, primary refractory and early relapsed diffuse large B-cell lymphoma (DLBCL) had an extremely poor outcome.On the basis of randomized controlled trials, chimeric antigen receptor (CAR) T-cell therapy with axicabtagene ciloleucel or lisocabtagene maraleucel (liso-cel) is now the recommended second-line treatment for patients who are medically fit with primary refractory and early relapsed disease.For unfit patients with relapsed/refractory DLBCL, we recommend treatment with liso-cel therapy if available and if not, participating in a clinical trial with treatments such as bispecific T-cell engagers (BITE), or treatment with an approved agent such as tafasitamab with lenalidomide, polatuzumab-vedotin with bendamustine and rituximab, R-GemOx, or loncastuximab tesirine.There remain many areas for research in DLBCL including optimizing options for bridging therapy, sequencing of treatments, such as CAR T-cell and BITE therapy, and when to treat a patient who may experience a complete response during salvage chemotherapy while awaiting CAR T-cell therapy.

P2, N=36, Not yet recruiting, City of Hope Medical Center | Initiation date: May 2023 --> Aug 2023

P2, N=36, Recruiting, Shayna Sarosiek, MD | Trial primary completion date: May 2023 --> May 2025

Novel treatments for patients with R/R DLBCL include chimeric antigen receptor T-cell (CAR T) therapy, polatuzumab vedotin plus bendamustine and rituximab (pola-BR), tafasitamab plus lenalidomide (tafa-len), loncastuximab (lonca), and selinexor. Outcomes for patients treated with pola-BR and tafa-len–based regimens remain suboptimal. These outcomes appear to worsen as patients advance to subsequent LOT, with particularly worse outcomes when new treatments are used after CAR T therapy.

Among heavily pretreated pts in LOTIS-2, Lonca continued to demonstrate durable, long- term responses in pts with CR with a manageable safety profile; 31% of the 36 CR pts were event-free for ≥2 yr with no evidence of disease and no new anticancer therapy post-Lonca. Further study is needed to identify factors predictive of long-term response to Lonca.