Efficacy and Safety of Single-Agent Zandelisib Administered By Intermittent Dosing in Patients with Relapsed or Refractory (R/R) Follicular Lymphoma (FL): Final Results of the Tidal Phase 2 Study

Zelenetz, Andrew D.; Jurczak, Wojciech; Ribrag, Vincent; Linton, Kim; Collins, Graham P.; Bishton, Mark; Jiménez, Javier López; Dholaria, Bhagirathbhai; Mengarelli, Andrea; Phillips, Tycel; Sungala, Nagendra Prasad; Chan, Henry; Musuraca, Gerardo; Sheehy, Oonagh; Yan, Jun; Xu, Weiming; Azoulay, Michel; Zinzani, Pier Luigi

doi:10.1182/blood-2022-165409

Cited by 5 publications

(3 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…No trial is being conducted to examine the combination of loncastuximab tesirine with PI3K inhibitors, which appears promising based on the in vitro and in vivo anti-tumor activity. The novel highly specific PI3Kδ inhibitors seem to have an improved toxicity profile (41,42), which might overcome the problems observed with first-generation compounds (43).…”

Section: Discussionmentioning

confidence: 99%

Targeting CD19-positive lymphomas with the antibodydrug conjugate loncastuximab tesirine: preclinical evidence of activity as a single agent and in combination therapy

Tarantelli,

Wald,

Munz

et al. 2024

haematol

View full text Add to dashboard Cite

Antibody-drug conjugates (ADCs) represent one of the most successful therapeutic approaches introduced in clinical practice in the last few years. Loncastuximab tesirine (ADCT-402) is a CD19 targeting ADC, in which the antibody is conjugated through a protease cleavable dipeptide linker to a pyrrolobenzodiazepine (PBD) dimer warhead (SG3199). Based on the results of a phase 2 study, loncastuximab tesirine was recently approved for adult patients with relapsed/refractory large B-cell lymphoma. We assessed the activity of loncastuximab tesirine using in vitro and in vivo models of lymphomas, correlated its activity with CD19 expression levels, and identified combination partners providing synergy with loncastuximab tesirine. Loncastuximab tesirine was tested across 60 lymphoma cell lines. Loncastuximab tesirine had strong cytotoxic activity in B-cell lymphoma cell lines. The in vitro activity was correlated with CD19 expression level and intrinsic sensitivity of cell lines to the ADC’s warhead. Loncastuximab tesirine was more potent than other anti-CD19 ADCs (coltuximab ravtansine, huB4-DGN462), albeit the pattern of activity across cell lines was correlated. Loncastuximab tesirine activity was also largely correlated with cell line sensitivity to R-CHOP. Combinatorial in vitro and in vivo experiments identified the benefit of adding loncastuximab tesirine to other agents, especially BCL2 and PI3K inhibitors. Our data support the further development of loncastuximab tesirine as a single agent and in combination for patients affected by mature B-cell neoplasms. The results also highlight the importance of CD19 expression and the existence of lymphoma populations characterized by resistance to multiple therapies.

show abstract

Section: Discussionmentioning

confidence: 99%

Targeting CD19-positive lymphomas with the antibodydrug conjugate loncastuximab tesirine: preclinical evidence of activity as a single agent and in combination therapy

Tarantelli,

Wald,

Munz

et al. 2024

haematol

View full text Add to dashboard Cite

show abstract

“…No trial is currently exploring the combination of loncastuximab tesirine with PI3K inhibitors, which based on the in vitro and in vivo anti-tumor activity, appears promising. The novel highly specific PI3Kδ inhibitors seem to have an improved toxicity profile (46,47), which might overcome the problems observed with first generation compounds (48). The combination of loncastuximab tesirine with ibrutinib, also supported by other preclinical work (49), has been clinically evaluated with results reported in R/R DLBCL or MCL (50).…”

Section: Discussionmentioning

confidence: 99%

Targeting CD19-positive lymphomas with the antibody-drug conjugate (ADC) loncastuximab tesirine: preclinical evidence as single agent and as combinatorial approach

Tarantelli,

Wald,

Munz

et al. 2023

Preprint

View full text Add to dashboard Cite

Purpose. Antibody-drug conjugates (ADCs) represent one of the most successful therapeutic approaches introduced in clinical practice in the last years. Loncastuximab tesirine (ADCT-402) is a CD19 targeting ADC, in which the antibody is conjugated through a protease cleavable dipeptide linker to a pyrrolobenzodiazepine (PBD) dimer warhead (SG3199). Based on the results of a phase 2 study, loncastuximab tesirine was recently approved for adult patients with relapsed/refractory large B-cell lymphoma. Experimental Design. We assessed the activity of loncastuximab tesirine in in vitro and in vivo models of lymphomas, correlated its activity with CD19 expression levels and identified combination partners providing synergy with loncastuximab tesirine. Results. Loncastuximab tesirine was tested across 60 lymphoma cell lines. Loncastuximab tesirine has strong cytotoxic activity in B-cell lymphoma cell lines and the in vitro activity is correlated with CD19 expression level and with intrinsic sensitivity of cell lines to the warhead of the ADC. Loncastuximab tesirine was more potent than other anti-CD19 ADCs (coltuximab ravtansine, huB4-DGN462), albeit the pattern of activity across cell lines was correlated. Loncastuximab tesirine activity also largely correlated with cell line sensitivity to R-CHOP. Combinatorial in vitro and in vivo experiments identified the benefit of adding loncastuximab tesirine to other agents, especially BCL2 and PI3K inhibitors. Conclusions. Our data support the further development of loncastuximab tesirine as single agent and in combination for patients affected by mature B-cell neoplasms. The results also highlight the importance of CD19 expression, and the existence of lymphoma populations characterized by resistance to multiple therapies.

show abstract

“…Parsaclisib demonstrated a high overall response rate (ORR) of 75.4% and median progression-free survival (PFS) of 14.0 months—however, the New Drug Application (NDA) for parsaclisib was withdrawn in 2022 as the FDA requested confirmatory studies that its manufacturer elected not to pursue [ 24 , 25 ]. Similarly, zandelisib monotherapy was associated with high ORR (72.5%) with an estimated median PFS of 11.4 months—however, further development of zandelisib outside of Japan was stopped abruptly in 2022 after the FDA requested further changes to the phase 3 COASTAL trial [ 26 , 27 ].…”

Section: Overview Of Targeted Therapiesmentioning

confidence: 99%

Targeted Therapy in Follicular Lymphoma: Towards a Chemotherapy-Free Approach

Chen,

Choi,

Heyman

2023

Cancers

View full text Add to dashboard Cite

Background: The treatment of follicular lymphoma (FL) has previously centered on chemoimmunotherapy, which can be disadvantageous due to patient intolerance, cumulative toxicities, and disease refractoriness. Targeted therapies can produce deep responses and improve progression-free and overall survival with more tolerable adverse event profiles. Methods: We summarize the current literature and key clinical trials regarding targeted therapies in follicular lymphoma both in the front-line and in the relapsed-refractory setting. Results: Targeted therapies studied in FL include immune modulators, anti-CD20 antibodies, Bruton’s tyrosine kinase (BTK) inhibitors, enhancers of zeste homolog 2 (EZH2) inhibitors, phosphoinositide 3-kinase (PI3K) inhibitors, and B-cell lymphoma 2 (BCL-2) inhibitors. Chimeric antigen receptor (CAR-T) therapy and bispecific T-cell engager (BiTE) therapies also show promise in monotherapy and in combination with targeted therapies. These therapies exhibit high overall response rates and substantial progression-free survival and overall survival, even in high-risk patients or patients previously refractory to chemotherapy or rituximab. Adverse events vary substantially but are generally manageable and compare favorably to the cumulative toxicities of chemotherapy. Conclusion: Targeted therapies represent a paradigm shift in the treatment of FL. Further studies are needed to directly compare these targeted therapies and their combinations, as well as to investigate biomarkers predictive of response.

show abstract

Efficacy and Safety of Single-Agent Zandelisib Administered By Intermittent Dosing in Patients with Relapsed or Refractory (R/R) Follicular Lymphoma (FL): Final Results of the Tidal Phase 2 Study

Cited by 5 publications

References 0 publications

Targeting CD19-positive lymphomas with the antibodydrug conjugate loncastuximab tesirine: preclinical evidence of activity as a single agent and in combination therapy

Targeting CD19-positive lymphomas with the antibodydrug conjugate loncastuximab tesirine: preclinical evidence of activity as a single agent and in combination therapy

Targeting CD19-positive lymphomas with the antibody-drug conjugate (ADC) loncastuximab tesirine: preclinical evidence as single agent and as combinatorial approach

Targeted Therapy in Follicular Lymphoma: Towards a Chemotherapy-Free Approach

Contact Info

Product

Resources

About