Patients with relapsed or refractory ( R/R ) diffuse large B-cell lymphoma ( DLBCL ) or mantle cell lymphoma ( MCL ) have a poor prognosis and many do not have long-term disease control with salvage therapies.
Combining two agents with different mechanisms of action has the potential for increased antitumor activity compared with single agents.
Loncastuximab tesirine ( Lonca ) is an antibody-drug conjugate comprising a humanized anti-CD19 antibody conjugated to a pyrrolobenzodiazepine dimer toxin.
Ibrutinib ( Imbruvica ) is a small-molecule inhibitor of Bruton’s tyrosine kinase ( BTK ), a mediator of the B-cell–receptor signalling pathway, which is implicated in the pathogenesis of B-cell cancers. Pre-clinically, the combination of Loncastuximab tesirine and Ibrutinib has shown synergy in vitro in DLBCL cell lines ( Tarantelli et al, ICML 2019 ).
Initial results from this phase 1/2 study of Loncastuximab tesirine and Ibrutinib have demonstrated encouraging antitumor activity, manageable toxicity and good exposure coverage throughout the dosing interval in pts with R/R DLBCL and R/R MCL, and have identified the maximum tolerated dose ( MTD ) of Loncastuximab tesirine with Ibrutinib ( Depaus et al, EHA25 Virtual, 2020 ).
Updated phase 1 data for patients receiving the MTD of Loncastuximab tesirine 60 µg/kg in combination with Ibrutinib 560 mg during this ongoing study, were presented.
This two-part, open-label, single-arm dose escalation and expansion study is enrolling patients aged greater than or equal to 18 years with pathologically confirmed R/R DLBCL or mantle cell lymphoma.
Primary objectives of phase 1 are to characterize the safety and tolerability of Loncastuximab tesirine with Ibrutinib, and to identify the recommended dose and schedule for phase 2.
The primary objective of phase 2 is to evaluate the efficacy of Loncastuximab tesirine with Ibrutinib, with a primary endpoint of complete response ( CR ) rate.
Secondary objectives include further evaluation of efficacy, pharmacokinetics, and immunogenicity of the combination.
In phase 1, Loncastuximab tesirine doses of 60 or 90 µg/kg ( 30-minute intravenous infusion ) with fixed-dose Ibrutinib ( 560 mg/day, oral ) are being evaluated using a 3+3 dose escalation design.
In phase 2, Loncastuximab tesirine 60 µg/kg with Ibrutinib 560 mg is being assessed in three patient cohorts: non-germinal center B-cell ( non-GCB ) DLBCL, GCB DLBCL, and MCL.
Patients receive 3-weekly cycles for the first 2 cycles: Loncastuximab tesirine is given once every 3 weeks for 2 doses ( Day 1 of Cycles 1 and 2 ) in combination with daily Ibrutinib. Cycles 3 onwards are 4-weekly cycles of daily Ibrutinib alone, given for up to 1 year.
During phase 1, patients with a partial response ( PR ) or stable disease at the second disease evaluation ( 14 weeks after first dose ) may receive 2 additional doses of Loncastuximab tesirine 4 weeks apart on Day 1 of Cycles 5 and 6.
As of June 30, 2020, 34 patients had received Loncastuximab tesirine at 60 µg/kg plus Ibrutinib 560 mg: 28 patients with DLBCL, comprising 23 patients with non-GCB DLBCL and 5 patients with GCB DLBCL, and 6 patients with MCL.
Patients had received a median of 3.5 cycles of Ibrutinib ( range 1–14 ) given daily ( median treatment duration 45 days; range 1–379 ), and had received a median of 2 cycles of Loncastuximab tesirine ( range 1–4 ).
Treatment-emergent adverse events ( TEAEs ) were reported in 29/34 ( 85.3% ) patients, and grade 3 or more TEAEs in 14 ( 41.2% ) patients.
The most common all-grade TEAEs ( 15% or more of patients ), regardless of relationship to study treatment, were thrombocytopenia ( 10 patients [ 29.4% ] ), anemia ( 7 [ 20.6% ] ), and fatigue, diarrhea, nausea, and rash ( each 6 patients [ 17.6% ] ).
Grade 3 or more TEAEs reported in greater than or equal to 5% of patients were anemia ( 3 patients [ 8.8% ] ), and thrombocytopenia and neutropenia ( each 2 patients [ 5.9% ] ).
The efficacy analysis set comprised 22 patients. Overall response rate ( ORR ) was 77.3% ( 17 patients ); 45.5% ( 10 ) had a complete response; 31.8% ( 7 ) had a partial response.
ORR in patients with DLBCL was 73.7% ( 14/19 ), and 47.4% ( 9 ) had a complete response. Only 1 patient with GCB DLBCL was evaluable and had a partial response.
ORR in patients with MCL was 100% ( 3/3 ), and 33.3% ( 1 ) had a complete response.
In conclusion, interim results have shown that Loncastuximab tesirine at 60 µg/kg in combination with Ibrutinib 560 mg continues to have encouraging antitumor activity and manageable toxicity in patients with R/R diffuse large B-cell lymphoma or mantle cell lymphoma.
Safety data were consistent with those reported previously for this combination. ( Xagena )
Source: American Society of Hematology ( ASH ) Virtual Meeting, 2020