Planned Interim Analysis of a Phase 2 Study of Loncastuximab Tesirine Plus Ibrutinib in Patients with Advanced Diffuse Large B-Cell Lymphoma (LOTIS-3)
Authors: Carlo-Stella Carmelo , Zinzani Pier Luigi Luigi , Janakiram Murali , Dia Vivian , He Xiaomin , Ervin-Haynes Annette , Depaus Julien 
Published: November 2021

Abstract
Introduction: Treatment options are limited in patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Combined therapy using agents with different mechanisms of action, such as an antibody-drug conjugate (ADC) with an inhibitor of Bruton's tyrosine kinase (BTK), may improve therapeutic outcomes. Loncastuximab tesirine (loncastuximab tesirine-lpyl; Lonca) is an ADC comprising a humanized anti-CD19 monoclonal antibody conjugated to a pyrrolobenzodiazepine dimer toxin, approved for the treatment of patients with R/R DLBCL after ≥2 lines of prior systemic therapy. Ibrutinib, a small-molecule inhibitor of BTK, has shown antitumor activity - particularly as a combination treatment - in patients with R/R DLBCL (Depaus et al, abstract 2099, ASH Dec 5-8, 2020). Here, we present the results of a planned interim analysis in patients with DLBCL (irrespective of cell of origin), non-germinal center B-cell-like DLBCL (non-GCB DLBCL), and GCB DLBCL.
Methods: In this ongoing, Phase 2, open-label, single-arm study, patients aged ≥18 years with R/R DLBCL, measurable disease (per 2014 Lugano classification), and ECOG performance status 0-2 were enrolled. Patients were treated with Lonca 60 μg/kg once every 3 weeks for 2 cycles (patients who had a complete response [CR], partial response [PR], or stable disease were permitted to have an additional Lonca dose at Day 1 of Cycles 5, 6, 9, and 10), plus ibrutinib 560 mg/day taken orally for up to 1 year. The primary objective of the study was to evaluate the complete response rate (CRR) achieved with Lonca plus ibrutinib in patients with R/R non-GCB DLBCL (cell of origin, as determined by the investigator), assessed by central review. A Simon's 2-stage design was used in this study with a planned interim analysis conducted when the 22nd patient in the non-GCB DLBCL cohort had 2 tumor assessments. The objective of this planned interim analysis was to determine if CRR in the non-GCB DLBCL cohort warranted continuation of patient enrollment for study completion; if ≥6 patients achieved a CR the study was planned to proceed to the next stage. Thirteen patients with GCB DLBCL who met the defined cut-off for the interim analysis were also included in the dataset.
Results: As of April 21, 2021, 35, 22, and 13 patients with DLBCL overall, non-GCB DLBCL, and GCB DLBCL, respectively, were included in the planned interim analysis. In the overall DLBCL cohort, patients had a median age of 72 years (range 19-82) and had received a median of 3 prior therapies (range 1-6), including stem cell transplant. Patients in the overall DLBCL cohort received a median of 2 (range 1-6) cycles of Lonca and 4 (range 1-10) cycles of ibrutinib.
CRRs among the planned interim analysis population were 34.3% (12/35; 95% CI: 19.1-52.2), 27.3% (6/22; 95% CI: 10.7-50.2), and 46.2% (6/13; 95% CI: 19.2-74.9) in the overall DLBCL cohort, non-GCB DLBCL cohort, and GCB DLBCL cohort, respectively. ORR (CR + PR) was 57.1% (20/35; 95% CI: 39.4-73.7) in the overall DLBCL cohort, and 45.5% (10/22; 95% CI: 24.4-67.8) and 76.9% (10/13; 95% CI: 46.2-95.0) in the non-GCB DLBCL and GCB DLBCL cohorts, respectively (Figure 1). Median (95% CI) duration of response in the overall DLBCL cohort was 5.49 (5.49-not reached) months and was not reached in the non-GCB DLBCL or GCB DLBCL cohorts.
In the overall DLBCL cohort, non-GCB DLBCL cohort, and GCB DLBCL cohort, 32 (91.4%), 21 (95.5%), and 11 (84.6%) patients, respectively, had at least 1 treatment-emergent adverse event (TEAE). In total, 16 (45.7%) patients in the overall DLBCL cohort (15 [68.2%] with non-GCB DLBCL; 1 [7.7%] with GCB DLBCL) had Grade ≥3 TEAEs; the most common (≥10%) were neutropenia in 7 (20%) patients and thrombocytopenia in 4 (11.4%) patients. Overall, 17 (48.6%) patients had TEAEs leading to dose reduction, delay, or interruption. TEAEs leading to treatment discontinuation occurred in 8 (22.9%) patients.
Conclusions: At the doses tested, treatment with Lonca plus ibrutinib showed encouraging anti-tumor activity and a manageable safety profile in patients with R/R DLBCL. The study protocol will be amended to investigate whether Lonca given at each cycle in combination with ibrutinib improves efficacy outcomes in patients with R/R DLBCL.
Funding: ADC Therapeutics SA (NCT03684694).
Figure 1 Figure 1.

Disclosures
Carlo-Stella: AstraZeneca: Honoraria; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Oncology: Honoraria; Incyte: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Research Funding. Zinzani: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck Sharp & Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ImmuneDesign: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Janakiram: FATE Therapeutics: Research Funding; Takeda Pharmaceuticals: Research Funding; Kyowa Kirin Therapeutics: Honoraria; ADC Therapeutics: Research Funding. Dia: ADC Therapeutics America, Inc.: Current Employment, Current equity holder in publicly-traded company. He: ADC Therapeutics America, Inc.: Current Employment, Current equity holder in publicly-traded company; State University of New York Research Foundation: Current Employment. Ervin-Haynes: ADC Therapeutics America, Inc.: Current Employment, Current equity holder in publicly-traded company. Depaus: Celgene: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Takeda: Consultancy.

OffLabel Disclosure:
Ibrutinib is not approved for DLBCL.