Interim Results of Loncastuximab Tesirine Combined with Ibrutinib in Diffuse Large B-Cell Lymphoma or Mantle Cell Lymphoma (LOTIS-3)

Introduction: Patients (pts) 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 is a small-molecule inhibitor of Bruton’s tyrosine kinase, a mediator of the B‑cell–receptor signalling pathway, which is implicated in the pathogenesis of B-cell cancers. Pre-clinically, the combination of Lonca and ibrutinib has shown synergy in vitro in DLBCL cell lines (Tarantelli et al, ICML 2019; abstract 083). Initial results from this Phase 1/2 study of Lonca and ibrutinib 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 identified the maximum tolerated dose (MTD) of Lonca with ibrutinib (Depaus et al, EHA25 Virtual, 2020; abstract EP1284). We present updated Phase 1 data for pts receiving the MTD of Lonca 60 µg/kg in combination with ibrutinib 560 mg during this ongoing study.

Methods: This two-part, open-label, single-arm dose escalation and expansion study (NCT03684694) is enrolling pts aged ≥18 years with pathologically confirmed R/R DLBCL or MCL. Primary objectives of Phase 1 are to characterize the safety and tolerability of Lonca 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 Lonca with ibrutinib, with a primary endpoint of complete response (CR) rate. Secondary objectives include further evaluation of efficacy, pharmacokinetics (PK), and immunogenicity of the combination. In Phase 1, Lonca 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, Lonca 60 µg/kg with ibrutinib 560 mg is being assessed in three pt cohorts: non-germinal center B-cell (non-GCB) DLBCL, GCB DLBCL, and MCL. Pts receive 3-weekly cycles for the first 2 cycles: Lonca 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, pts with a partial response (PR) or stable disease at the second disease evaluation (14 weeks after first dose) may receive 2 additional doses of Lonca 4 weeks apart on Day 1 of Cycles 5 and 6.

Results: As of June 30, 2020, 34 pts had received Lonca at 60 µg/kg plus ibrutinib 560 mg: 28 pts with DLBCL, comprising 23 pts with non-GCB DLBCL and 5 pts with GCB DLBCL, and 6 pts with MCL. Pt characteristics are summarized in Table 1. Pts 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 Lonca (range 1–4).

Treatment-emergent adverse events (TEAEs) were reported in 29/34 (85.3%) pts, and grade ≥3 TEAEs in 14 (41.2%) pts. The most common all-grade TEAEs (≥15% of pts), regardless of relationship to study treatment, were thrombocytopenia (10 pts [29.4%]), anemia (7 pts [20.6%]), and fatigue, diarrhea, nausea, and rash (each 6 pts [17.6%]). Grade ≥3 TEAEs reported in ≥5% of pts were anemia (3 pts [8.8%]), and thrombocytopenia and neutropenia (each 2 pts [5.9%]).

The efficacy analysis set comprised 22 pts. Overall response rate (ORR) was 77.3% (17 pts); 45.5% (10 pts) had a CR; 31.8% (7 pts) had a PR (Figure 1). ORR in pts with DLBCL was 73.7% (14/19 pts), and 47.4% (9 pts) had a CR. Only 1 pt with GCB DLBCL was evaluable and had a PR. ORR in pts with MCL was 100% (3/3 pts), and 33.3% (1 pt) had a CR.

Conclusions: Interim results show that Lonca at 60 µg/kg in combination with ibrutinib 560 mg continues to have encouraging antitumor activity and manageable toxicity in pts with R/R DLBCL or MCL. Safety data were consistent with those reported previously for this combination. The study is continuing to enroll pts and updated results, including efficacy and PK data, will be presented at the meeting.

Funding: Study funded by ADC Therapeutics SA, with the support of Pharmacyclics LLC, an AbbVie company, which supplies ibrutinib (clinicaltrials.gov/show/NCT03684694).