Final results of a phase 1 study of loncastuximab tesirine in relapsed/refractory B-cell non-Hodgkin lymphoma

Abstract

The prognosis for patients with relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) remains poor, with a need for alternatives to current salvage therapies. Loncastuximab tesirine (ADCT-402) is an antibody-drug conjugate comprising a humanized anti-CD19 monoclonal antibody conjugated to a pyrrolobenzodiazepine dimer toxin. Presented here are final results of a phase 1 dose-escalation and dose-expansion study in patients with R/R B-NHL. Objectives were to determine the maximum tolerated dose (MTD) and recommended dose(s) for expansion and evaluate safety, clinical activity, pharmacokinetics, and immunogenicity of loncastuximab tesirine. Overall, 183 patients received loncastuximab tesirine, with 3 + 3 dose escalation at 15 to 200 µg/kg and dose expansion at 120 and 150 µg/kg. Dose-limiting toxicities (all hematologic) were reported in 4 patients. The MTD was not reached, although cumulative toxicity was higher at 200 µg/kg. Hematologic treatment-emergent adverse events were most common, followed by fatigue, nausea, edema, and liver enzyme abnormalities. Overall response rate (ORR) in evaluable patients was 45.6%, including 26.7% complete responses (CRs). ORRs in patients with diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, and follicular lymphoma were 42.3%, 46.7%, and 78.6%, respectively. Median duration of response in all patients was 5.4 months and not reached in patients with DLBCL (doses ≥120 µg/kg) who achieved a CR. Loncastuximab tesirine had good stability in serum, notable antitumor activity, and an acceptable safety profile, warranting continued study in B-NHL. The recommended dose for phase 2 was determined as 150 µg/kg every 3 weeks for 2 doses followed by 75 µg/kg every 3 weeks. This trial was registered at www.clinicaltrials.gov as #NCT02669017.

Graphical abstract

Figure 1.

Patient disposition. ^aA patient was considered to have completed the study after 12 months posttreatment follow-up data were obtained.

Figure 2.

Best percent change from baseline in tumor size by dose. Patients with B-NHL (A), DLBCL (B), MCL (C), and FL (D).

Figure 3.

DOR to loncastuximab tesirine, PFS, and OS. DOR by B-NHL subtype (A), for patients with DLBCL by dose (B), and for patients with DLBCL by response (C). (D) PFS for all patients with B-NHL and those with DLBCL, MCL, and FL. (E) OS for all patients with B-NHL and those with DLBCL, MCL, and FL.

Figure 4.

Correlation between C_max and AUC of loncastuximab tesirine–conjugated antibody during cycle 1 and baseline peripheral CD19⁺ B cells. (A) C_max. (B) AUC. Linear regression models were used with natural log of baseline peripheral CD19⁺ B-cell values as the independent variable and natural log of C_max or AUC as the dependent variable. Zero baseline CD19⁺ cells was set to 0.1 cells per μL and LN(0.1) = −2.30. The estimated slope (standard error) was −0.0617 (0.0239; 95% CI, −0.109 to −0.0143) for C_max and −0.232 (0.0370; 95% CI, −0.305 to −0.158) for AUC.