Zynlonta

Pharmacotherapeutic group: Antineoplastic and immunomodulating agents, antineoplastic agents, monoclonal antibodies and antibody drug conjugates, other monoclonal antibodies and antibody drug conjugates, ATC code: L01FX22 Mechanism of action Loncastuximab tesirine is an antibody-drug conjugate (ADC) targeting CD19. The monoclonal IgG1 kappa antibody component binds to human CD19, a transmembrane protein expressed on the surface of cells of B-lineage origin. The small molecule component is SG3199, a PBD dimer and alkylating agent. Upon binding to CD19, loncastuximab tesirine is internalised followed by release of SG3199 via proteolytic cleavage. The released SG3199 binds to the DNA minor groove and forms highly cytotoxic DNA interstrand crosslinks, subsequently inducing cell death. Pharmacodynamic effects Higher loncastuximab tesirine exposure in Cycle 1 was associated with higher efficacy over the dose range of 0.015-0.2 mg/kg (0.1 to 1.33 times the maximum recommended dose). Higher loncastuximab tesirine exposure in Cycle 1 was associated with higher incidence of some Grade ≥2 adverse reactions, including skin and nail reactions, liver function test abnormalities and increased γ‑glutamyltransferase. Cardiac electrophysiology At the maximum recommended therapeutic dose of 0.15 mg/kg during Cycle 1 and Cycle 2, loncastuximab tesirine does not cause large mean increases (i.e., >20 msec) in the QTc interval. Clinical efficacy and safety The efficacy of Zynlonta was evaluated in ADCT-402-201 (LOTIS‑2), an open‑label, single-arm study in 145 adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after at least 2 prior systemic regimens. The study excluded patients with bulky disease (defined as any tumour ≥10 cm in the longest dimension), due to lower response rate, and active central nervous system lymphoma. Patients received Zynlonta 0.15 mg/kg every 3 weeks for 2 cycles, then 0.075 mg/kg every 3 weeks for subsequent cycles. Patients received treatment for 1 year, or beyond if they were clinically benefitting, or until progressive disease or unacceptable toxicity. Among the 145 patients who received Zynlonta, the median number of cycles was 3 (range 1 to 26), with 60% receiving three or more cycles and 34% receiving five or more cycles. Twelve (12) patients received stem cell transplantation directly following treatment with Zynlonta. Of the 145 patients enrolled, the median age was 66 years (range 23 to 94) while 14% were 75 years of age and older, 59% were male, and 94% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Race was reported in 97% of patients; of these patients, 90% were White, 3% were Black, and 2% were Asian. The diagnosis was DLBCL not otherwise specified (NOS) in 88% (including 20% with DLBCL arising from low grade lymphoma) and high-grade B‑cell lymphoma in 7%. The median number of prior therapies was 3 (range 2 to 7). 43% of the patients received 2 prior therapies whereas 24% received 3 prior therapies and 32% received more than 3 prior therapies. 63% of patients had refractory disease, 17% with prior stem cell transplant, and 9% with prior chimeric antigen receptor (CAR) T‑cell therapy. Efficacy was evaluated on the basis of overall response rate (ORR) as assessed by an Independent Review Committee (IRC) using Lugano 2014 criteria (Table 3). The median follow-up time was 7.8 months (range 0.3 to 31). Table 3: Efficacy results in patients with relapsed or refractory DLBCL Efficacy parameter Zynlonta N = 145 Overall response rate by IRC a , (95% CI) 48.3% (39.9, 56.7) Complete response rate (95% CI) 24.8% (18.0, 32.7) Median time to response (range), months 1.3 (1.1, 8.1) Duration of overall response N = 70 Median (95% CI), months 13.4 (6.9, NE) CI = confidence interval, NE = not estimable a IRC = independent review committee using Lugano 2014 criteria Immunogenicity As with all therapeutic proteins, there is potential for an immune response in patients treated with loncastuximab tesirine. In ADCT-402-201 (LOTIS‑2), 0 of 134 patients tested positive for antibodies against loncastuximab tesirine after treatment. Elderly population Of the 145 patients with large B‑cell lymphoma who received Zynlonta in the ADCT-402-201 (LOTIS‑2) study, 55% were 65 years of age and older. No overall differences in safety or effectiveness were observed between these patients and younger patients. Paediatric population The MHRA has deferred the obligation to submit the results of studies with Zynlonta in one or more subsets of the paediatric population in treatment of B-cell non-Hodgkin Lymphoma (B‑NHL) (see section 4.2 for information on paediatric use). Conditional approval This medicinal product has been authorised under a so-called 'conditional approval' scheme. This means that further evidence on this medicinal product is awaited. The MHRA will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.