In such cases, the available effective treatment options are limited and the prognosis is poor. An alternative has been developed by Sobi and licensed to ADC Therapeutics. Loncastuximab tesirine is an antibody–drug conjugate (ADC) directed at CD-19.
Once the antibody has bound to CD-19 on a cell surface, it is internalised by the cell and its payload is released.
This payload is a pyrrolobenzodiazepine, which binds to the DNA minor groove to initiate cell cycle arrest and tumour cell death. As this binding causes little distortion, it is less visible to DNA repair mechanisms.
A first-in-human study was done in patients with B-cell non-Hodgkin lymphoma.1 In all, 88 patients aged 18 or older with relapsed or refractory disease were given the ADC every 3 weeks in a dose escalation study (with doses ranging from 15–200 µg/kg).
Almost all experienced some form of treatment-emergent adverse event, with the most common being haematologic abnormalities, oedema, fatigue, nausea, rash, dyspnoea and abnormal liver tests.
With doses of at least 120 µg/kg, which were given to 69 of the patients, the overall response rate was 59%, with 28 complete responses and 13 partial responses. A dose of 150 µg/kg was selected for further studies.
In a multicentre, open label, single arm Phase II trial, 145 adult patients with relapsed or refractory DLBCL who had previously had at least two multi-agent systemic treatments were given 150 µg/kg of the ADC intravenously on the first day of each of the first two 21-day cycles, and 75 µg for the third and subsequent cycles.2
Treatment continued for up to a year or until the disease relapsed or progressed or unacceptable toxicity occurred.
A complete or partial response was achieved by 70 of the treated patients — 35 partial and 35 complete — giving an overall response rate of 48%.
The most common treatment-emergent adverse events of grade 3 or higher were neutropenia, thrombocytopenia and an increase in gamma-glutamyltransferase; serious adverse events were experienced by 57 of the patients.
Although eight of the patients had a fatal outcome from a treatment-emergent adverse event, none were deemed to be related to the ADC. The drug is also being investigated in other forms of B-cell malignancy.3
These include acute lymphoblastic leukaemia and it’s also being looked at as an earlier line of therapy.4
References
- B.S. Kahl, Clin. Cancer Res. 25, 6986 (2019).
- P.F. Caimi, et al., Lancet Oncol. 22, 790 (2021).
- E. Calabretta, et al., Blood 140, 303 (2022).
- N. Jain, et al., Blood Adv. 4, 449 (2020).