On 20 July, ADC Therapeutics announced its plan to discontinue the Phase II LOTIS-9 trial investigating the combination of ADC Therapeutics’s Zynlonta (loncastuximab tesirine) and rituximab in unfit or frail previously untreated diffuse large B-cell lymphoma (DLBCL) patients following excessive respiratory-related treatment-emergent adverse events. Once treatment concludes for reconsenting patients who were seeing a clinical benefit from the experimental regimen, ADC Therapeutics will end the trial and will not pursue the Zynlonta-rituximab regimen in this patient population. This failure demonstrates the historical challenge to develop alternative noncytotoxic treatments in unfit and frail patients due to the difficulty of striking the right balance between minimizing toxicity and optimizing a response. Zynlonta was approved in 2021 and is marketed in the US and Europe for adults with relapsed or refractory (R/R) large B-cell lymphoma after two or more lines of systemic therapy. 

Zynlonta is an antibody-drug conjugate (ADC) directed to tumour cells expressing B-lymphocyte antigen CD19, which is internalised upon binding and releases its cytotoxic payload, leading to cell death. The Phase II LOTIS-2 trial of Zynlonta as a monotherapy boasted impressive results in patients with R/R DLBCL, with an overall response rate of 48.3% and a complete response rate of 24.8%. The results of the LOTIS-2 trial generated hope for Zynlonta’s administration in earlier lines of therapy. 

Prior to the clinical trial failure, Zynlonta’s projected yearly sales were expected to reach $408m by 2029, according to GlobalData’s analyst consensus forecast. However, the negative trial results will impact this value. Additionally, Zynlonta is ADC Therapeutics’ only approved marketed agent. Therefore, the company must expand its current pipeline and continue its investigation of Zynlonta in other patient populations. Some optimism remains for ADC Therapeutics through the confirmatory Phase III LOTIS-5 trial assessing the Zynlonta-rituximab regimen as a second-line therapy for transplant-ineligible R/R DLBCL to solidify its placement as a treatment option in the second-line and third-line setting, for which Zynlonta is already approved. However, competition in the third-line continues to increase, with approved agents such as Roche’s Polivy (polatuzumab vedotin), a CD79b-directed ADC, and expected launches from companies developing other ADCs, monoclonal antibodies, or bispecific antibodies. Significant opportunity remains for competing pharmaceutical companies in the treatment of unfit or frail DLBCL patients.