Loncastuximab tesirine plus rituximab explored in relapsed or refractory follicular lymphoma.

Evidence before this study

We searched PubMed on Sept 14, 2024, using the search terms “follicular lymphoma,” “relapsed,” “refractory,” “progression of disease within 24 months”, “GELF criteria,” “chemotherapy,” “CAR T-cell,” or “bispecific,” and filtered for “clinical trial”, to identify articles published in any language over the past 10 years since Sept 1, 2014. Before the initiation of this study, few treatment options for patients with relapsed or refractory follicular lymphoma were available. Standard first-line regimens included immunochemotherapy such as bendamustine with an anti-CD20 antibody or regimens with rituximab (rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone; or rituximab, cyclophosphamide, vincristine sulfate, and prednisone). The phase 3 randomised AUGMENT trial enrolled 358 patients with relapsed or non-rituximab-refractory indolent lymphoma, including 295 patients with follicular lymphoma. The experimental intervention of lenalidomide with rituximab had a progression-free survival benefit over single-agent rituximab. The complete response rate assessed by CT in follicular lymphoma was 35% (n=51 of 147). Emerging therapies aiming to improve outcomes in patients with relapsed or refractory follicular lymphoma were in development when this clinical trial was initiated, including chimeric antigen receptor (CAR) T-cell therapies (eg, axicabtagene ciloleucel, lisocabtagene maraleucel, and tisagenlecleucel) and CD20 × CD3 bispecific antibodies (epcoritamab, mosunetuzumab, and odronextamab). In the pivotal corresponding studies of approved CAR T-cell therapies, response rates were high with prolonged median duration of response, but studies also reported the need for complex procedures, including prolonged hospitalisation, and serious adverse events such as grade 3 or worse cytokine release syndrome and neurotoxicity. CD20 × CD3 bispecific antibodies are off-the-shelf therapies delivered in the outpatient setting; however, they could still be associated with toxicity, similar to CAR T-cell therapy, including grade 3 or worse cytokine release syndrome, neurotoxicity, hypogammaglobulinaemia, and infections associated with indefinite or prolonged administration for some of these agents. As lenalidomide with rituximab became a standard approach in relapsed or refractory follicular lymphoma when this study was designed, we aimed to develop an ambulatory fixed-duration regimen of loncastuximab tesirine with rituximab, targeting a complete response rate of at least 50%, with response assessed by [F]fluorodeoxyglucose-PET-CT.

Added value of this study

Results from this single-arm, phase 2, investigator-initiated study provide evidence of the activity and manageable safety of loncastuximab tesirine in combination with rituximab in relapsed or refractory follicular lymphoma. This combination led to an overall response rate of 97% (n=38 of 39) after 12 weeks of treatment, with a complete response rate of 67% (n=26 of 39), in relapsed or refractory follicular lymphoma. In addition, high rates of complete response were observed in difficult-to-treat groups, such as patients with high tumour burden based on Groupe d'Etude des Lymphomes Folliculaires criteria progression or relapse of disease within 24 months (POD24) after the first line of treatment, or high-risk Follicular Lymphoma International Prognostic Index score. The present results are of particular importance because of this trial's specific inclusion criteria; this trial only included patients with high tumour burden or POD24 after the first line of treatment, or patients with second relapse (albeit none of the latter were included), and to our knowledge these requirements have not been universal across CAR T-cell and CD20×CD3 bispecific antibody studies. The safety profile was consistent with previous reports of loncastuximab tesirine in diffuse large B-cell lymphoma, with a low treatment discontinuation rate in the present study. Responses appeared robust, with most responder patients (36 [95%] of 38) maintaining a response at the last assessment before the data cutoff, and a median follow-up similar to pivotal publications of axicabtagene ciloleucel, tisagenlecleucel, lisocabtagene maraleucel, mosunetuzumab, and epcoritamab.

Implications of all the available evidence

Loncastuximab tesirine with rituximab showed clinically meaningful activity in relapsed or refractory follicular lymphoma, including high rates of response in difficult-to-treat groups, with manageable safety. This study suggests that a fixed-duration and ambulatory regimen of loncastuximab tesirine with rituximab is a promising combination in the second-line and later treatment of follicular lymphoma.

Source: The Lancet Haematology