Combination of 177Lu-lilotomab satetraxetan with rituximab synergistically improves in-vivo therapeutic efficacy in a rituximab-resistant non-Hodgkin lymphoma (NHL) model

351 Objectives: The anti-CD20 antibody rituximab alone or in combination with chemotherapy is the treatment of choice for NHL. However, many patients either do not primarily respond to rituximab or experience disease relapse after an initial response, implying a need for circumventing rituximab resistance. Consequently, we assessed if the combination of the anti-CD37 radioimmunoconjugate 177Lu-lilotomab satetraxetan with rituximab might lead to improved in-vivo therapeutic efficacy in a rituximab-resistant NHL model. This investigation derived from previous work showing that 177Lu-lilotomab satetraxetan treatment of rituximab-resistant NHL cells in-vitro increased binding and antibody-dependent cell cytotoxicity of rituximab. Methods: Female athymic nude mice were subcutaneously injected in each flank with 1×107 Raji 2R NHL cells. Between 7 and 14 days after inoculation, the mice were distributed into 6 treatment groups (10 mice/group). Two groups were intravenously given 177Lu-lilotomab satetraxetan at either 150 MBq/kg or 350 MBq/kg and subsequently intravenously injected with 4 doses of 10 mg/kg rituximab separated by 3 to 4 days. Mice were also given single agent treatment of saline (control), rituximab (4×10 mg/kg), or 150 MBq/kg or 350 MBq/kg of 177Lu- lilotomab satetraxetan. The study endpoint was tumor diameter of 16 mm measured by calipers or weight loss of 20 % from the highest recorded weight. Survival across 70 days was analysed using the log-rank test and Holm-Sidak test for multiple pairwise comparisons. Assessment for interaction effects of the combination was performed using Cox proportional hazards regression for the survival. The Bliss independence model was used to analyse tumor volume data, 20 days into the study. To avoid bias, unobserved tumor volume data due to endpoint restrictions was extrapolated by linear regression of log tumor volume. Results: Combination treatment with 350 MBq/kg 177Lu-lilotomab satetraxetan and rituximab resulted in significantly delayed tumor growth compared to that of either treatment alone. Comparison of the observed growth data with Bliss independence model indicated a statistically significant synergistic effect (p < 0.05) of the 350 MBq/kg 177Lu-lilotomab satetraxetan and rituximab combination, while the synergistic effect of the combination of 150 MBq/kg 177Lu-lilotomab and rituximab was not statistically significant. Combination of 350 MBq/kg 177Lu-lilotomab satetraxetan with rituximab resulted in significantly improved survival (50 ±7 days) compared to that of rituximab alone (13 ±3 days; p < 0.001). However, the effect of the combination on survival was additive and not synergistic. Conclusions: Combination of 177Lu-lilotomab satetraxetan and rituximab synergistically decreased tumor growth compared with either treatment alone and had an additive effect with respect to survival. A clinical phase 1b study for relapsed follicular lymphoma where 177Lu-lilotomab satetraxetan is given in combination with rituximab (the Archer-1 study) is currently underway to investigate the safety and preliminary efficacy of the combination of 177Lu-lilotomab satetraxetan and rituximab. The data for the current preclinical study suggests that 177Lu-lilotomab satetraxetan could potentially reverse rituximab resistance.