Promising efficacy of BI-1206, an antibody targeting FcγRIIB in combination with rituximab and acalabrutinib in R/R NHL patients NHL

Abstract Background: Anti-CD20 antibodies like rituximab are crucial for treating non-Hodgkin's B-cell lymphoma. However, 15% of patients do not respond to treatment, and 25% relapse within 3 years following treatment. The inhibitory Fc receptor FcγRIIb triggers rituximab internalization, and higher tumor FcγRIIb expression correlates with lower response rates in MCL, FL, and DLBCL. BI-1206, an anti- FcγRIIb IgG1 antibody, blocks rituximab internalization and enhances its efficacy, overcoming resistance in experimental models. In R/R FL patients, BI-1206 combined with rituximab showed promising results, with a 50% ORR (CRR 36%, DCR 84%, n=22) and excellent tolerability when administered subcutaneously. The combination of obinutuzumab + zanubrutinib in the ROSEWOOD1 trial demonstrated the beneficial effect of adding BTK inhibition to CD20 blockade for the treatment of follicular lymphoma. Obinutuzumab is an anti-CD20 mAb engineered to enhance its affinity to activating FcgRs. Obinutuzumab vs obinutuzumab + zanubrutinib, showed an ORR increase from 45% to 69%. However, a clinical study by Strati et al2 adding acalabrutinib to rituximab did not result in a similar treatment benefit, with an ORR of 31% in R/R FL. Given that acalabrutinib and zanubrutinib have similar tyrosine kinase inhibition profiles, the large improvement of efficacy in the ROSEWOOD study underscores the importance of addressing rituximab resistanceIn this context and given that BI-1206 specifically targets the mechanism of resistance, the combination of BI-1206 with rituximab + acalabrutinib can be expected to provide an even greater increase in response to treatment. 1Zinzani et al JCO 2023 41(33) 2Strati et al Br J Hem 2024 205(6)Aim: To investigate the safety and efficacy of BI-1206 in combination with rituximab and acalabrutinib in R/R NHL with a focus on FL. Methods: This is a single arm study of BI-1206 in combination with rituximab and acalabrutinib, aiming to enroll 30 R/R NHL patients in total. It consists of a safety run-in with escalating SC doses of BI-1206 (150 & 225 mg) and an expansion phase at selected dose level. BI-1206 +rituximab will be given weekly for a 4-week induction period, and patients exhibiting disease control at week 6 are eligible for an additional induction period, followed by maintenance therapy with dosing of BI-1206 and rituximab every 8 weeks for up to 6 cycles. Acalabrutinib will be dosed at 100 mg BID throughout study duration (1 year). Results: We report here the results of the safety run-in portion of the study, whereas of August 4th 12 patients have been treated with BI-1206 in combination with rituximab + acalabrutinib. 11 patients had recorded AE related to study medication. Most adverse events were classified as mild or moderate (87%). Six subjects had Gr3 events considered related or possibly related to at least one of the study drugs: two subjects had Gr3 neutropenia, 2 subjects had Gr2 lymphopenia, one patient had Gr3 urticaria and Gr3 headache, while the 6th patient had grade 3 IRR related to rituximab. With regards to safety events of particular interest, two patients had Gr2 thrombocytopenia which were resolved within 5 days. No related serious adverse events were recorded and there were no Gr4 or Gr5 events. A high number of responses have been observed (ORR=89%) and warrant the continuation trial into the expansion phase. Out of 9 evaluable patients, 3 patients showed CR, 5 patient PR and 1 patient SD as best response. There was no apparent difference in safety or efficacy between the two studied dose levels of BI-1206. More complete data will be disclosed in poster. Conclusion: The combination of BI-1206 with rituximab and acalabrutinib shows highly promising efficacy in R/R NHL, with 89% ORR and 100% DCR. The combination appears to be safe and adverse drug reactions are manageable. We would like to thank AstraZeneca for providing acalabrutinib in this study.