#1491 Low rate of infusion-related reactions and high treatment adherence with obinutuzumab in patients with active lupus nephritis: analysis of the NOBILITY and REGENCY studies

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Abstract Background and Aims The randomised, placebo-controlled Phase II NOBILITY (NCT02550652) and Phase III REGENCY (NCT04221477) studies demonstrated superiority of obinutuzumab plus standard therapy over placebo plus standard therapy in achieving complete renal responses in patients with active lupus nephritis (LN) while maintaining an acceptable safety profile. Obinutuzumab is approved in certain haemato-oncology indications, and infusion-related reactions (IRRs) are a known risk (Table 1). Here, we characterised the IRR profile of obinutuzumab in participants from the NOBILITY and REGENCY studies. Method NOBILITY and REGENCY randomised adults with biopsy-proven active LN 1:1 to receive placebo (physiological saline) or obinutuzumab plus standard therapy (mycophenolate mofetil plus glucocorticoids). All patients met the 1997 American College of Rheumatology classification criteria for systemic lupus erythematosus and had biopsy-proven proliferative LN. To reduce the risk of IRRs, patients were premedicated with methylprednisolone (80 mg intravenously [IV]), acetaminophen (650–1000 mg) orally and an antihistamine orally or IV. IRRs were defined as any adverse event occurring during or within 24 hours after IV infusion of obinutuzumab or placebo and judged by study investigators to be related to the infusion. Systemic IRRs were considered adverse events of special interest (AESIs). NOBILITY randomised patients 1:1 to placebo or obinutuzumab (1000 mg: Day 1, Weeks 2, 24, 26) plus standard therapy. REGENCY randomised patients 1:1 to placebo or obinutuzumab (1000 mg: Day 1, Weeks 2, 24, 26, ± 50, 52) plus standard therapy. In NOBILITY, the primary endpoint was at Week 52 and patients were followed up until Week 104; in REGENCY, the primary endpoint was at Week 76. NOBILITY and REGENCY IRR data were pooled through Week 76 for safety assessment. Results Overall, 200 patients received obinutuzumab for a total of 944 infusions. AESIs of IRRs were numerically greater in the obinutuzumab arm (30 patients [15.0%]) compared with the placebo arm (21 patients [10.9%]) (Table 2). In the majority of cases, IRRs were mild to moderate (Grade 1–2) and managed by slowing or temporarily halting the infusion. IRRs in both arms primarily occurred at the first infusion, with decreasing incidence of IRRs at subsequent infusions (Table 2). All Grade 3–4 IRRs (n = 4) occurred during/after the first or second infusion (Table 1). IRRs led to a temporary interruption of the infusion in more patients in the obinutuzumab arm (13 patients [6.5%]) than the placebo arm (2 patients [1.0%]). Only 1 patient in the obinutuzumab arm had an IRR leading to discontinuation of study treatment, which was a serious Grade 4 event related to respiratory distress that resolved after ≈1 hour without any reported intervention. All other IRRs in both arms were nonserious. Conclusion Although the incidence of IRRs was higher in patients receiving obinutuzumab compared with placebo, the overall risk of IRRs was low, and IRRs also occurred in the placebo arm. In the majority of cases, IRRs were mild to moderate and managed by slowing or temporarily halting the infusion. IRRs primarily occurred at the first infusion in both arms and only 1 patient in the obinutuzumab arm had an IRR leading to discontinuation of study treatment. Furthermore, the rate of IRRs and high-grade IRRs associated with obinutuzumab in patients with active LN was considerably lower than what was previously observed in patients with haematologic malignancies. These observations suggest that infusions were related to cell killing rather than immunogenicity, with patients with LN having lower numbers of CD20-positive target cells. These data, along with the acceptable safety profile of obinutuzumab, support the possibility of increased treatment adherence in patients with LN.

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