Adding a single cycle of rituximab to belimumab (Benlysta) did not improve disease control for patients with systemic lupus erythematosus (SLE) in comparison with belimumab alone in a phase 3 randomized, controlled trial.
Among patients with SLE who were randomly assigned to receive belimumab with either rituximab, placebo, or standard care, there were no statistically significant differences between the rituximab and placebo arms for the primary endpoint of the proportion of patients with disease control at week 52 or in the secondary endpoints of clinical remission at week 64 or disease control at week 104, Cynthia Aranow, MD, reported in a late-breaking poster session presented during the American College of Rheumatology (ACR) 2021 Annual Meeting, which was held online
“Using a new, clinically meaningful endpoint underscores the efficacy of belimumab for disease control, with some patients maintaining disease control with considerable reductions in steroids, and no immunosuppressants,” said Aranow, a rheumatologist specializing in SLE and rheumatoid arthritis in New York City and director of the Clinical Autoimmunity Center of Excellence at Feinstein Institutes for Medical Research, Manhasset, New York.
Use of the combination of belimumab and rituximab was, however, associated with significant improvement over belimumab and placebo in several secondary efficacy endpoints.
Investigators in the randomized controlled trial, dubbed BLISS-BELIEVE, had previously published a rationale for sequential therapy with belimumab, a human monoclonal antibody that binds to soluble B-lymphocyte stimulator, and rituximab, a B-cell-depleting anti-CD20 monoclonal antibody.
“These biologics, which operate through complementary mechanisms, might result in an enhanced depletion of circulating and tissue-resident autoreactive B lymphocytes when administered together. Thus, belimumab and rituximab combination may be a highly effective treatment of SLE,” they wrote in an article published in 2019 in BMJ Open.
Three-Arm Trial
The investigators screened 396 patients, of whom 292 were randomly assigned in a 1:2:1 ratio to receive either subcutaneous belimumab 200 mg/wk plus intravenous placebo at weeks 4 and 6 (BEL/PBO, 72 patients), belimumab plus IV rituximab 1000 mg at weeks 4 and 6 (BEL/RTX, 144 patients), or open-label belimumab plus standard therapy. Patients were allowed to continue taking antimalarial and nonsteroidal anti-inflammatory drugs throughout the study.
The primary disease-control endpoint was defined as a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of ≤2, achieved without other immunosuppression, equivalent to that achieved with prednisone ≤5 mg/d.
As noted before, there were no significant differences between the BEL/RTX and BEL/PBO arms in either disease control at week 52 or in the secondary endpoints of clinical remission at week 64 (SLEDAI-2K score, 0) or in the proportion of patients with disease control at week 104.
However, use of BEL/RTX was associated with a significantly longer duration of disease control through 52 weeks than was BEL/PBO (mean, 105.4 days vs 60.1 days; P = .0188) and with a large SLEDAI-2K mean change from baseline at week 104 (-7.2 vs 5.1; P = .0033).
In addition, there was a trend toward a shift in proteinuria from baseline high (>0.5 g/24 h) to normal in the BEL/RTX group at week 52 and a significantly greater shift at week 104 (P = .0085).
The overall adverse event profiles were generally consistent with those of the individual agents, although serious infections and infestations occurred more frequently with BEL/RTX than BEL/PBO.
Further Analyses Planned to Look for Subgroups That Benefit
In a poster discussion session, Akshat Khanna, PhD, of Newtown, Pennsylvania, a consultant with Effimed Life Sciences Research, asked Aranow about the rationale for giving rituximab and belimumab concurrently and noted that in the BEAT-LUPUS and CALIBRATE trials, anti-CD20 agents were given first, followed by belimumab, to prevent activation of humoral immunity.
“The two B-cell agents were given sequentially. Belimumab was given first to maximize the effect of peripheral B-cell depletion and [was] then continued after rituximab to suppress the elevation [of B-lymphocyte stimulator] that occurs after rituximab monotherapy. We used this approach (instead of that used in CALIBRATE and BEAT LUPUS), as we thought this might be more efficacious,” she explained.
Asked by Medscape Medical News whether there were subgroups of patients who might still benefit from the combination compared with belimumab alone, Aranow replied, “There may be individual patients in which it might be considered. Further analyses of the data are ongoing/planned.”
The study was supported by GlaxoSmithKline. Aranow has received grant/research support from GlaxoSmithKline and has consulted for Bristol-Myers Squibb. Khanna has disclosed no relevant financial relationships.
American College of Rheumatology (ACR) 2021 Annual Meeting: Abstract L13. Presented November 9, 2021.
Neil Osterweil, an award-winning medical journalist, is a long-standing and frequent contributor to Medscape.
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