Ibrutinib (Imbruvica), an oral blocker of cancer-cell signaling, is widely used in the treatment of patients with chronic lymphocytic leukemia (CLL). However, for patients with CLL who have certain high-risk features, chances of long-term disease control with ibrutinib are low. Ublituximab is a monoclonal antibody treatment that targets specific types of receptors, called CD20, on cancer cells. Ublituximab has been engineered to kill cancer cells more effectively than older CD20 antibodies, such as rituximab (Rituxan).
Researchers presented results from the GENUINE study during the ASCO 2020 Virtual Scientific Program.1 This large clinical trial compared the use of ublituximab combined with ibrutinib to the use of ibrutinib alone in patients with high-risk CLL who had relapsed or were refractory to ≥1 previous treatment. After following patients for more than 3.5 years, the investigators presented final efficacy and safety results from this study.
Patients enrolled in the GENUINE trial had relapsed after or were refractory to prior therapy for CLL. They also had specific types of high-risk features, including genetic mutations known as deletion 17p, deletion 11q, and/or TP53. Patients were randomized to receive either ibrutinib alone 420 mg by mouth once daily or ibrutinib combined with ublituximab 900 mg given via intravenous infusion on 3 different days during the first 28-day cycle, once during the next 5 cycles, and once every 3 cycles thereafter.
The primary goal of the GENUINE study was to determine patients’ chances of responding to treatment using strict testing criteria developed by CLL experts. Researchers also looked for minimal residual disease (MRD) using blood tests. When patients are MRD-negative, it means that no disease can be detected after treatment.
A total of 117 patients were treated in the GENUINE study: 59 received ublituximab plus ibrutinib and 58 received ibrutinib alone. The median age of patients was 66 years, and they had received a median of 1 prior treatment (range, 1-5). The study was relatively balanced between the 2 study arms regarding age, gender, overall performance status (ability to perform day-to-day functions), and median time since CLL diagnosis (≥6 years in both arms). The percentage of patients with deletion 17p (a high-risk feature) was higher in the ibrutinib arm of the study compared with the combination treatment arm (50% vs 44%). The percentage of patients with bulky disease (ie, more parts of the body affected by CLL) was higher in the combination treatment arm compared with the ibrutinib arm (47% vs 28%).
After following patients for 3.5 years, researchers determined that the combination of ublituximab and ibrutinib was significantly more effective than ibrutinib alone. Improvements were seen with the combination when researchers evaluated rates of overall disease response (90% vs 69%), complete disease response (20% vs 5%), MRD negativity (46% vs 7%), and progression-free survival (PFS). Patients with a 17p deletion or TP53 mutation were more likely to benefit from the combination compared with patients who did not have high-risk features.
Rates and types of side effects were similar between the 2 study arms. Two exceptions were infusion reactions and low white blood cell counts (neutropenia), which occurred more frequently in patients on combination therapy.
GENUINE is the first randomized clinical trial to demonstrate longer PFS for patients treated with an anti-CD20 monoclonal antibody plus ibrutinib. Previous clinical trials that tested a combination of rituximab, an older CD20 monoclonal antibody, with ibrutinib did not show a PFS benefit compared with ibrutinib alone. As of June 2020, ublituximab has not yet been FDA-approved for use in the United States. However, clinical trials assessing the agent in CLL and other cancers are ongoing.
Reference
- Sharman JP, Brander DM, Mato AR, et al. Effect of adding ublituximab to ibrutinib on PFS, ORR, and MRD negativity in previously treated high-risk chronic lymphocytic leukemia: final results of the GENUINE phase 3 study. J Clin Oncol. 2020;38(15_suppl). Abstract 8022.
