Ublituximab Plus Ibrutinib Improves PFS in Relapsed/Refractory High-Risk CLL

Michael S. Weiss, executive chairman and chief executive officer of TG Therapeutics

Michael S. Weiss

The combination of ublituximab and ibrutinib (Imbruvica) improved progression-free survival (PFS), as determined by an Independent Review Committee (IRC), compared with ibrutinib alone in patients with relapsed/refractory high-risk chronic lymphocytic leukemia (CLL), according to final long-term findings of the phase III GENUINE study.¹

At a median follow-up of >4 years, the combination was also found to be well tolerated with no new safety signals identified, TG Therapeutics, Inc., the developer of ublituximab, stated in a press release. The final results will be presented at an upcoming medical meeting and will also be shared with the FDA.

“We are pleased with the final results from the phase III GENUINE trial with median follow-up of over 4 years,” Michael S. Weiss, executive chairman and chief executive officer of TG Therapeutics, stated in the press release. “The improvement in PFS observed in these high-risk CLL patients is extremely encouraging, and we look forward to presenting the full data at a future medical conference.”

In the open-label, multicenter, phase III GENUINE trial, investigators evaluated the safety and efficacy of ublituximab in combination with ibrutinib compared with single-agent ibrutinib in 126 adult patients with high-risk CLL who received ≥1 prior therapy. High-risk status was defined as having 17p deletion, 11q deletion, and/or p53 mutation.

The study was conducted at 160 clinical trial sites in the United States and Israel. Patients received ibrutinib orally at 420 mg once daily in both arms and in the treatment arm, patients also received intravenous ublituximab at 900 mg on days 1, 8, and 15 of cycle 1 and day 1 of cycles 2 through 6. Patients in the treatment arm who had not progressed received quarterly infusions of ublituximab maintenance at 900 mg.

The mean age of patients in both arms was 67 years and most had an ECOG performance status of 0 or 1. In both groups, patients had received a median 3 prior lines of therapy. Nearly half of patients had Rai stage III/IV disease and approximately 80% were IgHV unmutated.

Initially, the trial was designed to have coprimary endpoints of ORR and PFS with an enrollment goal of 300 patients. However, due to recruitment challenges, PFS was changed to a secondary endpoint and the target enrollment was modified to be 120 patients. This alteration left the trial inappropriately powered to show statistical significance for PFS.

Prior GENUINE data, which were presented at the 2017 ASCO Annual Meeting, demonstrated that the trial had met its primary endpoint of improved IRC-assessed overall response rate (ORR), as well as increased centrally assessed minimal residual disease (MRD) rate.²

The ORR was 78% with the combination, which included a complete response (CR) rate of 7%, compared with a 45% ORR in the single-agent ibrutinib arm where there were no CRs. Additionally, 19% of patients in the ublituximab arm were MRD negative versus 2% of patients on ibrutinib alone. Overall, 66% of patients had a >75% decrease in lymph node size with ublituximab plus ibrutinib compared with 52% for single-agent ibrutinib.

The trial was designed to look at ORR by International Workshop on Chronic Lymphocytic Leukemia 2008 response criteria, which did not account for higher rates of lymphocytosis seen following treatment with BTK inhibitors. When patients with a PR who had lymphocytosis (PR-L) were included, the ORR in the ublituximab arm jumped to 83% versus 59% with single-agent ibrutinib. The PR-L rate was 5% in the combination arm and 14% in the single-agent ibrutinib group.

With these data, there was a 44% reduction in the risk of progression or death with the addition of ublituximab, but this did not reach statistical significance (95% CI, 0.216-1.443; P = .229). The median time to response was 1.97 months with the combination versus 3.8 months with ibrutinib alone.

Regarding safety, the most common all-grade adverse events (AEs) with the combination and monotherapy, respectively, were diarrhea (42% vs 40%), fatigue (27% vs 33%), insomnia (24% vs 10%), nausea (22% vs 21%), and headache (20% vs 28%). Infusion reactions occurred in 54% of patients in the combination arm, 5% of which was grade 3 or 4. Other key AEs included neutropenia (22% vs 12%), anemia (14% vs 17%), and thrombocytopenia (14% vs 10%).

References

1. TG Therapeutics Announces Final Long-Term Results from the Phase 3 GENUINE Study Demonstrated that Ublituximab in Combination with Ibrutinib Improved Progression-Free Survival in Patients with High-Risk Relapsed/Refractory Chronic Lymphocytic Leukemia as Compared to Ibrutinib Monotherapy. TG Therapeutics, Inc. Published October 24, 2019. https://bit.ly/2NdWtwR. Accessed October 24, 2019.
2. Sharman JP, Brander DM, Mato AR, et al. Ublituximab and ibrutinib for previously treated genetically high-risk chronic lymphocytic leukemia: Results of the GENUINE phase 3 study. J Clin Oncol. 2017;35 (suppl; abstr 7504). doi: 10.1200/JCO.2017.35.15_suppl.7504.