Jeff Sharman, MD
The combination of ublituximab (TG-1101) and ibrutinib (Imbruvica) demonstrated an objective response rate (ORR) of 78% for patients with previously treated high-risk chronic lymphocytic leukemia (CLL), according to findings from the phase III GENUINE trial presented at the 2017 ASCO Annual Meeting.
"The GENUINE study met its primary endpoint, demonstrating that ublituximab in combination with ibrutinib yields superior ORR to ibrutinib alone in high-risk CLL," said lead investigator Jeff Sharman, MD, medical director, Hematology Research, US Oncology. "With the exception of infusion-related reactions, ublituximab did not alter the safety profile of ibrutinib monotherapy."
The open-label phase III study was initially designed to have co-primary endpoints of ORR and progression-free survival (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, Sharman said.
Overall, the trial ultimately enrolled 126 patients to receive oral ibrutinib alone (n = 58) or in combination with intravenous ublituximab (n = 59). Ibrutinib was given once daily at 420 mg. Ublituximab was administered at 900 mg on days 1, 8, and 15 during the first cycle and then on day 1 alone for cycles 2 through 6. Those who did not progress after 6 cycles continued to receive maintenance ublituximab once every 3 months at 900 mg. All patients in the trial had received at least 1 prior therapy. High risk was defined as having a 17p deletion, 11q deletion, and/or p53 mutation.
The mean age of patients in both arms was 67 years and most had an ECOG performance status of 0 and 1. In both groups, patient shad received a median of 3 prior lines of therapy. Nearly half of patients had Rai stage III/IV disease and approximately 80% were IGHV
The ORR of 78% with the combination include a complete response (CR) rate of 7%. In the single-agent ibrutinib arm, the ORR was 45% and there were no CRs. Nineteen percent of patients in the ublituximab arm were negative for minimal residual disease compared with 2% for ibrutinib alone. Overall, 66% of patients had a >75% decrease in lymph node size with ublituximab plus ibrutinib compared with 52% for ibrutinib alone.
The trial was designed to look at ORR by iwCLL 2008 response criteria, which did not account for higher rates of lymphocytosis seen following treatment with BTK inhibitors, Sharman noted. When those with a PR with lymphocytosis (PR-L) were included, the response rate in the ublituximab arm jumped to 83% and the single-agent ibrutinib ORR was 59%. The PR-L rate was 5% in the combination arm and 14% in the single-agent ibrutinib group. When looking at absolute lymphocyte counts, the addition of ublituximab appears to limit lymphocytosis, which counts reaching baseline levels more rapidly with the combination.
The median PFS was not reported. At 20 months, nearly all events had occurred. 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 single-agent ibrutinib.
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%).
The GENUINE study was initially designed under a special protocol assessment (SPA) with the FDA, suggesting the agency would accept a surrogate endpoint for potential approval. However, the alterations made to the study design may have impacted this SPA. TG Therapeutics, the company developing the CD20 inhibitor, plans to share the data with the FDA later this year.
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).<<< View more from the 2017 ASCO Annual Meeting