ICML 2017: Phase III GENUINE Trial: Ublituximab Plus Ibrutinib in High-Risk CLL

Key Points

  • ORR in the ublituximab plus ibrutinib arm was 78% vs 45% in the ibrutinib-only arm.
  • CR was 7% in the ublituximab plus ibrutinib arm vs 0% in the ibrutinib-only arm.
  • Neutropenia, occurring in 9% of patients, was the most commonly reported grade 3/4 adverse event in the combination arm, followed by infusion related-reactions and anemia, each reported in 5% of patients.

Data was recently presented from the phase III GENUINE trial of ublituximab, a novel glycoengineered anti–CD20 monoclonal antibody, in combination with ibrutinib (Imbruvica), a Bruton tyrosine kinase (BTK) inhibitor, for the treatment of high-risk chronic lymphocytic leukemia (CLL), at the 14th International Conference on Malignant Lymphoma (ICML) in Lugano, Switzerland (Abstract 101). The dataset was presented previously at the ASCO Annual Meeting earlier this month (Abstract 7504).  

Michael S. Weiss, Executive Chairman and Chief Executive Officer of TG Therapeutics, Inc, stated, “[Patients with] CLL [with] high-risk cytogenetics continue to represent a challenge and continue to progress more rapidly on ibrutinib than other patients. Improving ibrutinib therapy for these hard to treat patients still represents an unmet medical need…as presented today at ICML, and…at ASCO, the GENUINE phase III trial showed that by adding [ublituximab] to ibrutinib, we could improve overall response rate, complete response rate, and minimal residual disease negativity in high-risk patients.” 

Trial Information

The GENUINE trial was conducted at 160 clinical trial sites in the United States and Israel and randomized 126 patients. Patients received ibrutinib orally at 420 mg once daily in both arms, and in the treatment arm, those patients also received intravenous infusions of ublituximab at 900 mg dosed on days 1, 8, and 15 of cycle 1 and day 1 of cycles 2 to 6. Patients in the treatment arm who had not progressed received quarterly infusions of ublituximab maintenance at 900 mg.

For the trial, high-risk CLL was defined as having any one or more of the following centrally confirmed features: 17p deletion, 11q deletion, or p53 mutation.

One hundred percent of patients were high-risk and had either 17p deletion, 11q deletion, or p53 mutation. Sixty-four percent of patients in the ublituximab plus ibrutinib arm and 66% of patients in the ibrutinib-alone arm had 17p deletion and/or a p53 mutation, while 36% and 34% of patients in the ublituximab plus ibrutinib and ibrutinib-alone arms, respectively, had an 11q deletion only. The median age of patients on either arm was 67 years, and the median number of prior lines of therapy for either arm was three.

Trial Results

The trial was powered to show a statistically significant improvement in overall response rate (ORR) of 30%, with a minimal absolute detectable difference between the two arms of approximately 20%.

The trial met its primary endpoint, demonstrating a statistically significant improvement in ORR as assessed by blinded independent central radiology and hematology review by iwCLL (Hallek 2008) criteria, compared to ibrutinib alone in both the intent-to-treat (ITT) population (P = .001) and treated population (P < .001). Per iwCLL guidelines, all responders required confirmation of response for a minimum duration of 2 months. The ITT population includes all 126 randomized patients (64 in the ublituximab plus ibrutinib arm and 62 in the ibrutinib-alone arm), while the treated population includes all ITT patients that received at least one dose of either study drug (59 in the ublituximab plus ibrutinib arm and 58 in the ibrutinib-alone arm). 

ORR in the ublituximab plus ibrutinib arm was 78% compared to 45% in the ibrutinib-alone arm (P < .001); CRs were observed in 7% of patients receiveing both ublituximab plus ibrutinib and 0% of those receiving ibrutinib only. In addition, 19% of patients in the ublituxumab plus ibrutinib arm were MRD-negative, compared to 2% in the ibrutinib-alone arm (P < .01). 

In addition to the improvements in ORR, CR, and MRD-negativity, there was a trend in improvement of progression-free survival (PFS) in the combination arm of ublituximab plus ibrutinib as compared to ibrutinib alone—however, it was not statistically significant at the time of the analysis.

Safety and Tolerability

One hundred and seventeen (117) patients were evaluable for safety (59 patients in the ublituximab plus ibrutinib arm and 58 patients in the ibrutinib-alone arm).

The combination was well-tolerated and, apart from infusion-related reactions, the addition of ublituximab did not appear to alter the safety profile of ibrutinib monotherapy. Neutropenia, occurring in 9% of patients, was the most commonly reported grade 3/4 adverse event in the combination arm, followed by infusion related-reactions and anemia, each reported in 5% of patients. Notably, the majority of infusion-related reactions were grade 1 or 2 in severity, with only 5% grade 3/4 infusion-related reactions observed. Median follow-up for this study was approximately 11.4 months.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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