Ublituximab Added to Ibrutinib Demonstrates ORR Benefit for Relapsed/Refractory CLL

The addition of ublituximab (TGTX-1101) to ibrutinib (Imbruvica) led to a statistically higher overall response rate (ORR) without impacting the previous safety profile of ibrutinib alone in patients with relapsed or refractory high-risk chronic lymphocytic leukemia (CLL), according to the final results of the phase 3 GENUINE study (NCT02301156) announced by TG Therapeutics, Inc, in a press release.1

The phase 3 study evaluated the glycoengineered anti-CD20 monoclonal antibody in combination with the Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib, which has been previously used as a monotherapy in this patient population. Of the 224 patients assessed for eligibility 126 patients with relapsed or refractory high-risk CLL were ultimately enrolled and 117 were treated with at least 1 dose. At a median follow-up of 41.6 months, results showed an 83% ORR with ublituximab and ibrutinib in comparison to 65% for patients on ibrutinib monotherapy. Progression-free survival (PFS) was not reached, but there were 15 PFS events observed within 35.9 months (95% CI, 17.0-NE) in the combination arm and 25 PFS events in the ibrutinib monotherapy arm (HR, 0.46; 95% CI, 0.24-0.87).

“The utility of adding anti-CD20 therapy in combination with BTK inhibitors, such as ibrutinib, has long been unclear with prior studies using rituximab having failed to demonstrate an improvement in long-term outcomes,” explained Jeff P. Sharman, MD, director of Research at the Willamette Valley Cancer Institute and the lead investigator of the GENUINE trial, in a press release. “These results published from the GENUINE study are encouraging and may suggest that next generation anti-CD20 antibodies could have value in combination approaches to treating CLL.”2

GENUINE was initially designed for PFS and ORR to be co-primary endpoints but the protocol was amended due to delays in patient enrollment leading to a single primary endpoint of independent review committee-assessed overall response rate based on the proportion of patients who had a partial response, complete response, or complete response with incomplete marrow recovery in the combination arm. Safety was assessed in this trial and found the addition of the investigational ublituximab did not impact the safety profile patients previously experienced on ibrutinib alone.

Fifty-nine patients in the ublituximab plus ibrutinib arm and 58 in the monotherapy group were assessed for safety, and investigators found most adverse events (AEs) were either grade 1 or grade 2. The most common grade 3 and 4 AE, occurring in 11 patients in the ublituximab plus ibrutinib group and seven in the monotherapy arm was neutropenia 5 patients in each group experienced anemia and 6 patients from the combination arm compared to 3 patients in the ibrutinib arm experienced diarrhea.1 Serious AEs included pneumonia, sepsis, febrile neutropenia, atrial fibrillation. Two patients in the combination group died due to AEs, one from cardiac arrest and the other failure to thrive, but neither were treatment related. In the ibrutinib alone arm, 5 patients died during treatment due to cardiac arrest cerebral infarction, intracranial hemorrhage, Pneumocystis jirovecii pneumonia infection, and one unexplained death, respectively. Of the 5 deaths, the cardiac arrest AE was considered to be treatment related.

“Significant unmet need still exists within the CLL landscape, and patients with high-risk relapsed or refractory CLL progress more rapidly than those without high-risk cytogenetics,” said Michael S. Weiss, the TG Therapeutics executive chairman and CEO, in the release. “The outcome of the GENUINE study is therefore very encouraging, and we believe these data are supportive of pursuing combination strategies with ublituximab for high-risk CLL patients.”

One-hundred and twenty-six patients were enrolled on the multicenter phase 3 trial, randomized 1:1 on either the combination of ublituximab and ibrutinib or ibrutinib alone. 420 mg of Ibrutinib was given orally for all cycle of treatment daily, while ublituximab was given intravenously in 28-day cycles increasing doses in the first cycle, less than or equal to 150 mg on day 1, 750 mg on day 2, and then 900 mg on days 8 and 15, which was continued at 900mg on day through cycles 2-6. Following cycle 6, 900 mg of ublituximab was given every three cycles till completion of treatment. Patients aged 18 years or older were included in the trial if they had either one 17p deletion, 11q deletion, or TP53 mutation. Patients had to have received at least one prior therapy for CLL and have an Eastern Cooperative Oncology Group performance status of 2 or lower. Patients were recruited and enrolled from 119 clinics in the USA and Israel.

“We look forward to bringing ublituximab to market as soon as possible as we pursue completion of a BLA submission with the FDA in the first half of 2021 for the combination of ublituximab plus umbralisib for patients with CLL,” Weiss said about the future of this treatment and this patient population.

_Reference

_{1. Sharman JP, Brander DM, Mato AR, et al. Ublituximab plus ibrutinib versus ibrutinib alone for patients with relapsed or refractory high-risk chronic lymphocytic leukaemia (GENUINE): a phase 3, multicentre, open-label, randomised trial. Lancet Haematol. Published online February 22, 2201. doi: 10.1016/S2352-3026(20)30433-6}

_{2. TG Therapeutics announces publication of final results from the phase 3 GENUINE Trial evaluating ublituximab plus ibrutinib in patients with relapsed/refractory high-risk chronic lymphocytic leukemia in the Lancet Haematology. News Release. TG Therapeutics, Inc. February 23, 2021. Accessed March 9, 2021. https://bit.ly/3kYJHCG}