Jeffrey Sharman, MD
The addition of ublituximab (TG-1101) to ibrutinib (Imbruvica) significantly improved objective response rates (ORR) compared with ibrutinib alone for patients with previously treated high-risk chronic lymphocytic leukemia (CLL), according to topline findings from the phase III GENUINE trial announced by TG Therapeutics, the company developing the glycoengineered anti-CD20 antibody.
In the open-label study, the ORR with ublituximab plus ibrutinib was 80% compared with 47% for ibrutinib alone (P
<.001). The combination was well tolerated with no new safety concerns, although data were not yet released for safety. Full findings from the trial are being prepared for presentation at an upcoming medical meeting. Additionally, TG Therapeutics plans to submit the data to the FDA for a potential approval.
"Ibrutinib has been a great addition to our CLL armamentarium, however we have long believed that ibrutinib alone may not be enough, particularly for patients with high-risk disease," lead investigator Jeffrey Sharman, MD, Medical Director for Hematology Research for the US Oncology Network, said in a statement. "This study demonstrates that the addition of ublituximab, can significantly enhance the response rates without compromising safety."
In the GENUINE study, 126 patients were randomized to receive 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.
In addition to improving ORR, the combination of ibrutinib and ublituximab also improved several secondary endpoints compared with single-agent ibrutinib. Overall, the combination improved radiographic complete response, progression-free survival, and time to response compared with ibrutinib alone, according to the statement.
"We believe the results observed in the combination arm are extremely compelling and the regimen has the potential to become the standard of care for treating patients with high risk CLL that have progressed from other therapies," Michael S. Weiss, executive chairman and chief executive officer of TG Therapeutics, said in a statement. "We believe that using combination therapy to accelerate and deepen response in poor prognosis high risk CLL is critically important for patient outcomes and we look forward to sharing these data with the FDA in the coming months to discuss filing for accelerated approval."
The company noted that safety and efficacy findings in the phase III GENUINE study were similar to a prior phase II investigation. In this trial, the combination demonstrated an ORR of 88% at 6 months in 41 evaluable patients with CLL. In 20 patients with high-risk CLL, the ORR was 95%, with a 15% minimal residual disease-negativity rate.
The median time to response was 8 weeks. In the full population, the median nodal reduction was 62% at week 8 and 77% at week 20. In those with high-risk CLL, the median nodal reduction was 64% at week 8 and 85% at week 20.
The most common all-grade adverse events (AEs) with the combination were infusion-related reactions (53%), diarrhea (40%), fatigue (33%), cough (27%), rash (27%), and nausea (24%). The most common grade 3/4 AEs were anemia (11%), neutropenia (11%), thrombocytopenia (7%), infusion-related reactions (7%), diarrhea (4%), and arthralgia (2%).
"We believe that the rapid responses seen in our phase II study with ublituximab plus ibrutinib are validated here in our phase III GENUINE study and are important markers of improved overall efficacy and patient outcomes," said Sharman. "I look forward to the presentation of the results at an upcoming medical meeting."
Several studies are currently assessing ublituximab for patients with hematologic malignancies. The agent is being explored in combination with TGR-1202, a PI3K-delta inhibitor, in comparison with obinutuzumab and chlorambucil for patients with untreated or relapsed CLL (NCT02612311). Ublituximab and TGR-1202 are also being looked at with or without ibrutinib or bendamustine for patients with B-cell malignancies (NCT02006485).
Sharman JP, Farber CM, Mahadevan D, et al. Ublituximab (TG-1101), a novel glycoengineered anti-CD20 antibody, in combination with ibrutinib is safe and highly active in patients with relapsed and/or refractory chronic lymphocytic leukaemia: results of a phase 2 trial. Br J Haematol.