In the phase 3 UNITY-CLL study, ublituximab in combination with umbralisib demonstrated synergistic activity in patients with chronic lymphocytic leukemia compared with standard of care chemoimmunotherapy irrespective of prior treatment.
In the phase 3 UNITY-CLL study, ublituximab in combination with umbralisib (U2) demonstrated synergistic activity in patients with chronic lymphocytic leukemia compared with standard of care chemoimmunotherapy irrespective of prior treatment.1
Results for the study of the CD20-targeting compound ublituximab and PI3Kδ-targeting agent umbralisib were presented during the American Society of Hematology (ASH) Virtual Annual Meeting.
At a median follow-up of 36.7 months, U2 significantly prolonged progression-free survival (PFS) compared with obinutuzumab (Gazyva) plus chlorambucil across subgroups. In the intention-to-treat population the median PFS was 31.9 months (95% CI, 28.2-35.8) versus 17.9 months (95% CI, 16.1-22.6), respectively (HR, 0.546; 95% CI, 0.413-0.720; P < .0001). The 24-month PFS rates were 60.8% and 40.4%, respectively.
In patients who were treatment-naïve at the time of enrollment, the median PFS was 38.5 months (95% CI, 33.2–not evaluable) with U2 compared with 26.1 months (95% CI, 19.4-33.1) with the obinutuzumab combination (HR, 0.482; 95% CI, 0.316-0.736; P < .001). The 24-month PFS rates were 76.6% and 52.1%, respectively.1
For the subgroup of patients who received a median of 2 prior therapies (range, 1-9), those randomized to the U2 cohort also had a PFS benefit with U2 compared with obinutuzumab plus chlorambucil (19.5 vs 12.9 months, respectively; HR, 0.601; 95% CI, 0.415-0.869; P < .01).1
Bruton tyrosine kinase [BTK] and BCL-2 [B-cell lymphoma] inhibitors have dramatically changed the therapeutic landscape of CLL, but not all patients are candidates for these agents and mechanisms of resistance have already been identified,” said global study chair, John G. Gribben, DSc, FRCP, FRCPath, FMedSci, during a presentation of the data. “I think PI3Kδ inhibitors offer a distinct mechanism of action from all the BTK and BCL-2 inhibitors and have demonstrated promising activity in the relapsed/refractory CLL setting.” Gribben is a professor of experimental cancer medicine, director of both the Experimental Cancer Medicine Centre and Stem Cell Transplantation at Saint Bartholomew’s Hospital, Queen Mary’s School of Medicine, University of London.
In addition to its efficacy, the U2 regimen has a favorable safety profile and exhibited low rates of immune-mediated toxicities that are typically associated with other PI3Kδ inhibitors, including diarrhea, colitis, pneumonia, and hepatic toxicity. In previously untreated patients these toxicities lead to discontinuation rates of over 50%.1,2
In total, 421 patients with treatment-naïve or relapsed/refractory CLL were included in the primary analysis of the UNITY-CLL trial (NCT02612311); 57% of patients were treatment-naïve and 43% had relapsed/refractory CLL.
Umbralisib was given orally at 800 mg once-daily until progression or treatment discontinuation. Ublituximab was administered intravenously at 900 mg on days 1/2 (150 mg on day 1 followed by 750 mg on day 2), 8, and 15 of cycle 1; day 1 of cycles 2 to 6, and on day 1 every 3 cycles after cycle 6. Obinutuzumab was given intravenously at 1000 mg on days 1/2 (100 mg on day 1 followed by 900 mg on day 2), 8, and 15 of cycle 1; day 1 of cycles 2 to 6. Chlorambucil was given orally at 0.5 mg/kg on day 1 and 15 of cycles 1 to 6. Each cycle was 28 days.
The primary end point was independent review committee (IRC)-assessed PFS and key secondary end points included IRC-assessed overall response rate (ORR), complete response (CR), and safety assessed from the first dose until 30 days after the last dose.
The ORR for 210 patients treated in the U2 cohort was 83.3% compared with 68.7% for the 211 patients in the obinutuzumab arm (P < .001). Of the responders, 5% achieved a CR or CR with incomplete marrow recovery and 79% had a partial response with U2 versus 1% and 67%, respectively, with obinutuzumab.1
In stratified analysis, the ORRs were 84%, 82%, and 57% for patients in the U2 cohort who were treatment naïve, were previously treated, and those who had prior treatment with a BTK inhibitor, respectively. The ORRs were 78%, 57%, and 25% for those treated with obinutuzumab.
“Responses [observed] with U2 were durable with 62% of patients maintaining response at 2 years and a 93% disease control rate was achieved using the U2 regimen,” said Gribben. The median treatment exposure for U2 was 21 months compared with 5 months for obinutuzumab and chlorambucil, Gribben added. At the time of follow-up treatment was ongoing for 77 patients (37%) with U2.
In a review of the safety analysis, Gribben noted that continuous treatment with U2 resulted in over 4-fold longer exposure and reporting period for the regimen compared with obinutuzumab and chlorambucil. Grade 3/4 adverse events of clinical interest for U2 versus the chemoimmunotherapy regimen included elevated alanine aminotransferase (8.3% vs 1.0%), elevated aspartate aminotransferase (5.3% vs 2.0%), noninfectious colitis (1.9% vs 0%), infectious colitis (0.5% vs 0.5%), pneumonitis (0.5% vs 0%), rash (2.4% vs 0.5%), and opportunistic infections (5.8% vs 1.5%). AEs led to treatment discontinuation in 35 patients (17%) and 16 patients (8%), respectively.1
“Focusing in on those grade 3 and 4 adverse events and looking at the treatment-naïve versus patients who were previously treated, diarrhea occurred slightly more frequently in the treatment-naïve patient population [13.8% vs 10.0%], but neutropenia was more common in those patients who were previously treated [24.1% vs 40.0%]. Other adverse events were relatively rare,” Gribben said.
TG Therapeutics Inc, the developer of the agents, plans to complete a new drug application submission for the U2 combination in CLL in the first half of 2021.3 The company initiated a rolling submission of a biologics application with the FDA based on these data.4
1. Gribben JG, Jurczak W, Jacobs R, et al. Umbralisib plus ublituximab (U2) is superior to obinutuzumab plus chlorambucil (O+Chl) in patients with treatment naïve (TN) and relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): results from the phase 3 Unity-CLL Study. Presented at: American Society of Hematology Meeting and Exposition; December 5-8, 2020; Virtual. Abstract 543. Accessed December 7, 2020. https://ash.confex.com/ash/2020/webprogram/Paper134783.html
2. Lunning M, Vose J, Nastoupil L, et al. Ublituximab and umbralisib in relapsed/refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood. 2019;134(21):1811-1820. doi:10.1182/blood.2019002118
3. TG Therapeutics announces pivotal data from the UNITY-CLL and UNITY-NHL clinical trials presented at the 62nd American Society of Hematology Annual Meeting. News release. TG Therapeutics, Inc. December 7, 2020. Accessed December 7, 2020. https://bit.ly/3mVFbFb
4. TG Therapeutics initiates rolling submission of biologics license application to US Food and Drug Administration for ublituximab in combination with umbralisib as a treatment for patients with chronic lymphocytic leukemia. News release. TG Therapeutics, Inc. December 1, 2020. Accessed December 7, 2020. https://bit.ly/3muaDKm