Patients with relapsed or refractory high-risk chronic lymphocytic leukemia achieved a statistically higher rate of overall response when the glycoengineered, type I anti-CD20 monoclonal antibody ublituximab was added to the Bruton’s tyrosine kinase inhibitor ibrutinib, according to results from the phase 3 GENUINE study.
Patients with relapsed or refractory (R/R) high-risk chronic lymphocytic leukemia (CLL) achieved a statistically higher rate of overall response when the glycoengineered, type I anti-CD20 monoclonal antibody ublituximab (TGTX-1101) was added to the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica), according to results from the phase 3 GENUINE study (NCT02301156).
“These findings warrant further study of this combination in a fully powered phase 3 study evaluating progression-free survival and overall survival as primary end points in patients with chronic lymphocytic leukaemia with high-risk features,” the study authors, led by Jeff P. Sharman, MD, wrote in their published report.
CLL has been shown to be a heterogeneous disease, and therefore, certain disease factors correlate with poor outcomes. Patients who have high-risk features, such as genetic abnormalities, are among those with poor outcomes. Although ibrutinib monotherapy has improved outcomes in patients with CLL and was granted approval by the FDA for the treatment of patients with untreated, R/R disease, including those with del(17p), the agent has not shown improvement for the high-risk subset.
Based on previous findings of single-agent ublituximab, which showed better FcγRIIIA binding and superior antibody-dependent cellular cytotoxicity when compared with rituximab (Rituxan), the GENUINE study was launched to further explore its capability in R/R high-risk CLL.
GENUINE is a fixed-dose, randomized study that was conducted in 199 sites in the United States and Israel. Patients in the study were treated outpatient in 28-day cycles. Dosing of ibrutinib was 420 mg given orally daily, and ublituximab was administered intravenously (IV) at ≤150 mg over 4 hours on day 1, 750 mg over 4 hours on day 2, and at 900 mg over 3 hours on days 8 and 15 of cycle 1. On day 1 of cycles 2 through 4, IV ublituximab 900 mg was administered over 3 hours. Patients also received IV ublituximab 900 mg over 90 minutes as maintenance therapy every 3 cycles following cycle 6. Treatments in the study were continued until disease progression, unacceptable toxicity, or withdrawal of patient consent. To off-set infusion-related toxicity, patients were also given an antihistamine and corticosteroid during the study.
The primary end point evaluated in the study was independent review committee–assessed overall response rate (ORR). The secondary end points were progression-free survival (PFS), minimal residual disease (MRD) negativity rate, complete response (CR) rate, duration of response (DOR), time to response (TTR), and safety.
GENUINE was 90% powered to detect a 30% difference in overall response rate with a 5%, 2-sided, type 1 error rate in a group of 120 patients who were randomized to receive either ublituximab plus ibrutinib or ibrutinib alone.
Ublituximab plus ibrutinib (n = 64) achieved an ORR of 83% compared with 65% with ibrutinib alone (n = 62; P = .020). The primary end point of the study was met with this result. With ublituximab/ibrutinib 17% of patients had a CR, 2% had a CR with incomplete marrow recovery, 63% had a partial response (PR), 3% had a PR with lymphocytosis, and 3% had stable disease (SD). With ibrutinib monotherapy, 3% of patients achieved a CR, 2% had a CR with incomplete marrow recovery, 60% achieved a PR, 8% had a PR with lymphocytosis and 13% had SD. There were no cases of progressive disease in either treatment arm.
The MRD negativity rate observed with ublituximab plus ibrutinib was 42% versus only 6% in the ibrutinib-only arm (P < .0001). Most of the MRD negativity responses were reported in the peripheral blood, though 1 case was observed in the bone marrow in the ublituximab/ibrutinib arm.
With the ublituximab plus ibrutinib group, the median DOR was not reached (95% CI, not estimable [NE]) and the median DOR was also not reached with ibrutinib (95% CI, 27.7-NE). In the TTR assessment, investigators found that the median time to first PR was 2.0 months (interquartile range [IQR], 1.9-3.7) in the ublituximab plus ibrutinib arm compared with 4.4 months (IQR, 2.0-9.8) in the ibrutinib arm. For CRs, the median TTR was 22.1 months (IQR, 15.5-28.8) in the ublituximab plus ibrutinib arm versus 24.8 months (IQR, 23.6-31.4) in the ibrutinib group.
For IRC-assessed PFS, patients were followed for a median of 41.6 months (IQR, 36.7-47.3). The median PFS was not reached for the combination arm (95% CI, NE-NE) and 35.9 months (95% CI, 17.0-NE) in the ibrutinib arm (HR, 0.46; 95% CI 0.24-0.87; P = .016).
All patients in the study experienced adverse events. Grade 3 or higher AEs were observed in
76% of 59 patients in the ublituximab plus ibrutinib arm compared with 83% of the 58 patients in the ibrutinib arm. Among those who received the combination, the most common grade 1/2 AEs were infusion-related reactions (49%), diarrhea (46%), cough (42%), and fatigue (36%). With ibrutinib monotherapy, the most common grade 1/2 AEs were diarrhea (41%), contusion (34%), fatigue (33%), and cough (31%).
Characteristics of the patients in the GENUINE were well balanced between the treatment arms. Both populations were mostly male, including 69% of the combination arm and 74% of the monotherapy arm. Most patients in the study also had an ECOG performance status of 0 or 1, including 98% of those randomized to ublituximab plus ibrutinib and 97% of those randomized to receive ibrutinib alone. Fifty-one percent of subjects in the combination arm had Rai stage III-IV disease, as did 44% of the ibrutinib arm. Forty-eight percent of the combination arm had bulky disease, and 28% of the ibrutinib-only arm also had bulky disease.
In terms of genetic abnormalities, the most common abnormalities in the combination and monotherapy arms, respectively, were del(17p) deletion (44% and 48%), TP53 mutation (31% and 45%), and 11q deletion (47% and 44%). In addition, IGHV-unmutated disease was seen in 83% of the ublituximab/ibrutinib and 84% of the ibrutinib arm.
The ublituximab plus ibrutinib group had a time from diagnosis of 7.1 years (range, 3.6-10.1). The ibrutinib arm’s time from diagnosis was 5.3 years (range, 3.3-8.2). In terms of prior treatment, the combination arm had a median of 1 prior line of therapy (range, 1-2), which was identical to the ibrutinib arm.
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, randomized trial. Published online February 22, 2021. Lancet Haematol. doi:10.1016/ S2352-3026(20)30433-6