Addition of ublituximab to ibrutinib improves response in r/r CLL
Ibrutinib, the Bruton’s tyrosine kinase (BTK) inhibitor, has transformed the treatment landscape for patients with relapsed or refractory (r/r) chronic lymphocytic leukemia (CLL).
Yet for patients with high-risk molecular features, such as 11q deletion, 17p deletion, or TP53 mutation, relapse remains problematic.
Investigators evaluated whether the addition of ublituximab to ibrutinib would improve the outcome of patients with genetically high-risk CLL in the GENUINE (UTX-IB-301) phase 3 study.
Jeff P. Sharman, MD, of Willamette Valley Cancer Institute and Research Center in Springfield, Oregon, reported the results at the 2017 ASCO Annual Meeting (abstract 7504).*
Ublituximab is a glycoengineered, anti-CD20 type 1 monoclonal antibody that maintains complement-dependent cytotoxicity and enhances antibody-dependent cell-mediated cytotoxicity. In a phase 2 study in combination with ibrutinib, it achieved an ORR of approximately 88%.
Protocol design
Originally, the study had co-primary endpoints of overall response rate (ORR) and progression-free survival (PFS). To adequately power for both endpoints, the target enrollment was 330 patients.
Dr Sharman explained that after 22 months of open enrollment, the trial sponsor determined that the original enrollment goal could not be met in a timely manner and elected to redesign the protocol.
In the modified protocol, ORR became the primary response rate and PFS a secondary endpoint. This allowed for a reduced target enrollment of 120. However, the study was no longer powered to detect a change in PFS.
Investigators stratified the patients by lines of prior therapy and then randomized them to receive ibrutinib or ublituximab plus ibrutinib.
The ibrutinib dose was 420 mg daily in both arms. Ublituximab dose was 900 mg on days 1, 8, and 15 of cycle 1, day 1 of cycles 2 through 6 and every third cycle thereafter.
The primary endpoint was ORR as assessed by Independent Central Review (IRC) using the iwCLL 2008 criteria.
Secondary endpoints included PFS, the complete response (CR) rate and depth of response (minimal residual disease [MRD] negativity), and safety.
The investigators assessed patients for response on weeks 8, 16, 24, and every 12 weeks thereafter.
The primary endpoint was evaluated when all enrolled patients had at least 2 efficacy evaluations.
The median follow-up was 11.4 months.
Patient characteristics
Patients with relapsed or refractory high-risk CLL had their disease centrally confirmed for the presence of deletion 17p, deletion 11q, and/or TP53 mutation.
They had measurable disease, ECOG performance status of 2 or less, no history of transformation of CLL, and no prior BTK inhibitor therapy.
The investigators randomized 126 patients, and 117 received any dose of therapy.
“The dropout was because in part ibrutinib was via commercial supply and not every patient could get access,” Dr Sharman noted.
Fifty-nine patients were treated in the combination arm and 58 in the monotherapy arm.
All patients had at least one of the specified mutations, which were relatively balanced between the 2 arms.
Patients were a mean age of 67 (range, 43 – 87), had a median of 3 prior therapies (range, 1 – 8), and more than 70% were male.
Patient characteristics were similar in each arm except for bulky disease, with 45% in the combination arm having bulky disease of 5 cm or more at baseline, compared with 26% in the monotherapy arm.
Twenty percent of the patients were considered refractory to rituximab.
Safety
Infusion reactions occurred in 54% of patients in the combination arm and 5% had grade 3/4 reactions. None occurred in the ibrutinib arm, since the latter is an orally bioavailable drug.
