Time-Limited Ublituximab/Umbralisib Plus Ibrutinib Shows Efficacy, Tolerability in CLL

The addition of ublituximab and umbralisib (Ukoniq; U2) to ibrutinib (Imbruvica) demonstrated a 77% undetectable minimal residual disease (uMRD) rate in patients with chronic lymphocytic leukemia (CLL), along with a tolerable safety profile, according to phase 2 results presented at the 47th Annual Oncology Nursing Society (ONS) Congress.¹

“This novel patient care approach of ‘add-on’ combination therapy was well tolerated and effective, with achievement of uMRD in 77% of evaluable patients allowing for tailored, time-limited therapy and sustained treatment-free observation,” lead study author Colleen Dorsey, RN, BSN, of Memorial Sloan Kettering Cancer Center, and coinvestigators wrote in the poster presented during the meeting. “This approach may assist nurses with patient care challenges such as management of adverse events due to indefinite ibrutinib therapy.”

The findings with this combination mirror what was presented during the 2021 ASH Annual Meeting. In the phase 2 trial (NCT04016805), the addition of U2 to ibrutinib led to a 77% uMRD rate in this patient population.² Moreover, 4% of patients came off treatment after 24 cycles and continued to have detectable MRD.

Time-limited therapy has shown efficacy in the form of high and durable response rates in previous data; however, this approach has also been linked with an increase in adverse effects (AEs) as well as a risk of overtreatment, the authors noted.

In the data presented at the ONS Congress, investigators utilized an “add-on” and MRD-driven, time-limited treatment approach with U2 following single-agent ibrutinib. To be eligible for enrollment, patients had to be receiving ongoing ibrutinib for at least 6 months and have detectable MRD.

In addition to ibrutinib, umbralisib was administered orally at 800 mg daily and ublituximab was given intravenously on days 1 and 2 at a split dose of 150 mg and 750 mg, and then at 900 mg total on days 8 and 15 of cycle 1, day 1 of cycles 2 through 6, and on day 1 every 3 cycles after cycle 6.

Following confirmation of uMRD, patients were entered into a treatment-free observation. For those who did not have a confirmed uMRD, patients continued therapy for up to 24 cycles followed by a treatment-free observation.

Outcome measures included uMRD rate, safety, and duration of clinical benefit after treatment discontinuation.

Of the 27 evaluable patients, the median age was 64 years and 79% of patients were male. The median time to first uMRD was 7.4 months (95% CI, 4.6-20.2) and 77% of patients had at least 1 uMRD assessment.

Sixteen patients (67%) entered TFO and were off therapy for a median of 242 days off treatment (range, 5-538). TFO appeared durable and at the last follow-up, 73% of these patients remained in uMRD. Retreatment was not required in any patients per International Workshop on CLL criteria.

Regarding safety, the triplet regimen was well tolerated. Overall all-causality grade 3/4 AEs of special interest included hypertension (7%), alanine aminotransferase/aspartate aminotransferase increase (4%), COVID-19 (4%), and diarrhea (4%). There were 2 treatment discontinuations due to rash (n = 1) and rash plus arthralgia (n = 1); however, both patients were in uMRD at the time of treatment discontinuation and remain in uMRD.

These results follow the April 2022 announcement that the pending biologics license application (BLA) and supplemental new drug application (sNDA) seeking the approval of the combination of ublituximab and umbralisib in adult patients with CLL and small lymphocytic lymphoma (SLL) had been voluntarily withdrawn by the developer of U2, TG Therapeutics, Inc.³

The decision follows updated overall survival data yielded from the phase 3 UNITY-CLL trial (NCT026112311), which demonstrated an increasing imbalance in survival in favor of the control arm.

TG Therapeutics also announced the decision to voluntarily withdraw umbralisib from sale for the approved indications of adult patients with marginal zone lymphoma (MZL) who have previously received at least 1 anti–CD20-based regimen and for adult patients with follicular lymphoma who previously received at least 3 systemic therapies.

The FDA granted an accelerated approval to umbralisib in February 2021 for these indications based on data from 2 single-arm cohorts of the open-label, multicenter, phase 2/3 UNITY-NHL trial (NCT02793583).⁴ Results showed that the objective response rate was 49% (95% CI, 37.0%-61.6%) in patients with MZL (n = 69), which included a complete response (CR) rate of 16%. The ORR achieved with the agent in patients with follicular lymphoma (n = 117) was 43% (95% CI, 33.6%-52.2%), which included a CR rate of 3%.

References

1. Dorsey C, Falco V, Pena-Velasquez CP, et al. A phase 2 study evaluating the addition of ublituximab and umbralisib (U2) to ibrutinib in patients with chronic lymphocytic leukemia (CLL): a minimal residual disease (MRD)-driven, time-limited approach. Presented at: 47th Annual Oncology Nursing Society Congress; April 27-May 1, 2022; Anaheim, CA. Abstract P303.
2. Roeker LE, Leslie LA, Soumerai JD, et al. A phase 2 study evaluating the addition of ublituximab and umbralisib (U2) to ibrutinib in patients with chronic lymphocytic leukemia (CLL): a minimal residual disease (MRD)-driven, time-limited approach. Blood. 2021;138(suppl 1):395. doi:10.1182/blood-2021-146999
3. TG Therapeutics announces voluntary withdrawal of the BLA/sNDA for U2 to treat patients with CLL and SLL. News release. TG Therapeutics, Inc.; April 15, 2022. Accessed April 15, 2022. https://bit.ly/36lqqZm
4. FDA grants accelerated approval to umbralisib for marginal zone lymphoma and follicular lymphoma. News release. FDA; February 5, 2021. Accessed April 15, 2021. http://bit.ly/3aCBqQa