Pushing Toward Time-Limited Options and More Tolerable PI3K Inhibitors in CLL

Seema A. Bhat, MD

Afforded by time-limited treatment strategies, the armamentarium of chronic lymphocytic leukemia (CLL) has the potential to become one defined by cost efficiency, convenience, and minimal toxicity, according to Seema A. Bhat, MD. 

“Even though we have made so many advancements and have highly effective treatment options for our patients that are well tolerated, we are still learning,” said Bhat. “For example, [we are beginning to understand] how to use [these effective therapies] in particular patient populations. We are trying to put these targeted agents together to learn whether we can get time-limited therapy, which can benefit patients from all standpoints, including cost, AEs, and patient convenience.”

The 5-year analysis of the phase 3 MURANO trial (NCT02005471), which was presented virtually during the 2020 American Society of Hematology (ASH) Annual Meeting and Exposition, showed sustained progression-free survival (PFS) and overall survival (OS) benefit with the time-limited combination of venetoclax (Venclexta) and rituximab (Rituxan) vs bendamustine and rituximab (BR) in patients with relapsed/refractory CLL.¹

Moreover, patients who achieved undetectable minimal residual disease (MRD) status at the end of treatment with venetoclax/rituximab had improved OS compared with patients who were MRD positive at the end of treatment.

“[The updated results of the MURANO trial] are very encouraging for our patients because they can have a time where they are not coming [to the clinic] for treatment,” Bhat said. “Plus, [the treatment-free interval spares patients] from the toxicity of treatment, including financial toxicity.”

Additionally, the investigational agent umbralisib, an inhibitor of PI3Kδ and CK1ε, may be a key to introducing time-limited options with decreased immune-related adverse effects (AEs) to the space. Currently, umbralisib in combination with ublituximab (U2) is moving toward FDA approval as a treatment for patients with CLL.^2,3 However, the U2 regimen in combination with venetoclax as time-limited therapy has demonstrated efficacy and tolerability in patients with relapsed/refractory disease.⁴ As such, the ongoing phase 2 ULTRA-V trial (NCT03801525) is enrolling to further evaluate this regimen in patients with CLL.⁵

In an interview with OncLive^® during a 2020 Institutional Perspectives in Cancer webinar on hematologic malignancies, Bhat, a hematologist at The Ohio State University Comprehensive Cancer Center–James and an assistant professor in the Department of Internal Medicine in the Division of Hematology at The Ohio State University, discussed updates from key studies and highlighted the promise of novel PI3K inhibitors in CLL.

OncLive^®: How does the 5-year analysis of the MURANO trial inform the understanding of time-limited treatment in CLL?

Bhat: MURANO was a global, open-label, phase 3 study of patients with relapsed/refractory CLL who needed treatment. The study accrued about 389 patients who were randomized into 1 of 2 arms. The standard arm was chemoimmunotherapy, with BR given for 6 cycles, [vs] the experimental arm of venetoclax plus rituximab. [Rituximab] was given in the initial 6 months [of treatment], and then venetoclax was continued [alone] for a total of 2 years.

In 2018, [the investigators] made an amendment [to the study design] to allow retreatment for patients who progressed or crossed over from the BR arm to the venetoclax/rituximab arm.

Previous reports showed that venetoclax plus rituximab was far superior compared with BR. The 5-year follow-up data confirmed that [in terms of] PFS and OS. The data also showed a difference in PFS between patients who had undetectable MRD status and patients who had MRD-positive disease at the end of combination treatment. Patients who had undetectable MRD had superior PFS compared with patients who had detectable disease. The data also showed that about 130 patients were able to complete 2 years of treatment with venetoclax plus rituximab. Of those patients, 83 had undetectable MRD at the end of treatment.

These patients were followed, and it was shown that about 38% of them continued to have undetectable MRD. The others had a resurgence of MRD as they were monitored, and some eventually had progressive disease. The [investigators] were able to show that the median time from the end of treatment and [achievement of] MRD-negative status to resurgence of MRD positivity was about 19 months. To disease progression, the median time was 25 months. This means that most patients derived a 44-month treatment-free interval before they progressed and needed additional treatment.

One interesting point that was observed from the study was that baseline high-risk characteristics predicted early resurgence of MRD positivity and further disease progression. Patients who had baseline 17p deletions, genomic complexity defined as 3 or more cytogenetic abnormalities, or unmutated IGHV status had a rapid doubling time of their MRD-positive status, which eventually led to disease relapse. Patients with good genomic characteristics who were MRD negative at the end of 2 years of treatment can derive long disease-free and treatment-free intervals before going on to the next treatment.

During the 2020 ASH Annual Meeting and Exposition, data from the MRD cohort of the phase 2 CAPTIVATE study were presented. How do these data solidify the role of MRD as a relevant tool in CLL?

The phase 2 CAPTIVATE study [NCT02910583] was an interesting global study in patients with treatment-naïve [CLL]. We have these highly active, targeted agents, including ibrutinib [Imbruvica] and venetoclax. Both agents are oral, which make them very convenient for patients, and they are very well tolerated. Other studies have shown that [ibrutinib and venetoclax] have synergistic and complementary activity, as well as nonoverlapping toxicity. This makes it very feasible to combine them.

The combination of [ibrutinib and venetoclax] has been used in some small studies [and yielded] interesting data. As such, a global study [was opened wherein] 164 treatment-naïve patients were accrued. Patients initially got 3 cycles of single-agent ibrutinib. After the 3 cycles, they received combined venetoclax and ibrutinib for a total of 12 cycles. At the end of the 12 cycles, patients were tested for MRD status. Patients with confirmed undetectable MRD status were [blindly] randomized to placebo or single-agent ibrutinib. The primary end point of this [phase of the study] was 1-year disease-free survival [DFS].

Those patients who did not have confirmed undetectable MRD status were randomized in an open-label fashion to continue the doublet [of ibrutinib and venetoclax] or single-agent ibrutinib.

Data from the undetectable MRD arm, which were presented during the [2020 ASH Annual Meeting and Exposition], showed that the combination caused deep responses in the blood and bone marrow. This was expected. In the blood, the confirmed [rate of] MRD-negative status was about 75%. In the bone marrow, the rate was 72%. We saw good concordance of about 93% between the bone marrow and the peripheral blood results where we had matched samples available. Therefore, the combination led to very deep remissions with a high [rate] of undetectable MRD status.

We also saw that the combination was safe. Major AEs were seen in the initial 6 months of the combination treatment. As patients continued treatment, AEs became [less common]. Grade 3 and higher AEs were very uncommon. The toxicity profile did not show any unexpected AEs and included arthralgias, high blood pressure, and diarrhea.

As far as the primary end point of 1-year DFS, the study showed no major difference between the 2 arms where patients discontinued the combination treatment at 12 months or continued ibrutinib further on. The 1-year DFS was 95.3% for placebo and 100% with continued ibrutinib. This was not statistically different, which means that we can comfortably discontinue treatment at 1 year after patients achieve MRD-negative status.

What is the current role of PI3K inhibitors in CLL?

We currently have 2 approved PI3K inhibitors, idelalisib [Zydelig] and duvelisib [Copiktra], for the treatment of patients with relapsed/refractory CLL. We don’t have any PI3K inhibitors approved for patients with treatment-naïve disease.

Duvelisib was approved based on the phase 3 DUO trial [NCT02004522]. Patients with relapsed/refractory CLL were randomized to single-agent duvelisib vs ofatumumab [Arzerra], which is a CD20-directed monoclonal antibody. The primary end point was PFS. The study showed that the PI3K inhibitor had superior PFS compared with ofatumumab. These findings led to the eventual approval of duvelisib in 2018 for the treatment of patients with relapsed/refractory CLL.

How could the approval of umbralisib affect the utility of PI3K inhibitors in CLL? How does the agent differ from idelalisib and duvelisib?

We are excited about the novel PI3K inhibitor umbralisib. One of the issues with idelalisib and duvelisib is that they are associated with immune-related AEs, such as colitis, diarrhea, pneumonitis, and hepatitis. That has limited their uptake in practice in treating patients with relapsed/refractory CLL. We are excited about umbralisib because it is selective to the delta isomer of the PI3 kinase, which translates to lesser immune-related AEs.

[During the 2020 ASH Meeting and Exposition], data were presented from the UNITY-CLL trial [NCT02612311]. This was a phase 3 trial of umbralisib in combination with ublituximab, an anti-CD20 monoclonal antibody, compared with chlorambucil and obinutuzumab [Gazyva]. Patients with treatment-naïve and relapsed/refractory CLL were accrued. The study showed that [umbralisib plus ublituximab] was superior to chemoimmunotherapy [in patients irrespective of disease state]. 

We are really excited [by these results], more so because patients reported less immune-related AEs [with umbralisib/ublituximab compared with approved PI3K inhibitors]. For example, pneumonitis was reported in about 3% of patients, increased liver function tests in about 8%, grade 3 or higher diarrhea in about 12%, and colitis in about 3.4%. We are excited about the new compound that we can potentially have available for our patients.

How do you anticipate time-limited options and more personalized approaches adding to the current treatment paradigm of CLL?

We’ve learned that CLL is not a single disease. Various subpopulations exist within this disease. Some patients have a higher-risk disease profile, whereas others have a standard-risk disease profile. We want to learn about which populations of patients would be best suited for time-limited therapy vs which ones should be targeted for these combinations. That is something we are trying to learn with these upcoming studies. Hopefully, in the future, the results of these studies [will provide insight] into how we can best individualize treatment for patients.

References

1. Kater AP, Kipps TJ, Eichhorst B, et al. Five-year analysis of Murano study demonstrates enduring undetectable minimal residual disease (uMRD) in a subset of relapsed/refractory chronic lymphocytic leukemia (R/R CLL) patients (pts) following fixed-duration venetoclax-rituximab (VenR) therapy (tx). Presented at: 2020 ASH Annual Meeting and Exposition; December 5-8, 2020; Virtual. Abstract 125.
2. TG Therapeutics initiates rolling submission of biologics license application to U.S. 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 January 27, 2021. https://bit.ly/3muaDKm.
3. TG Therapeutics announces fast track designation granted by the FDA to ublituximab in combination with umbralisib for the treatment of adult patients with chronic lymphocytic leukemia. News release. TG Therapeutics. October 21, 2020. Accessed January 27, 2021. https://bit.ly/3oczEey.
4. Barr PM, Ma S, Zent CS, et al. A phase 1/2 study of umbralisib, ublituximab, and venetoclax (U2–Ven) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). Presented at: 2020 ASH Annual Meeting and Exposition; December 5-8, 2020; Virtual. Abstract 3137.
5. Study to assess the efficacy and safety of ublituximab plus umbralisib in combination with venetoclax in subjects with CLL (ULTRA-V). ClinicalTrials.gov. Posted January 11, 2019. Updated January 8, 2021. http://bit.ly/2YjcA1V.