Umbralisib/Ublituximab Plus Venetoclax Induces High Objective Response Rate in Relapsed/Refractory CLL

Paul M. Barr, MD

The combination of umbralisib (TGR-1202) plus ublituximab (TGTX-1101; U2) plus venetoclax (Venclexta) demonstrated encouraging efficacy as treatment of patients with relapsed/refractory chronic lymphocytic leukemia (CLL), including those who are refractory to prior therapy with a Bruton tyrosine kinase (BTK) inhibitor, according to findings from a phase 1/2 study presented during the 2020 American Society of Hematology (ASH) Annual Meeting.¹

Overall, 100% of patients on the study achieved an objective response with the triplet regimen, including a high rate of undetectable minimal residual disease (MRD).

Two separate mechanisms of action at play include the inhibition of B-cell receptor signaling, which has demonstrated synergy with BCL2 in vitro, and targeting of PI3K, which has the potential to prevent BCL2 inhibitor resistance. Ublituximab is a glycoengineered anti-CD20 monoclonal antibody that has enhanced antibody-dependent cellular toxicity compared with the standard-of-care agent, rituximab (Rituxan).^2,3 In addition, selectivity and dual inhibition with umbralisib, a novel small molecule inhibitor targeting PI3Kd and CK1 epsilon, has translated to a limited effect on regulatory T cells and improved tolerability in prior studies, according to lead investigator Paul M. Barr, MD, who presented the data during this year’s meeting.¹

“Given the growing use of BTK inhibitors in the first-line setting, we aimed to develop an effective venetoclax-containing regimen of limited duration for our relapsed/refractory patients,” said Barr, medical director of the Clinical Trial Office and professor of Medicine at the James P. Wilmot Cancer Institute of the University of Rochester Medical Center in New York.

The phase 1/2 study aimed to evaluate the combination of U2 with the BCL2 inhibitor venetoclax in a multicenter design. The phase 1 portion of the trial, which was presented during the 2019 ASH Annual Meeting, determined the recommended phase 2 dose of ublituximab at 900 mg and umbralisib at 800 mg to be administered with the standard 5-week ramp up to 400 mg of venetoclax.⁴ The primary objective of the trial is to evaluate the safety of this regimen with secondary objectives including clinical efficacy defined by complete response (CR) rate, progression-free survival (PFS), and undetectable minimal residual disease (MRD).¹

All patients on the study received 3 cycles of U2 followed by the standard venetoclax ramp up to 400 mg, which was continued for 9 total cycles. Patients underwent a full response assessment following completion of the 12-cycle treatment plan. To date, 43 patients have been enrolled and are evaluable for safety, and 39 patients have completed the first 3 cycles of treatment and are evaluable for efficacy.

The median age of patients was 64 years (range, 43-83) and the majority were male (n = 31). The ECOG performance status was 0 in 5 patients, 1 in 36, and 2 in 2. The median number of prior lines of therapy was 2 (range, 1-6), and 33% of patients were refractory to their immediate prior therapy. Overall, 74% of patients had prior anti-CD20 therapy, 70% had prior chemoimmunotherapy, 58% had prior BTK inhibitor therapy, 5% had a prior PI3K inhibitor, and 2% had prior venetoclax. Among those who received a BTK inhibitor (n = 25), either ibrutinib (Imbruvica) or acalabrutinib (Calquence), 52% were refractory to the therapy, with 7 of 8 tested patients having a BTK or PLCy mutation detected.

Seventy-nine percent of patients had at least 1 high-risk feature, including 11q deletion (30%), 17p deletion (26%), TP53 mutation (18%), NOTCH1 mutation (27%), or SF3B1 mutation (15%); 74% of patients were IGHVunmutated.

All-cause adverse effects (AEs) of any grade occurring in at least 20% of patients included infusion reactions (60%), anemia (56%), thrombocytopenia (53%), neutropenia (51%), creatine decrease (49%), leukopenia (47%), fatigue (42%), and diarrhea (40%). The most common grade 3/4 AEs included neutropenia (21%), leukopenia (12%), infusion reaction (7%), anemia (5%), and diarrhea (5%).

Grade 3/4 AEs of special interest included lung infection/pneumonia (7%), colitis (5%), tumor lysis syndrome (TLS; 2%), and rash (2%). Dose reductions for umbralisib were needed in 2 patients (4%); discontinuations occurred with umbralisib and venetoclax in 4 (9%) and 2 patients (4%), respectively. No pneumonitis events or grade 3 LFT elevations were observed.

“Three cycles of U2 induction appeared effective at reducing the tumor lysis risk. Six and 21 patients, respectively, had high and medium TLS risk, and most were relegated to having low TLS risk after the induction. This represented an 81% relative reduction in tumor lysis risk after the 3 U2 cycles,” said Barr. Following 3 cycles of U2, no patients had developed clinical or laboratory TLS during the venetoclax ramp up.

The objective response rate (ORR) after 3 cycles of U2 induction was 77%, composed exclusively of partial responses (PRs), with 23% of patients having stable disease. The ORR among patients who received 7 cycles of treatment (n = 31) was 100%, with all patients achieving a PR. Among patients who completed all 12 cycles (n = 27), the ORR was 100%, with 41% of patients achieving a CR and 59% having a PR.

At cycle 3, the ORR was 64% among the BTK-refractory population and 74% among those who received a prior BTK inhibitor.

Overall, 96% of patients had undetectable MRD (<0.01%) in the peripheral blood and 77% in the bone marrow. Corresponding rates of intermediate MRD (0.01%-1.0%) were 4% and 23%.

The median PFS was 15.6 months (range, 1.3-30.8). One patient progressed 10 months after reaching undetectable MRD in the peripheral blood and bone marrow and discontinued therapy.

In conclusion, the U2 regimen in combination with venetoclax was well-tolerated at the recommended phase 2 doses. Only 3 patients (7%) had discontinued therapy with the triplet prior to completing the final cycle. Expansion cohorts for Richter transformation and mantle cell lymphoma are being explored based on this efficacy. A separate phase 2 study, ULTRA-V (NCT03801525), will explore the regimen further, including in treatment-naïve and relapsed/refractory patients with CLL.

_Reference

_{1. Barr PM, Ma S, Zent CS, et al. A phase 1/2 study of umbralisib ublituximab and venetoclax in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). Presented at: 2021 ASH Annual Meeting; December 4, 2020. Abstract 3137.}

_{2. Cervantes-Gomez F, Lamothe B, Woyach JA, et al. Pharmacological and protein profiling suggests venetoclax (abt-199) as optimal partner with ibrutinib in chronic lymphocytic leukemia. Cancer Res. 2015;21:3705-3715 doi: 10.1158/1078-0432.CCR-14-2809}

_{3. Choudhary GS, Al-Harbi S, Mazumder S, et al. MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT-199 can be overcome by preventing PI3K/AKT/mTOR activation in lymphoid malignancies. Cell Death Dis. 2015 Jan 15;6e1593}

_{4. Barr PM, Hill BT, Ma S, et al. A phase 1/2 study of umbralisib ublituximab and venetoclax in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). Blood. 2019;134:360 doi: 10.1182/blood-2019-123404}