Promising Umbralisib Combinations Tested in NHL Subtypes

Bruce Cheson, MD

Patients with relapsed/refractory non-Hodgkin lymphoma (NHL) have limited options for treatment, and effective advancedstage therapies must be developed for many subtypes of the disease. In the search for solutions, investigators are turning to combination therapies.

The phase IIb UNITY-NHL clinical trial (NCT02793583) is an attempt to determine whether these needs can be addressed using the novel drug umbralisib (TGR-1202) as monotherapy or as part of a doublet or a triplet. The doublet includes ublituximab (TG-1101), and the triplet includes ublituximab and bendamustine (Treanda).

The UNITY-NHL study is enrolling patients with 4 different subtypes: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), small lymphocytic lymphoma (SLL), and marginal zone lymphoma (MZL). Umbralisib is being tested as monotherapy in FL, SLL, and MZL, while the DLBCL subtype is being treated with doublet or triplet therapy. Each lymphoma subtype has its own eligibility criteria, according to Bruce D. Cheson, MD, principal investigator at the Georgetown University Hospital Lombardi Comprehensive Cancer Center in Washington, DC. He said all participants must have relapsed/ refractory NHL that has not responded to standard treatment (Figure).

“Each of the settings being studied in this trial is an unmet medical need,” Cheson said. He noted that the nonchemotherapy doublet of umbralisib and ublituximab could prove to be more effective and tolerable than idelalisib (Zydelig), a PIK3δ inhibitor that is approved for patients with relapsed FL or SLL who have received at least 2 prior therapies.¹

“The study was designed to start with monotherapy treatments and move to combinations in later stages of the trial. The future cohorts will evaluate umbralisib and ublituximab for indolent lymphoma, as well,” said Cheson, who is a professor of medicine, deputy chief of hematology and oncology, and head of hematology and cellular therapy at the Lombardi Comprehensive Cancer Center.

Umbralisib has a unique mechanism of action that makes it a good candidate for combinations and monotherapy. The drug is an orally available PI3Kδ inhibitor that has demonstrated strong activity in numerous preclinical models and in primary cells from patients with hematologic malignancies, according to the drug’s developer, TG Therapeutics in New York, New York. PI3Kδ is strongly expressed in hematopoietic cells and believed to be important in the proliferation and survival of B-cell lymphocytes.²

Ublituximab, also developed by TG Therapeutics, is a monoclonal antibody that targets an epitope on the B-lymphocyte CD20 antigen. Anti-CD20 antibodies target and aid in the depletion of B-lymphocytes.³ The chemotherapy bendamustine is a bifunctional mechlorethamine derivative that has shown alkylator and antimetabolite activity. The exact mechanism of action is unknown, but the bifunctional covalent linkage can lead to cell death via several pathways, and the drug is active against both quiescent and dividing cells.⁴

“They all have nonoverlapping mechanisms of action—you’re attacking the cancer in multiple ways at the same time, with potentially improved response over monotherapy,” Cheson said of the 3 agents.

Umbralisib stands out among PI3K inhibitors for its superior safety and tolerability. “Given the track record for prior PI3K inhibitors, we were concerned about severe diarrhea, rash, and opportunistic infections, but we really didn’t see much of that,” Cheson said. “As far as ublituximab goes, the primary reactions are infusion reactions, with very little subsequent consequence. For bendamustine, the myelosuppression, nausea, vomiting, and some immunosuppression are well known.”

In patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and lymphoma (n = 90), umbralisib induced an objective response rate (ORR) of 37%, according to phase I findings published in the Lancet Oncology.⁵

In the dose-escalation study, 62% of 90 patients experienced reduction in disease burden. The highest response rates occurred in patients with CLL (85%) and FL (53%). Investigators also found that grade 3/4 immune-mediated adverse events (AEs) commonly associated with other PI3Kδ inhibitors were limited—3 patients (<3%) experienced transaminitis, and 2 (<2%) each experienced pneumonia and colitis. The most common treatment-emergent AEs regardless of cause were diarrhea (43%), nausea (42%), and fatigue (31%). The most common grade 3/4 AEs were neutropenia (13%), anemia (9%), and thrombocytopenia (7%).⁵

Promising findings from a study on the combination of umbralisib and ublituximab were presented at the 2017 Congress of European Hematology Association, Madrid, Spain. The study combined the 2 agents with ibrutinib (Imbruvica), and investigators reported that the combination was well tolerated and had activity across heavily pretreated patients with high-risk B-cell malignancies. An ORR of 100% was reached in CLL, mantle cell lymphoma, and MZL, according to slide material presented at the conference. The ORR was 80% in 5 patients with FL, which included 1 complete response (CR) and 4 partial responses (PRs). In DLBCL, just 1 of the 6 patients in the cohort showed a PR, for an ORR of 17%.⁶

A separate study presented in 2017 at the 14th International Conference on Malignant Lymphoma in Lugano, Switzerland, showed that the combination of umbralisib, ublituximab, and bendamustine was safe and highly active in patients with advanced indolent and aggressive NHL, including those not eligible for stem cell transplant or CD19 chimeric antigen receptor T-cell therapy.⁷

In patients with relapsed DLBCL, there was an ORR of 100%, with a 50% CR rate. In patients with refractory DLBCL, there was an ORR of 50% with a CR rate of 42%, with durable responses observed. In patients with relapsed or refractory indolent NHL, there was an 88% ORR with a 50% CR rate. The investigators also concluded that the nonchemotherapy doublet of ublituximab and umbralisib is “a safe and efficacious backbone regimen on which to build novel multidrug combinations.”⁷ These results served as the rationale for the UNITY-NHL trial.

“There are a lot of novel therapies being developed for lymphoma. We have 3 or 4 PI3K inhibitors, 4 or 5 [Bruton tyrosine kinase] inhibitors, a couple of BCL-2 inhibitors, and a few checkpoint inhibitors,” Cheson said. Based on the strength of prior studies, the doublet and triplet combinations involving umbralisib, ublituximab, and, for some histologies, bendamustine show a lot of promise for addressing the issue “of what is the better way to do things,” he said.

References

1. Zydelig [prescribing information]. Foster City, CA: Gilead Sciences, Inc; 2014. accessdata.fda.gov/drugsatfda_docs/label/2014/206545lbl.pdf. Accessed April 18, 2018.
2. Umbralisib (TGR-1202). Pipeline. TG Therapeutics website. tgtherapeutics.com/pipeline/TGR-1202.cfm. Updated 2018. Accessed April 17, 2018.
3. Ublituximab (TG-1101). Pipeline. TG Therapeutics website. tgtherapeutics.com/pipeline/TGTX-1101.cfm. Updated 2018. Accessed April 17, 2018.
4. Treanda [prescribing information]. Frazer, PA: Cephalon, Inc; 2010. accessdata.fda.gov/drugsatfda_docs/label/2010/022249s005lbl.pdf. Accessed April 17, 2018.
5. Burris HA 3rd, Flinn IW, Patel MR, et al. Umbralisib, a novel PI3Kδ and casein kinase-1ε inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study. Lancet Oncol. 2018;19(4):486-496. doi: 10.1016/S1470-2045(18)30082-2.
6. Nastoupil L, Lunning MA, Vose JM, et al. Chemo-free triplet combination of TGR-1202, ublituximab, and ibrutinib is well tolerated and highly active in patients with advanced CLL and NHL. Abstract presented at: 22nd Congress of European Hematology Association; June 22-25, 2017; Madrid, Spain. Abstract S772. learningcenter.ehaweb.org/eha/2017/22nd/182059/loretta.nastoupil.chemo-free.triplet.combination.of.tgr-1202.ublituximab.and.html?f=media=3.
7. Lunning M, Bierman PJ, Bociek RG, et al. Combination of TGR-1202, ublituximab, and bendamustine is safe and highly active in patients with advanced DLBCL and follicular lymphoma. Poster presented at: 14th International Conference on Malignant Lymphoma; June 14-17, 2017; Lugano, Switzerland. tgtherapeutics.com/U2%20Benda%20ICML%20Final.pdf.