Durable Responses Demonstrated in Phase I/II With U2 Triplet Regimen in CLL

Anthony R. Mato, MD

Anthony R. Mato, MD

Umbralisib (TGR-1202) and ublituximab (TG-1101; U2) in combination with pembrolizumab (Keytruda) was well tolerated among patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and Richter’s transformation (RT), according to a phase I/II trial presented at the 18th International Workshop on CLL. Responses were durable in high-risk patients who are BTK-refractory, including 2 complete responses (CRs) in patients with RT.

“Immune-mediated toxicities were not increased above what would be expected with either umbralisib or pembrolizumab alone,” study authors, led by Anthony R. Mato, MD, of the CLL Program at Memorial Sloan Kettering Cancer Center, wrote in their poster. “Data suggest that [patients with] CLL who achieve less than CR with a checkpoint inhibitor—containing regimen can achieve durable remissions and that time-limited schedules should be explored.”

Umbralisib is a next-generation PI3K-delta inhibitor that is given orally once daily. Ublituximab is a novel, glycoengineered chimeric monoclonal antibody that targets an epitope on the CD20 antigen. Ublituximab is currently being investigated in a phase III trial for the treatment of patients with CLL or non-Hodgkin lymphoma.

This multicenter phase I/II dose-escalation trial assessed the safety and efficacy of the triplet regimen in patients with relapsed/refractory CLL and RT. The primary objective was to determine the safety of U2 plus pembrolizumab in these patients. Secondary objectives included efficacy and determination of the immunophenotypic and cytokine profiles of B and T cells.

To be eligible, patients with CLL or RT had to have progressed on at least 1 prior therapy, with no limit on the number of prior treatments. Absolute neutrophil count had to be greater than 750/μL and platelet counts above 40,000/μL. Patients were not excluded due to prior exposure to a PD-1 or PI3K inhibitor.

A mid-study amendment was made to require that patients with CLL be BTK-refractory, meaning they had progressed on or within 6 months of treatment with a prior BTK inhibitor. Patients with RT had to be chemo-immunotherapy refractory or ineligible for high-dose chemotherapy.

Patients with CLL received ublituximab on days 1, 8, and 15 of cycles 1 and 2, as well as day 15 of cycles 4 and 6. Pembrolizumab was given on day 1 of cycles 3 through 6. Umbralisib was given daily starting on day 1, cycle 1. Patients with RT received pembrolizumab on day 3 of cycle 1 and day 2 of cycles 2 through 4, as well as ublituximab on days 1, 8, and 15 of cycle 1; day 1 of cycle 2 through 4; day 1 of cycles 7 and 10; and then every 3 months after cycle 10 until month 12. Umbralisib was given daily starting on day 1, cycle 1.

In cohort 1, patients received a dose of ublituximab at 900 mg, umbralisib at 800 mg, and pembrolizumab at 100 mg. Cohort 2 received the same doses of ublituximab and umbralisib, but received a 200-mg dose of pembrolizumab.

Overall, 11 patients with CLL were evaluable for safety and efficacy, while 9 patients with RT were evaluable for safety and 8 for efficacy. The median age for patients with CLL was 70 years and 66 years for patients with RT.

In the CLL group, the median number of prior treatments was 1 (range, 1-4); 7 patients had a prior BTK inhibitor (64%) and 6 were refractory to BTK (86%). Eight patients were refractory to their last treatment (73%). Additionally, 8 patients had at least 1 high-risk feature (73%), including 6 with at least 2 high-risk features (55%). Three patients had a 17p deletion or were TP53 mutated (27%), 5 had complex karyotype (25%), 5 had NOTCH1/ATM/SF3B1 mutations (45%), and 5 were IGHV unmutated (45%). Seven patients also had bulky disease (64%).

In the RT group, the median number of prior treatments was 5 (range, 1-9). Eight patients were previously treated with ibrutinib (Imbruvica; 89%) and were refractory (100%). Additionally, all of the patients had received a prior chemotherapy regimen (100%), 3 had prior venetoclax (Venclexta; 33%), 3 had prior CAR T-cell therapy or allogenic transplant (33%), and 2 received prior idelalisib (Zydelig) plus rituximab (Rituxan; 22%). Eight patients were refractory to an immediate prior therapy (89%).

The objective response rate (ORR) was 83% in patients with BTK-refractory CLL, while the ORR was 91% among all patients with CLL. Additionally, 80% of the BTK-refractory patients achieved a response after U2 induction, prior to the administration of pembrolizumab.

Overall, 1 patient with CLL achieved a CR (9%), 9 achieved a partial response (PR; 82%), and 1 had stable disease (9%. After a median follow-up of 24.7 months, the 12-month progression-free survival (PFS) was 91%, but the median PFS had not yet been reached.

In the RT cohort, the ORR was 38% (n = 8). Additionally, 2 patients with RT achieved a CR (25%), while 1 had a PR (12.5%) and 2 had stable disease (25%).

Study authors highlighted a patient with RT who had 6 prior lines of therapy, including an allogenic transplant. This patient achieved a CR by the end of cycle 8 and remained on study in CR after over 20 months of follow-up. The combination of U2 plus 100 mg of pembrolizumab was well tolerated by the patient, with 1 event of grade 3 hypophosphatemia and 1 of grade 3 hyperglycemia.

The most common adverse events (AEs) overall included neutropenia (65%), fatigue (55%), cough (50%), diarrhea (50%), and pyrexia (50%). The most common grade 3/4 AEs were neutropenia (40%) and thrombocytopenia (15%). Other grade 3/4 AEs that were seen included fatigue, nausea, and anemia.

Grade 3/4 liver function test elevations occurred in 4 patients (20%), but there were no cases of grade 3/4 diarrhea or pembrolizumab-associated autoimmune events. No events of colitis were observed in this trial. No patients had their dose of pembrolizumab reduced, but 3 patients had the dose of umbralisib reduced.

The study authors also noted that the observed maintenance of regulatory T cells throughout therapy could explain the limited autoimmune sequelae.