Promising Covalent BTK Inhibitor Shows Results in Relapsed/Refractory CLL

TG-1701 demonstrated promising activity and a manageable safety profile in patients with chronic lymphocytic leukemia (CLL) whether used as a single agent or as part of a combination regimen with U2 (umbralisib [Ukoniq] plus ublituximab), according to dose-escalation and dose-expansion findings presented at the 2021 International Workshop on Chronic Lymphocytic Leukemia (iwCLL).¹

In a dose-escalation phase of the study and at a median follow-up of 28 months (range, 18-31), TG-1702 monotherapy elicited an objective response rate (ORR) of 83% (n = 5/6). When TG-1702 was combined with U2 in this phase, the ORR increased to 100% (n = 3/3) at a median follow-up of 19 months (range, 2-22).

In dose-expansion cohorts, in which TG-1701 was tested at 200-mg and 300-mg doses, the ORRs were 95% (n = 19/20) and 100% (n = 19/19), respectively, at median follow-ups of 19 months (range, 16-22) and 12 months (range, 9-14), respectively.

Treatment was ongoing for the majority of patients with CLL across cohorts.

“TG-1701 exhibits an encouraging safety and efficacy profile in patients with CLL,” lead study author Chan Y. Cheah, MBBS, DMSc, a hematologist and clinical investigator of linear clinical research at Sir Charles Gairdner Hospital in Nedlands, Australia, said during a virtual presentation at the meeting.

It is rare for patients with CLL to achieve deep remissions from single-agent Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib (Imbruvica) and acalabrutinib (Calquence), Cheah explained. However, TG-1701 is an irreversible covalently bound BTK inhibitor that has been shown to have superior selectivity vs ibrutinib. When used in BTK-resistant xenograft models, TG-1701 in combination with the U2 regimen was found to inhibit tumor growth.

In December 2020, it was announced that a rolling submission of a biologics license application to the FDA had been initiated for ublituximab in combination with umbralisib for the treatment of patients with CLL. It was accepted in May 2021.2,3 The Prescription Drug User Fee Act target action date is March 25, 2022.

In the ongoing phase 1 trial (NCT03671590), investigators are enrolling patients to receive TG-1701 as monotherapy or in combination with U2. Patients must have had relapsed or refractory disease with prior standard therapy and histologically confirmed B-cell lymphoma or CLL that warrants systemic therapy; they also must have adequate organ function. Cheah noted that for disease-specific cohorts, treatment-naive patients could be enrolled if they were ineligible for standard frontline chemoimmunotherapy.

Those who had received prior BTK inhibitor therapy, had any severe or uncontrolled conditions, or had received concomitant warfarin therapy were excluded; however, other anticoagulation treatments were permitted.

The study design encompasses a dose-escalation phase where patients are treated with TG-1701 alone orally daily in 28-day cycles or with U2. Once an optimal dose is determined, patients will be enrolled onto disease-specific/dose-expansion cohorts of CLL, Waldenström macroglobulinemia, and mantle cell lymphoma, where patients will still be treated with either single-agent TG-1701 or with U2.

In the combination arm, TG-1701 is given in escalating doses along with 600 or 800 mg of oral umbralisib daily plus intravenous ublituximab at 900 mg on days 1, 8, and 15 of cycle 1; day 1 of cycles 2 through 6; and day 1 every 3 cycles for up to 24 cycles.

In the single-agent dose-escalation phase, where intrapatient dose escalations were permitted, patients were treated with daily doses of TG-1701 at 100 mg (n = 3), 200 mg (n = 9), 300 mg (n = 3), and 400 mg (n = 10). Patients in the combination dose-escalation phase received TG-1701 at 100 mg plus U2 (n = 7), TG-1701 at 200 mg plus U2 (n = 6), and TG-1701 at 300 mg plus U2.

Also at the 2021 iwCLL meeting, data were reported for patients with CLL in the single-agent, dose-expansion cohort, in which TG-1701 was given as monotherapy at 200-mg (n = 20) or 300-mg (n = 20) doses.

In the dose-escalation phase of single-agent (n = 6) or combination therapy (n = 4), 7 patients were male, and the median age was 61.5 years (range, 47-83); 2 patients were at least 75 years of age. Half of patients had an ECOG performance status of 0, and the median number of prior lines of therapy was 1 (range, 1-2). One patient on the combination arm was refractory to their last prior therapy. Ninety percent of patients had unmutated IGHV status; 50% had a 17p deletion or a TP53 mutation, and the other half had both abnormalities.

In the dose-expansion cohorts of monotherapy (n = 20) and combination therapy (n = 20), 17 patients were male, and the median age was 70.5 years (range, 49-86); 9 patients were at least 75 years of age. Moreover, 32.5% of patients had an ECOG performance status of 0, and the median number of prior lines of therapy was 1 (range, 0-7); 5 patients were refractory to their last prior line of treatment and 9 were treatment-naive. Moreover, 56.5% of patients in this cohort had unmutated IGHV status, 12.5% had 17p deletion or TP53 mutation, and 14.5% had both 17p deletion and TP53 mutation.

Outcome measures included safety, recommended phase 2 dose of TG-1701 as monotherapy and in combination with U2, pharmacokinetics, antitumor activity, and BTK occupancy.

As of the last data cutoff, Cheah said that most patients remain on active therapy. Three patients on single-agent TG-1701 in the dose-escalation phase required dose reductions, compared with 1 on single-agent treatment in the dose-expansion cohort. Two patients on TG-1701 monotherapy in each cohort discontinued treatment, along with an additional 2 on combination therapy in the dose-expansion cohort.

Two patients on single-agent TG-1701 in the dose-escalation phase discontinued due to disease progression by iwCLL criteria and other reasons (n = 1 each). One patient on TG-1701 monotherapy in the dose-expansion phase stopped treatment due to patient or physician decision. No patients discontinued treatment due to adverse effects (AEs), however, 3 patients in the dose-expansion cohort died—1 on single-agent treatment and 2 on combination therapy.

Any-grade AEs in the dose-escalation phase included contusion (n = 4 for TG-1701 alone), diarrhea (n = 1 for combination therapy), upper respiratory tract infection (n = 3 for TG-1701 alone), nausea (n = 1 each for single-agent and combination therapy), neutropenia (n = 1 for TG-1701 alone), increased alanine aminotransferase (ALT; n = 2 for TG-1701 alone), increased aspartate aminotransferase (AST; n = 1 for TG-1701 alone), and anemia (n = 1 for combination therapy). Grade 3 or higher AEs in this phase occurred only in the monotherapy arm and were reported as neutropenia and increased ALT/AST.

All-grade BTK inhibitor–related AEs of special interest included grade 3 or higher arthralgia (n = 1 for single-agent treatment) and atrial fibrillation (n = 1 for single-agent treatment).

In the dose-expansion cohort, all-causality AEs at the 200-mg dose included contusions (n = 4), diarrhea (n = 4), upper respiratory tract infection (URTI; n = 2), COVID-19 (n = 1), neutropenia (n = 2, grade 3 or higher), increased ALT (n = 4), and increased AST (n = 2), anemia (n = 3, 1 of which was grade 3 or higher).

Finally, in the 300-mg cohort, any-grade all-causality AEs were contusion (n = 1), diarrhea (n = 2), URTI (n = 3), nausea (n = 3), COVID-19 (n = 3, 1 of which was grade 3 or higher), neutropenia (n = 4; all grade 3 or higher), and increased ALT and AST (n = 3 each; 1 case of each was grade 3 or higher). Two BTK inhibitor–related AEs were arthralgia and hypertension.

_REFERENCES:

_{1. Chan CY, Jurczak W, Lasica M, et al. TG-1701, a selective Bruton tyrosine kinase (BTK) inhibitor, as monotherapy and in combination with ublituximab and umbralisib (U2) in patients with chronic lymphocytic leukemia. Presented at: 2021 International Workshop on Chronic Lymphocytic Leukemia; September 17-20, 2021; virtual. Abstract 1083634.}

_{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 September 19, 2021. https://bit.ly/3muaDKm}

_{3. TG Therapeutics announces FDA acceptance of biologics license application for ublituximab in combination with UKONIQ (umbralisib) as a treatment for patients with chronic lymphocytic leukemia and small lymphocytic lymphoma. News release. TG Therapeutics, Inc. May 25, 2021. Accessed October 15, 2021. https://bit.ly/3aHQXhW}