Chan Cheah, MBBS, discusses TG-1701 as a more target-specific BTK inhibitor, the outcomes in response rates in the cohorts of the trial, and where future research is headed with this agent.
TG-1701 administered as monotherapy or in combination with ublituximab (TGTX-1101) and umbralisib (Ukoniq) demonstrated promising overall response rates (ORR) and with relatively few adverse events (AEs) in patients with chronic lymphocytic leukemia (CLL), according to lead author Chan Cheah, MBBS. He added that the agent is a more specific targeting BTK inhibitor which reduces off-target toxicities.
According to data from an ongoing phase 1 trial (NCT03671590), TG-1702 elicited an objective response rate (ORR) of 83% (n = 5/6) when given as a monotherapy. When TG-1702 was combined with ublituximab and umbralisib, the ORR increased to 100% (n = 3/3) at a median follow-up of 19 months (range, 2-22).
“It's clear that combining [TG-1701], a novel agent, with a PI3 kinase and CD20 is both active and deliverable, both in CLL and other B-cell malignancy histologic subtypes,” Cheah said. “The study is ongoing and recruitment continues in disease specific cohorts and varying dose levels of TG-1701 and umbralisib to fine-tune the balance of toxicity vs efficacy, and phase 3 trials are planned.”
In an interview with OncLive®, Cheah, clinical professor, University of Western Australia (WA), consultant hematologist, lymphoma lead, fellowship program director, Sir Charles Gairdner Hospital, Pathwest Laboratory Medicine WA, Linear Clinical Research and Hollywood Private Hospital, founder, Blood Cancer Research WA, discussed TG-1701 as a more target-specific BTK inhibitor, the outcomes in response rates in the cohorts of the trial, and where future research is headed with this agent.
TG-1701 is a covalent and selective BTK inhibitor. BTK inhibitors have an established role in the management of patients with CLL, however, existing agents are limited by toxicity and eventual treatment failure. The rationale for exploring this agent in CLL [was that], firstly, TG-1701 is a relatively clean and specific BTK inhibitor with less off-target kinase inhibition. Theoretically, this should lead to a reduction in off-target toxicity. Secondly, TG-1701 in this study is combined with the PI3K delta and casein epsilon inhibitor umbralisib, along with ublituximab.
The design of the study was straightforward. There were 2 parallel arms and there was a phase 1 component in which TG-1701 was escalated from a 100 mg [dose] to a 400 mg [dose] in parallel the doses of TG-1701 were combined with ublituximab and umbralisib after the single agent dose levels were cleared. A range of patients with B-cell malignancies were included and, during dose escalation, we included patients with previously treated disease. There were disease specific cohorts for the monotherapy arm. In CLL, this included 20 patients treated at 200 mg and [and another 20 treated at] 300 mg.
[TG-1701] is certainly an effective agent unsurprisingly, given that we know that BTK inhibitors are active in CLL. The ORR was 83% in the monotherapy cohort and all 3 patients treated with triplet therapy achieved an OR. We also saw impressive responses in the disease-specific cohorts which included 40 patients, the 200 mg and 300 mg cohorts resulted in ORRs of 95% and 100%, respectively, with a medium follow-up of 19 and 12 months, [respectively]. So [the agent was] highly active both in monotherapy and in combination.
The single agent was very well tolerated in the patients with CLL who we reported on here. Most of the AEs were low-grade, with mild bruising or contusion [being] the most frequent, seen in around 20% of patients. Diarrhea was observed as well in around 20% of patients in the 200 mg cohort.
The safety profile was a little bit different when we added in ublituximab and umbralisib, and we started to see some of the AEs which you may expect from PI3 kinase inhibitors [with] nausea, we've only got 4 patients with CLL treated and the triplet combination that we're reporting on here, but in the broader experience, which we've previously presented at ASH, we did see a little bit more diarrhea and nausea when you add in [ublituximab and umbralisib].
When we're talking about covalent BTK inhibitors, people always ask about the incidence of AEs like atrial fibrillation, hypertension, and arthralgia, and those were all infrequent in the study. [There were only] around 50 patients with CLL that we are reporting on here, but only 1 instance of arthralgia and 1 instance of atrial fibrillation. [We had] 2 patients with hypertension, although this is AE seen with ongoing exposure to BTK inhibitors and we've only got around about 20 months of follow-up in the study.
The main implications are that we clearly have a another BTK inhibitor on our hands here, which is safe and effective in patients with CLL.