Preclinical Models Show Benefit for Novel BTK Inhibitor in MCL, NHL

Activity seen with novel irreversible Bruton’s tyrosine kinase (BTK) inhibitor TG-1701 in mantle cell lymphoma (MCL) cells as monotherapy and synergistic activity in combination provides evidence of the scientific rationale for the combination with ublituximab and umbralisib in non-Hodgkin lymphoma, according to findings presented in a poster during the American Association for Cancer Research (AACR) Virtual Annual Meeting II.¹

TG-1701 is an orally available and covalently bound BTK inhibitor. The agent has been found to have similar in vitro antitumor activity to the first-in-class BTK inhibitor ibrutinib (Imbruvica), but has demonstrated superior selectivity in whole kinome screening.²

In patients with relapsed or refractory MCL, the development of a BTK C481S mutation or overactivation of the NF-kB pathway can lead to resistance to BTK inhibitors. When tested in REC-1 BTK C481S–mutant MCL cell lines, only TG-1701, in comparison with other reversible and irreversible BTK inhibitors, showed some inhibitory activity.

TG-1701 also showed similar cytotoxic activity to the other inhibitors as well in ibrutinib-sensitive MCL cells. In tumor-bearing mice with UPN1-resistant (ibrutinib-resistant) cells, modest antitumor activity was observed in vitro for ibrutinib and TG-1701, although greater activity was seen with ibrutinib.

“When compared to ibrutinib, TG-1701 used at high doses retained notable antitumor activity in MCL cells with BTK C481S mutation, while it did not show superior activity than the first-in-class BTK [inhibitor] in in vitro and in vivo models of ibrutinib-resistant MCL with constitutive activation of the non-canonical NF-kB pathway,” the study authors, led by Marcelo L. Ribeiro, MD, a postdoctoral investigator at the Josep Carreras Leukemia Research Institute in Badalona, Spain, wrote in their poster.

Although ibrutinib blocked antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cell phagocytosis (ADCP) derived from ublituximab in a multicellular co-culture system, TG-1701 did not.

These in vitroresults were confirmed in vivoin 2 MCL xenograft models showing no antagonistic effects when TG-1701 was combined with ublituximab and umbralisib in a REC-1 wild-type model (ibrutinib sensitive). Further, the triplet regimen was found to be more potent than the single agents used individually. In the UPN-1 resistant model, TG-1701 had modest single-agent activity, which was improved when used in combination treatment with umbralisib and ublituximab.

The study authors suggested that combination BTK and PI3K inhibition improved efficacy and that resistance could be overcome with the combination strategy.

“We first showed that TG-1701, contrarily to ibrutinib, does not block neither ublituximab-driven ADCC nor ADCP in vitro. In vivo xenograft studies suggested that TG-1701 synergized with ublituximab and umbralisib. Part of the mechanism is related to the pro-immune interleukin signature and infiltration of [natural killer] cells in the tumor,” Ribeiro et al wrote.

The investigators noted that these findings support the scientific rationale for the ongoing study of TG-1701 in a phase 1 trial alone or in combination with ublituximab, a CD20-directed monoclonal antibody, and umbralisib, a PI3Kδ inhibitor, in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NCT03671590).

In the dose-escalation phase of the trial, TG-1701 is being investigated in a monotherapy cohort as well as a parallel combination regimen cohort, followed by disease-specific cohorts studying the use of the BTK inhibitor in patients with CLL, Waldenström macroglobulinemia, and MCL. The trial is evaluating the maximum tolerated dose of TGR-1701, both as monotherapy and in combination, as the primary end point and overall response rate (ORR) as the secondary end point.

Patients with an ECOG performance status of 0 to 2 and adequate organ function are eligible for the trial. Those who have received prior BTK inhibition, have had recent surgery or anticancer therapy, or have known hepatitis B or C virus or HIV infection are excluded from the trial. For the disease-specific cohorts, previously untreated patients were able to participate If they were ineligible for standard frontline chemoimmunotherapy due to comorbidities and risk factors.

Ribeiro et al noted that preliminary data from the trial have shown strong activity for the triplet regimen.

From preliminary reports of the ongoing trial recently reported at the virtual 25th Congress of the European Hematology Association, reductions in tumor burden and responses have been seen across dose levels for both the monotherapy and combination treatments.³

In patients being treated with the combination regimen in the dose-escalation cohorts, early complete responses have already been seen, including 3 confirmed complete responses in 2 patients with follicular lymphoma and 1 with marginal zone lymphoma.

In the disease-specific expansion cohorts, the ORR was 86% in patients with Waldenström macroglobulinemia (n = 7), 33% in patients with MCL (n = 6), and 92% in patients with CLL (n = 12).

The maximum tolerated dose was not achieved for the monotherapy groups and dose escalation continues.

Overall the combination regimen was found to be well tolerated; the most common treatment-related adverse events were aspartate and alanine aminotransferase increases and the only grade 4 events were alanine aminotransferase increase and neutropenia in 1 patient each. No grade 4 events have been reported with TG-1701 monotherapy.

_References:

_{1. Ribeiro ML, Reyes-Garau D, Vinyoles M, et al. TG-1701, a novel irreversible Bruton’s kinase (BTK) inhibitor, cooperates with ublituximab-driven ADCC and ADCP in in vitro and in vivo models of ibrutinib-resistant mantle cell lymphoma. Presented at: 2020 American Association for Cancer Research Virtual Annual Meeting II; June 22-24, 2020. Abstract 2205.}

_{2. Normant E, Gorelik L, Shmeis R, et al. TG-1701 a novel, orally available, and covalently-bound BTK inhibitor. Presented at: 2018 European Hematology Association Annual Congress; June 14-17, 2018; Stockholm, Sweden. Accessed June 23, 2020. https://library.ehaweb.org/eha/2018/stockholm/215080/emmanuel.normant.phd.tg-1701.a.novel.orally.available.and.covalently-bound.btk.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2Asearch%3Dtg-1701.}

_{3. Cheah C, Wickham N, Yannakou C, et al. Safety and activity of the once daily selective bruton tyrosine kinase (BTK) inhibitor TG-1701 in patients with chronic lymphocytic leukemia (CLL) and lymphoma. Presented at: 2020 European Hematology Association Virtual Congress; June 11-21, 2020. Accessed June 23, 2020. https://library.ehaweb.org/eha/2020/eha25th/294623?evname=_T2drXJXBb8UnsrwwBqcng&evsign=x2nvJuCXhuswKmcRjHCMgc1cTOwlTbgCPmksUaL2jvM.}