nemtabrutinib (MK-1026)

P1/2, N=190, Active, not recruiting, ArQule, Inc., a subsidiary of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ USA) | Trial completion date: Sep 2024 --> Sep 2025 | Trial primary completion date: Sep 2024 --> Sep 2025

P1, N=12, Active, not recruiting, Merck Sharp & Dohme LLC | Recruiting --> Active, not recruiting

P3, N=1200, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting

With the worldwide approval of the oral covalent Bruton tyrosine kinase (BTK) inhibitors ibrutinib and zanubrutinib for treating patients with Waldenström macroglobulinemia (WM), targeted agents have certainly taken center stage in the therapeutic landscape of WM. Novel targeted agents of interest include BCL2 antagonists (e.g., venetoclax and sonrotoclax) and non-covalent BTK inhibitors (e.g., pirtobrutinib and nemtabrutinib), among others. The therapeutic landscape of patients with WM will benefit from the robust participation of patients in clinical trials.

In January 2023, the reversible BTK inhibitor pirtobrutinib was approved by the FDA for the treatment of relapsed or refractory MCL...ResultsNemtabrutinib demonstrated comparable growth inhibitory activity to ibrutinib in MCL cell lines with IC 50 values at micromolar concentrations (IC 50 = 0...The result demonstrated that nemtabrutinib enhanced the effector function and anti-MCL activity of anti-CD19 CAR T cells. ConclusionNemtabrutinib demonstrated favorable anti-MCL efficacy in both in vitro and in vivo studies, the promising synergistic effects observed in combination with CAR T cells warrants further investigation in both preclinical and clinical settings.

P3, N=1200, Not yet recruiting, Merck Sharp & Dohme LLC

We compared the efficacy and safety profiles of narazaciclib with three health authority-approved CDKi (palbociclib, abemaciclib or ribociclib) in association with covalent (ibrutinib, acalabrutinib) and non-covalent (pirtobrutinib, ARQ-531) BTKi, across a panel of 10 MCL cell lines with distinct sensitivity to the first-in-class BTKi, ibrutinib. In conclusion, our findings demonstrate that narazaciclib is safe and effective as a single agent in preclinical models of MCL, including BTKi-resistant cases. Its combination with ibrutinib achieved a synergistic tumoricidal effect in vitro and in vivo, accelerating cell cycle blockade and reverting the metabolic reprogramming characterizing MCL refractoriness to BTKi therapy.

Secondary end points for part 2 include undetectable minimal residual disease in bone marrow at month 14 as assessed by central laboratory, ORR, and DOR per iwCLL 2018 criteria by BICR, OS, and safety. Exploratory end points include ORR including partial response with lymphocytosis, pharmacokinetics, and health-related quality of life.

While these agents have led to an improved safety profile in comparison to Ibrutinib (both acalabrutinib and zanubrutinib), and improved efficacy (zanubrutinib), intolerance occasionally occurs, and resistance remains a challenge...By removing BTK, as opposed to inhibiting it, these drugs could remain efficacious irrespective of BTK resistance mutations, however clinical data are limited at this time. This review summarizes the evolution and ongoing development of newer BTKi and BTK degraders in the management of CLL, with a focus of future directions in this field, including how emerging clinical data could inform therapeutic sequencing in CLL management.

The optimal sequencing of therapies in CLL requires consideration of individual patient factors and disease characteristics. Double-refractory disease continuous to pose a clinical challenge with a focus on participation in clinical trials whenever possible.

P3, N=720, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting

The 2 trials were phase 1/2 and investigated outcomes with noncovalent BTKi (nemtabrutinib and pirtobrutinib) as 3L + treatments (Table 1). There remains a high unmet medical need for patients with 3L + R/R CLL/SLL previously treated with BTKi and venetoclax, with poor outcomes associated with conventional systemic therapies. Novel therapies such as CAR T cell therapy and noncovalent BTKi may provide better efficacy outcomes; however, no CR was observed with noncovalent BTKi in the included trials.

Several ncBTKis have been studied preclinically and in clinical trials, including pirtobrutinib and nemtabrutinib...Novel therapeutic strategies are being investigated to address the treatment of patients following disease progression on ncBTKis. Such strategies include novel agents (BTK degraders, bispecific antibody therapy, CAR T-cell therapy, PKC-beta inhibitors) as well as combination approaches incorporating a ncBTKi (e.g., pirtobrutinib and venetoclax) that may help overcome this acquired resistance.

P3, N=720, Not yet recruiting, Merck Sharp & Dohme LLC

Please check if the affiliations are presented correctly.Targeted therapies with continuous BTK inhibitors (BTKi) or fixed duration venetoclax plus anti-CD20 monoclonal antibody therapy have established superiority over chemoimmunotherapy in relapsed CLL and have become the preferred standard of care treatment. The second-generation more selective BTK inhibitors (acalabrutinib and zanubrutinib) have shown improved safety profile compared to ibrutinib...The novel non-covalent BTK inhibitors such as pirtobrutinib (Loxo-305) and nemtabrutinib (ARQ 531) are showing promising activities for relapsed CLL refractory to prior covalent BTKi...Patients with relapsed CLL now have more options for the treatment of the disease. The choice of therapy is best individualized especially in the absence of direct comparisons of targeted therapies, and the coming years will bring more data on the best sequence of use of the therapeutic agents.

Moreover, compound 3e suppressed the cell growth more potently than the small molecule inhibitors ibrutinib and ARQ-531 in several cells. Furthermore, compound 3e with the rigid linker displayed a significantly improved metabolic stability profile with the T increased to more than 145 min. Overall, we discovered a highly potent and selective BTK PROTAC lead compound 3e, which could be further optimized as potential BTK degradation therapy for BTK-associated human cancers and diseases.

Observations regarding the importance of B-cell receptor signalling for the survival and proliferation of CLL cells led to the development of the first-in-class BTK inhibitor (BTKi), ibrutinib, for the treatment of CLL...As a result, more specific inhibitors of BTK were developed, such as acalabrutinib and zanubrutinib, which have demonstrated equivalent/enhanced efficacy and improved tolerability in large randomized clinical trials...As these drugs all bind covalently to BTK, an alternative approach was to develop noncovalent inhibitors of BTK, including pirtobrutinib and nemtabrutinib...A further step in the clinical development of BTK inhibition has been the introduction of BTK degraders, which remove BTK by ubiquitination and proteasomal degradation, in marked contrast to BTK inhibition. This article will review the evolution of BTK inhibition for CLL and offer future perspectives on the sequencing of an increasing number of different agents, and how this may be impacted on by mutations in BTK itself and other kinases.

Nemtabrutinib 65 mg continued to show promising and durable antitumor activity in pts with R/R CLL/SLL and a manageable safety profile in pts with hematologic malignancies. Clinical trial, Chronic lymphocytic leukemia

Approximately 300 pts will be enrolled and randomly assigned 1:1 to receive nemtabrutinib (65 mg orally once daily until progressive disease, unacceptable toxicity, or discontinuation) or intravenous infusion of the investigator’s choice of chemoimmunotherapy for 6 cycles lasting 28 days each (FCR: fludarabine 25 mg/m2 and cyclophosphamide 250 mg/m2 on days 1, 2, and 3 of each cycle, plus rituximab 375 mg/m2 initially, followed by 500 mg/m2 on day 1 of each cycle; or BR: bendamustine 70-90 mg/m2 on days 1 and 2 of each cycle plus rituximab 375 mg/m2 initially, followed by 500 mg/m2 on day 1 of each cycle). Enrollment is ongoing. Clinical trial information: NCT05624554.

P3, N=300, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting

P3, N=300, Not yet recruiting, Merck Sharp & Dohme LLC

Nemtabrutinib (MK-1026, formerly ARQ-531) is a noncovalent, potent inhibitor of both wild-type and ibrutinib-resistant C481S-mutated BTK. Nemtabrutinib 65 mg continued to show promising and durable antitumor activity with a manageable safety profile in a highly relapsed/refractory population who had prior therapy with novel agents.

Here,we generated and comprehensively characterized BTK and PLCG2 mutations conferring resistance to ibrutinib and five different non-covalent BTKi namely pirtobrutinib (LOXO-305), vecabrutinib (SNS-062), nemtabrutinib (ARQ-531), fenebrutinib (GDC-0853), and RN-486. We also found that cells harboring these novel BTK mutations showed differential sensitivity to the covalent vs. non-covalent BTKi. We further demonstrate the potential of venetoclax as follow up treatment upon resistance to non-covalent BTKi.

UBX-382 was effective on seven out of eight known BTK mutants in in vitro experiments and was highly effective in inhibiting tumor growth in murine xenograft models harboring WT or C481S mutant BTK-expressing TMD-8 cells over ibrutinib, ARQ-531, and MT-802. UBX-382 also provoked the cell-type-dependent and selective degradation of cereblon (CRBN) neo-substrates in various hematological cancer cells. These results suggest that UBX-382 treatment is a promising therapeutic strategy for B-cell-related blood cancers with improved efficacy and diverse applicability.

It has also been studied in combination with idelalisib or entospletinib in CLL and other B-cell lymphomas though without clear benefi t for the combinations over monotherapy16,17. Tirabrutinib is approved in Japan for WM, lymphoplasmacytic lymphoma (LPL), and RRPCNSL, and in South Korea for RR-PCNSL18. TG-1701 is a selective covalent BTKi that has been studied as a monotherapy and in combination with ublituximab and umbralisib with preliminary results suggesting both effi cacy and manageable safety19. Orelabrutinib, another selective covalent BTKi, has been studied as a monotherapy in CLL in addition to other B-cell malignancies, also with favorable safety and effi cacy20,21 and it is approved in China for rel/ref CLL and MCL22. Finally, DTRMWXHS-12 is a covalent BTKi that uniquely is being studied in combination with everolimus and pomalidomide (triplet referred to as DTRM-555), given that this combination was determined to lead to synthetic lethality in both in vivo and in vitro screening studies, with safety and activity seen in early studies23,24...This resistance mechanism appears shared among available irreversible BTK inhibitors including ibrutinib, acalabrutinib and zanubrutinib26...Three such inhibitors have completed phase 1 studies in CLL: vecabrutinib, nemtabrutinib, and pirtobrutinib with another currently in phase 1, luxeptinib...Subsequently, pirtobrutinib is being further studied as both a monotherapy and in combination with venetoclax-rituximab in phase 3 trials in both the frontline and relapsed/refractory settings in CLL in addition to MCL...These non-C481 BTK mutations conferred resistance across multiple non-covalent BTKi’s (in addition to pirtobrutinib, vecabrutinib, nemtabrutinib and fenebrutinib were tested) in addition to variable levels of resistance to covalent BTKi’s36...This is being accomplished by improved tolerability, allowing for patients to stay on drug for longer, and potentially improved effi cacy, including activity despite acquisition of C481 resistance mutations, in the case of the non-covalent inhibitors. The non-covalent inhibitors would help fi ll a major area of unmet need for CLL patients progressing on covalent BTK inhibitors who are not candidates for or progress following venetoclax therapy.

The subsequent key areas hold promise: Alternative Inhibitors of BTK Here, non-covalent BTK inhibitors, such as pirtobrutinib (LOXO- 305) and nemtabrutinib (ARQ-531), have shown effi cacy in CLL resistant to covalent BTK inhibitors...AZD5991 is a highly selective BH3-mimetic that demonstrates high potency in MCL1-dependent cell lines.9 Our group has shown that selective targeting Mcl-1 induced metabolic dysfunction and abrogated survival of lymphoid cells in vitro and in vivo.10 Other BH3- mimetics targeting Mcl-1 include AMG-176 and S63845.11,12 However, Mcl-1 targeting agents may be associated with toxicities, including against the hematopoietic stem and progenitor cells, potentially leading to cytopenias in the clinic.13 The therapeutic window for these agents needs to be defi ned. BH3-mimetics which target Bcl-xL, such as navitoclax, are not being developed in CLL due to concerns of thrombocytopenia.14 However, AZD4320, an alternative Bcl-2/xL inhibitor, is being studied in lymphoid malignancies as an intravenous formulation, with hope to mitigate its effect on platelets.15 Therapeutic Antibodies Targeting surface receptors and inducing both direct and immunemediated apoptosis has been a success story in CLL with use of anti-CD20 agents...Lanalumab (VAY-736), a humanized defucosylated engineered antibody directed against BAFF-R, antagonized pro-survival effects of BAFF in CLL cells.16 In a phase 1 study in combination with ibrutinib in 32 patients with CLL, CR was achieved in 38% of patients, and 42% demonstrated undetectable minimal residual disease (uMRD) in the blood/bone marrow, a promising result not expected with ibrutinib alone.17 Alternative targets for therapeutic antibodies include ROR1 (cirmtuzumab) and CD19 (tafasitamab)...A recent report of a phase 1/2 study of lisocabtagene maraleucel, an autologous CD19-directed CAR T-cell therapy (TRANSCEND CLL 004), confi rmed effi cacy in patients with relapsed/refractory CLL.18 In this study, patients had a median of 4 prior therapies, including ibrutinib and venetoclax...In a Phase 1/2 trial, HLA-mismatched CD19-targeting CAR NK cells induced CRs in patients with CLL after a single infusion and without CRS or neurotoxicity attributable to the cellular product.19 Finally, bi-specifi c antibodies have demonstrated impressive effi cacy in non-Hodgkin lymphoma and are also an off-the-shelf product which boasts high tolerability. Development of bi-specifi c antibodies in CLL is still in early stages, however epcoritamab (a subcutaneously administered CD3xCD20 Duobody) demonstrated responses in an ongoing Phase 1 study.20 In sum, targeted therapy replaced chemo-immunotherapy in treatment of CLL, and emerging small molecule and cell therapy approaches auger an expansion of the therapeutic armamentarium for CLL in the next decade.

P1/2, N=190, Active, not recruiting, ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.) | Trial completion date: Sep 2023 --> Sep 2024 | Trial primary completion date: Sep 2023 --> Sep 2024

Methods WM cells (MWCL-1 cell line, MYD88 L265P CXCR4 WT ) pretreated with mavorixafor and B-cell targeted therapies (BTK antagonists: ibrutinib, zanubrutinib, evobrutinib, pirtobrutinib, nemtabrutinib; or BCL2 inhibitor venetoclax) were co-cultured with established BMSCs (HS27a cells). Conclusion Our studies provide preliminary evidence for the potential use of mavorixafor in disrupting the interaction of WM cells with the BMSC-based microenvironment, enhancing the efficacy of B-cell targeted therapies in the treatment of WM and potentially other lymphomas. Further studies using additional WM cell lines and/or primary patient cells are warranted to support these findings.

Conclusion Nemtabrutinib has promising antitumor activity with a manageable safety profile in pts with CLL/SLL exposed to multiple lines of therapy, including in those who had progression of disease on prior covalent BTKi. Further evaluation of nemtabrutinib in B-cell malignancies is ongoing.

Standard treatment regimens combine the anti-CD20 antibody rituximab with alkylating agents (eg, bendamustine, cyclophosphamide), nucleoside analogs (eg, fludarabine, cladribine), or proteasome inhibitors (eg, bortezomib, carfilzomib, and ixazomib). Covalent BTK inhibitors (eg, ibrutinib, acalabrutinib, zanubrutinib) have shown to be safe and highly effective in patients with WM. Novel and promising agents in this disease include next-generation covalent BTK inhibitors (eg, tirabrutinib, orelabrutinib), non-covalent BTK inhibitors (eg, pirtobrutinib, ARQ531), BCL-2 antagonists (eg, venetoclax), and CXCR4-targeted agents (eg, mavorixafor, ulocuplumab), among others. Future studies will focus on developing fixed-duration combinations regimens with these novel agents aimed at increasing durable responses while minimizing toxicity and cost.

P1/2, N=190, Active, not recruiting, ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.) | Recruiting --> Active, not recruiting

WM cells (MWCL-1 cell line, MYD88L265PCXCR4WT) pretreated with mavorixafor and BTK inhibitors (ibrutinib, zanubrutinib, evobrutinib, LOXO-305, ARQ 531) were co-cultured with established BMSCs (HS27a cells). Mavorixafor addition enhanced the efficacy of not only ibrutinib but the other BTK inhibitors tested, supporting the greater potential of this combination therapeutic strategy in WM patients with or without CXCR4WHIM mutations. Further studies using additional WM cell lines and/or primary patient cells are warranted to support these findings.

P1/2, N=190, Recruiting, ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.) | Trial completion date: Sep 2022 --> Sep 2023 | Trial primary completion date: Sep 2022 --> Sep 2023

These agents (pirtobrutinib, ARQ-531, SNS-062) reversibly bind BTK and overcome acquired resistance to covalent BTKis (cBTKi). In this first study to report outcomes of CLL and RT pts who have discontinued a ncBTKi, several important themes have emerged. For venetoclax naive CLL pts, venetoclax appears to be a promising strategy following ncBTKi discontinuation supporting the ability to stay within the BTKi class prior to switching to venetoclax. Cellular therapies including CAR T-cell therapy and allo SCT had a high ORR and warrant further investigation (80% of pts had prior cBTKi, ncBTKi and venetoclax and 100% had prior cBTKi and ncBTKi).

Conclusion : MK-1026 has promising antitumor activity with a manageable safety profile in participants with CLL/SLL exposed to multiple lines of therapy, including in those who had progression of disease on prior covalent BTKi. Further evaluation of MK-1026 in B-cell malignancies is ongoing.

For patients with MYD88 and CXCR4 mutations or without MYD88 or CXCR4 mutations, chemoimmunotherapy or proteasome inhibitor-based regimens are favored, but efficacy data with ibrutinib in combination with rituximab and with novel covalent BTK inhibitors are emerging. Participation in clinical trials is positively encouraged in WM patients in frontline and relapsed settings. Agents of interest include the BCL2 antagonist venetoclax, the CXCR4 inhibitor mavorixafor, and the non-covalent BTK inhibitors pirtobrutinib and ARQ-531.

P1/2, N=190, Recruiting, ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.) | N=146 --> 190