BTK C481

The first-in-class covalent BTK inhibitor, Ibrutinib, binds to the C481 amino acid residue to block the BTK enzyme and prevent the downstream signaling...To bypass the C481S mutation, non-covalent BTKi, such as Pirtobrutinib, were developed and are active against both wild-type and the C481S mutation...In addition, we discuss the new emerging class of BTK degraders, which utilize the evolution of proteolysis-targeting chimeras (PROTACs) to degrade the BTK protein and constitute an important avenue of overcoming resistance. The moving landscape of resistance to BTKi and the development of new therapeutic strategies highlight the ongoing advances being made towards the pursuit of a cure for B-cell lymphoid malignancies.

One acalabrutinib-treated patient and 4 ibrutinib-treated patients had emergent BTK/PLCG2 co-mutations. While common BTK C481 mutations were observed with both treatments, patterns of mutation and co-mutation frequency, mutation VAF, and uncommon BTK variants varied with acalabrutinib (T474I and E41V) and ibrutinib (L528W, A428D) in this patient population.

The findings of the RAINBOW trial (NCT046152), comparing the dexamethasone, rituximab, and cyclophosphamide (DRC) regimen to the first-generation, ibrutinib are awaited, but more studies are needed to draw definitive conclusions on the comparative efficacy of chemoimmunotherapy and BTKi. Complete response is elusive with BTKi, and combination regimens to improve upon the efficacy and limit the treatment duration are also under evaluation in WM.

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

This is the first study to describe the genomic landscape of patients with B-cell malignancies who were intolerant to ibrutinib and/or acalabrutinib. Here we show that the gene mutational profile of these patients at baseline or at/after disease progression is comparable with patients with relapse/refractory disease who tolerate ibrutinib and, consistent with other studies, patients with mutations in TP53, SF3B1 or ATM genes had less favorable prognosis on BTKi. Further, intolerant patients who progressed on zanubrutinib acquired new BTK mutations and/or had an increase in the frequency of BTK mutations.

Pts received 1 or more cBTKi: ibrutinib (n=44, 90%), acalabrutinib (n=10, 20%) or zanubrutinib (n=1, 2%). Whether similar resistance patterns would manifest if pirtobrutinib was utilized prior to cBTKi treatment remains uncertain. Figure 1.

Pirtobrutinib continues to demonstrate durable efficacy in pre-treated R/R CLL/SLL pts treated with a prior covalent BTKi, regardless of prior therapy, reason for prior BTKi discontinuation, age, high-risk TP53 mutations, C481 mutational status, and/or del(17p). It was well tolerated with low rates of discontinuation due to drug-related toxicity.

P1, N=160, Active, not recruiting, Nurix Therapeutics, Inc. | Recruiting --> Active, not recruiting

We performed whole exome sequencing on matched tumor and normal samples from 19 CLL patients treated with BTK inhibitors (Ibrutinib, Ibr, 42% (8/19); Acalabrutinib, Acala, 21% (4/19) and Pirtobrutinib, Pirto, 37% (7/19))...The ibr cohort had no prior BTKi therapy whereas 1 patient in the acala cohort had received spebrutinib, another cBTKi...The approach of combining WES data with growth pattern modeling can help unravel the complexities of tumor evolution and drug resistance for the different classes of BTKi. Data on comparative clone growth rates will be presented at the meeting.

In this real-world cross-sectional study, BTK C481 mutations were observed in 21% of BTKi-experienced pts with CLL/SLL, all of whom had a cumulative exposure to BTKis of >36 mo. Because two-thirds of BTKi-experienced pts had <36 mo of BTKi exposure, the prevalence of BTK C481 mutations may be higher in populations with longer BTKi exposure. Further analyses of the natural history of BTK C481 mutations will help identify patients who are at risk of covalent BTKi resistance.

Ibrutinib, Zanubrutinib, Orelabrutinib were administered in 55.3%,18.3% and 17.9% of patients respectively, in addition to 6 patients with Acalabrutinib and one with Loxo-305, among them 47.7% (125/262) received BTKi as first line treatment...Venetoclax-based regimen might be an effective salvage therapy which could showed a benefit trend in PFS as compared to other post BTKi therapy (10.1 months vs 3.1 months, p= 0.1818)...Acquired BTK/PLCG2 mutations remained to be key drivers of BTKis resistance and BTKC481S mutation was the dominant mutation, while BTKT474 mutation was only detected in Orelabrutinib-resistant patients. The prognosis was rather poor for relapsed patients especially for RTs, treatment strategy after disease progression remains to be optimized.

Background: Covalent Bruton's tyrosine kinase (BTK) inhibitors such as ibrutinib are approved for treating patients with B-cell malignancies, but their long-term efficacy is limited by toxicity related to off-target kinase inhibition and acquired resistance due to BTK C481 mutation...Changes in the level of biomarkers such as CCL3 and CCL4 chemokines and B-cell receptor pathway signaling will be evaluated prior to, during therapy, and at time of disease progression. The RP2D will be determined based on all the data generated in the study.

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.

In this phase 2 study, the addition of VEN to IBR decreased the BTK C481S mutation below the detection limit in 59% of pts after 12 cycles of treatment. This combination allowed 32% of pts to discontinue treatment in deep remission. The median PFS (40.7 months) supports further investigation of this approach.

Understanding of acquired resistance to cBTKi therapy has largely come from data on patients (pts) treated with the first-in-class cBTKi ibrutinib...In contrast, much less is known about genetic mechanisms of drug resistance in pts treated with next generation cBTKi acalabrutinib and zanubrutinib... After a median follow-up of 6.5 years (IQR 2.9-6.3), 23/48 (48%) pts developed PD (20 CLL, 3 RT). PD occurred in 17/32 (53%) R/R pts and 6/16 (38%) TN pts. Median progression-free survival was reached at 6.0 years.

To gain further insight into the genetic mechanisms of cBTKi resistance in a randomized population of pts with CLL, we performed next-generation sequencing (NGS) on samples from pts who had progression on zanubrutinib (zanu) or ibrutinib (ibr) in the phase 3 ALPINE study (NCT03734016; Brown et al. Of the 52 pts, most (82.6%) did not have acquired BTK or PLCG2 mutations. Among the zanu pts, 3/24 (12.5%) developed non-C481 BTK mutations. This rate was lower than that reported by Woyach et al (ICML 2023); shorter follow-up and fewer prior therapies in the ALPINE study may explain this discrepancy.

In primary CLL samples, AS-1763, pirtobrutinib or ibrutinib induced a modest apoptosis...Evaluation of drug interaction models utilizing Compusyn and Synergy Finder applications predominantly indicated additive effects between AS-1763 with BCL-2 inhibitor, venetoclax as well as p53 activator APR-246... AS-1763 is a selective ncBTKi that inhibits both wild-type and mutant BTKs listed in Table 1. In CLL cells, AS-1763 was effective in inhibiting BCR pathway signaling and sensitized cells to other agents such as venetoclax. Based on these encouraging data we have initiated a clinical trial to test AS-1763 in patients with CLL and other B cell malignancies who have failed or are intolerant to at least two prior lines of systemic therapy, including cBTKi (NCT05602363 Clinical Trials.gov).

We uncovered known and novel BTK resistance mutations and demonstrated BTK scaffolding activity independent of HCK, highlighting the need for other strategies to disrupt scaffolding-mediated BCR signaling. Beyond BTK mutations, our CRISPR KO screens illustrate a map of genetic modifiers of BTKi response and point to several potential resistance biomarkers for both acala and pirto. A better understanding of resistance mechanisms in the presence and absence of BTK mutations will help augment the use of BTKi treatments in patients.

BTK Cysteine 481 substitution is known to contribute to cBTKi acquired resistance to ibrutinib, acalabrutinib, and zanubrutinib. Despite this cohort representing the first relapsing CLL patients from BRUIN and presenting with frequent baseline BTK mutations, response to pirtobrutinib was high, with an ORR of 83%, and substantial clearance of BTK C481 clones. At progression, the majority of pts (56%) either acquired non-BTK mutations or did not acquire any resistance mutations in this targeted panel, suggesting alternative resistance mechanisms. A smaller group of patients (44%) displayed emergence of non-C481 clones, particularly gatekeeper T474 and kinase-impaired L528W mutations.

Covalent BTKi (cBTKi) including ibrutinib, acalabrutinib, and zanubrutinib, share a common resistance mechanism, acquisition of a C481 mutation in BTK. LP-168 has been well tolerated in this study, with no DLTs identified at doses up to 300 mg daily. Preliminary efficacy was observed in high risk CLL pts, including those treated with one or more BTKi. Considering safety, efficacy, and PK/PD, dose expansion will occur at 200 mg and 300 mg daily following the FDA Project Optimus guidelines to determine the recommended phase 2 dose.

In the frontline setting, the ELEVATE-TN study compared acalabrutinib, either alone or in combination with obinutuzumab, to chlorambucil plus obinutuzumab...Frontline phase 3 trial data comes from the SEQUOIA study, where zanubrutinib was compared with bendamustine plus rituximab...The combination of ibrutinib plus venetoclax has received frontline approval from the EMA. Ongoing studies may offer future options of time-limited therapy involving covalent BTK, but current approaches with indefinite covalent BTK treatment offer a safe and effective strategy to treat CLL patients at this time.

P1, N=160, Recruiting, Nurix Therapeutics, Inc. | Trial completion date: Nov 2023 --> Dec 2025 | Trial primary completion date: Oct 2023 --> Dec 2024

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

The C481S and C481R mutations eliminated the anti-proliferative effects of covalent inhibitors ibrutinib, acalabrutinib, and zanubrutinib, whereas the V416L, T474I, and L528W mutations had variable effects on the covalent inhibitors. By contrast, the non-covalent inhibitors pirtobrutinib, vecabrutinib, and fenebruitnib maintained activity against C481S but displayed partially reduced potency against the C481R mutation and dramatically reduced potency against the V416L, T474I, and L528W mutations...These degrader molecules may also have utility in earlier lines of therapy due to their ability to suppress scaffold-mediated BTK signaling. Phase 1a/b trials of NX-5948 and NX-2127 in patients with relapsed or refractory B-cell malignancies are ongoing (NX-5948: NCT05131022; NX-2127: NCT04830137).

main study Substudy patients treated with VenR (n = 194) patients treated with BR (n = 195) patients retreated with VenR (n = 25) Baseline characteristics mean age, years (SD) 63.9 (10.5) 64.4 (9.6) 65.8 (8.3) Number of prior cancer therapy, n (%) 1 111 (57.2) 117 (60.0) 0 (0.0) 2 58 (29.9) 43 (22.1) 20 (80.0) ≥3 25 (12.9) 35 (17.9) 5 (20.0) del(17p) and/or TP53 mutation (aCGh), n (%) mutated 53 (27.3) 55 (28.2) 14 (56.0) unmutated 104 (53.6) 98 (50.3) 9 (36.0) unknown 37 (19.1) 42 (21.5) 2 (8.0) Genomic complexity, n (%) n = 48 n = 46 n = 20 3–4 34 (70.8) 29 (63.0) 3 (15.0) ≥5 14 (29.2) 17 (37.0) 8 (40.0) iGhV, n (%) n = 180 n = 180 n = 23 mutated 53 (29.4) 51 (28.3) 2 (8.7) unmutated 123 (68.3) 123 (68.3) 21 (91.3) unknown 4 (2.2) 6 (3.3) 0 (0.0) efficacy results median follow-up, months 85.7 85.7 33.4 Best oRR, % 93.3 67.7 72.0 umRD at eoCT of main study, n (%) 121 (62.4) 26 (13.3) 16 (64.0) umRD at eoCT of substudy, n (%) N/a N/a 8 (32.0) umRD at eoT of main study, n (%) 83 (70.3)* N/a 14 (56.0) umRD at eoT of substudy, n (%) N/a N/a 0 (0.0) median pFS, months (95% Ci) 54.7 17.0 23.3 (52.3, 59.9) (15.5, 21.7) (15.6, 24.3) 3-year oS rate, % (95% Ci) 88.4 78.9 53.1 (83.8, 93.0) (72.8, 84.9) (25.1, 81.0) *patients who completed 2 years of Ven without pD (n = 118) aCGh: array comparative genomic hybridization; BR: bendamustine- rituximab; Ci: confidence interval; del(17p): deletion in chromosome 17p; eoCT: end of combination treatment; eoT: end of treatment; iGhV immu- noglobulin heavy chain gene; oRR: overall response rate; oS: overall sur- vival; pD: progressive disease; pFS: progression free survival; SD: standard deviation; TP53: tumor protein p53; umRD: undetectable minimal residual disease; Ven(R): venetoclax-(rituximab) cBTKi pre-treated CLL pts treated with pirtobrutinib monotherapy in the phase 1/2 BRUIN trial (NCT03740529) who subsequently developed disease progression (PD) were included in this analysis...Pts received one or more of the following cBTKi: ibrutinib (n = 44, 90%), acalabrutinib (n = 10, 20%), or zanubrutinib (n = 1, 2%)... Pts who progressed on pirtobrutinib showed clearance of BTK C481 clones and the emergence or outgrowth of non-C481 clones, particularly gatekeeper T474 and kinase-impaired L528W mutations, as well as other VUS. Many acquired BTK mutations were shown to pre-exist at baseline at low VAF, reflecting emergence on prior cBTKi. Importantly, these baseline kinase domain BTK mutations did not preclude pirtobrutinib efficacy.

Novel, non-C481 BTK mutations have been described, including BTK L528W, which has been reported in patients treated with ibrutinib, zanubrutinib, and pirtobrutinib (Maddocks, JAMA Oncol. This is the largest dataset characterizing the incidence and patterns of BTK and PLCG2 mutations in patients with CLL treated with ibrutinib. BTK C481 mutations are the most frequently occurring mutations. PLCG2 mutations occur across the gene at a low incidence per locus (<5%).

Patients previously treated with B-cell receptor pathway inhibitors (BCRi), such as ibrutinib and idelalisib, have lower response rates to Ven; those who are refractory to prior BCRi have a significantly higher risk of relapse than those who are not refractory [1]. With extended follow-up, Ven demonstrated durable responses in patients with CLL who progressed on BCRi, irrespective of BTK mutation status. BCL-2 resistance mutations were detected in 19.1% (13/68) of patients, generally at low VAF. These acquired mutations were detectable in patients with prolonged Ven exposure, supporting further exploration of strategies focused on time-limited Ven exposure.

Background and significance: The current standard of care for first-line therapy of chronic lymphocytic leukemia (CLL) is continuous therapy with a covalent Bruton’s tyrosine kinase inhibitor (BTKi), with or without an anti-CD20 monoclonal antibody, or fixed-duration therapy with venetoclax plus obinutuzumab. This study is registered with ClinicalTrial.gov (NCT05677919). The trial is currently open to accrual at Mayo Clinic in Rochester, MN, and we anticipate to complete accrual by early 2024.

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

The third-generation non-covalent BTK inhibitor Pirtobrutinib has obtained approval for marketing in the United States, thereby circumventing drug resistance caused by C481 mutation...This article systematically summarizes recently discovered covalent and non-covalent BTK inhibitors and classifies them according to their structures. This article also provides a detailed discussion of binding modes, structural features, pharmacological activities, advantages and limitations of typical compounds within each structure type, providing valuable references and insights for developing safer, more effective and more targeted BTK inhibitors in future studies.

If prior CIT, I no longer recommend re-treatment with CIT, regardless of duration of previous response, given the consistent evidence for superiority of targeted agents over CIT (discussed below), unless low intensity therapy such as oral chlorambucil or cyclophosphamide is used for purely palliative symptom control...The resulting score was clustered as low (0–1), intermediate (2–3) or high (4) and stratified probability of 24-month overall survival as 88%, 64%, and 44%, respectively in an external validation cohort.41 Among the choices of targeted agent drug classes, my least preferred are the PI3K inhibitors such as Idelalisib (±rituximab) as the efficacy is inferior and the toxicity profile,35, 42 especially infection risk and solid organ autoimmune complications (colitis/hepatitis/pneumonitis) are less favorable than the alternatives, as directly established in comparison against acalabrutinib in the ASCEND study.36 The major data from the most impactful randomized studies in R/R CLL are summarized in Table 2...The ELEVATE R/R study38 with acalabrutinib showed non-inferior PFS to ibrutinib (consistent in all biological subsets) but a clearly superior toxicity profile with lower rates of atrial arrhythmias, hypertension and cumulatively a lower cumulative toxicity burden.48 The ALPINE study compared zanubrutinib to ibrutinib and also displayed superior tolerability, fewer discontinuations and a lower rate of arrhythmias, but no difference in rates of hypertension (all grade; 21.9 vs. 19.8% and grade 3; 14.8 vs. 11.1%).39 A potential major advantage for zanubrutinib is that it also achieved statistically significantly superior PFS over ibrutinib (24 month rates of 79.5% vs. 67.3%; HR 0.65, p = 0.0024), but the PFS difference may in part be attributable to a relative “under performance” of ibrutinib in ALPINE relative to RESONATE and ELEVATE R/R.49 I personally prefer acalabrutinib or zanubrutinib over ibrtuinib noting that both have the slight inconvenience of twice daily dosing...2 TIME-LIMITED VENETOCLAX The early clinical evaluation and first regulatory approvals of venetoclax used a continuous single-agent treatment schedule,52 the largest clinical experience in the del(17p) subset used that approach,53, 54 and the most robust evaluation of prognostic factors for outcomes with venetoclax therapy was performed in a cohort predominantly so treated,55 identifying the following factors predictive of less durable disease control: bulky adenopathy (≥5 cm), disease refractoriness to either fludarabine or prior B-cell receptor inhibitors, TP53 aberrancy, and NOTCH1 mutation.55 While less durable than in BTKi-naïve disease, if BTKi refractory or intolerant, venetoclax is the preferred treatment with 70% response rate and median PFS of ∼24 months23. Combination therapy with an anti-CD20 antibody achieves a higher rate of uMRD (above 60% in R/R cohorts),56 enabling time-limited therapy for deep responders without evidence of impairing PFS relative to continuous therapy,57 and maintaining the opportunity for re-treatment with prolongation of duration of venetoclax benefit.57, 58 That approach with a fixed 24-month treatment duration was used in the MURANO study and compared to Bendamustine-rituximab.24, 30, 59, 60 The logistic complexities and resource burdens of the venetoclax dose-ramp up and tumor-lysis syndrome mitigation and monitoring, inconvenience of the parenteral anti-CD20 antibody administration are draw-backs from this approach, perhaps counterbalanced by the excellent tolerance and low adverse event rate beyond the first 6 months combination treatment period, and the attraction of time-limited therapy...4 RICHTER SYNDROME The development of Richter transformation as a clonally related evolution of underlying CLL is a profoundly adverse event and is usually fatal (median survival ∼6 months),1 unless able to receive a cellular immunotherapy (allogeneic transplant or CAR-T).65 The minority of patients where the DLBCL is clonally unrelated to their CLL, definitively recognized by comparative mutational analyses, but correlated with low expression of PD-1 by immunohistochemistry,66 is important to recognize, as their prognosis is far more favorable and may approach that of de novo DLBCL. Standard anthracycline- or ara-C/platinum-based regimens commonly used for DLBCL achieve response rates of 40%–65% but median PFS is consistently substantially less than 12 months (reviewed in ref #1) and clinical trials are therefore strongly preferred but have not shown major promise to date except for the addition of Venetoclax to DA-EPOCH-R,67 noting profound myelosuppression commonly encountered, and perhaps best utilized where subsequent allogeneic transplant can restore hematopoiesis,64 or inexplicably pirtobrutinib,68 despite low activity of other BTKi.

1, 2 Treatment of CLL cells with entospletinib, but not other BCR-signaling inhibitors, led to a disruption of BAFF-BCR cross-talk and downmodulation of MCL1 mRNA and protein, thus implicating SYK in transduction of multiple pro-survival signals emanating from the tumor microenvironment.1 Entospletinib has shown promising clinical activity in CLL, alone or in combination with obinutuzumab, including in patients with high-risk disease such as TP53 aberrant.3, 4 The drug is very well tolerated, however its development in CLL has been halted. Meanwhile, we have shown that luxeptinib, a dual SYK/BTK kinase inhibitor, has activity in BTK inhibitor-resistant lymphoid models in vitro.5 Luxeptinib is now being investigated in lcinical trials in hematologic malignancies...The early results of MS-553, a selective PKC-β inhibitor, indicates that this agent is tolerable and effective both as single agent and in combination with venetoclax.8 Proteolysis-targeting chimeras (PROTACs) are a new class of small molecules with two covalently-linked ligands recruiting target protein and E3 ubiquitin ligase together to trigger and enable proteasomal degradation of the target protein.9 “BTK degraders”, such as NRX- 2127 (Nurix Therapeutics) and BGB-16673 (Beigene), have entered clinical trials in patients with lymphoid malignancies...Additionally, NX-2127 has shown preclinical activity similar to immunomodulatory drugs (IMiDs) by catalyzing the ubiquitination of Ikaros (IKZF1) and Aiolos (IKZF3), resulting in increased T-cell activation.10 Early results of an ongoing clinical trial of NX-2127 demonstrate an ORR of 33% in heavily pre-treated patients with CLL, and overall good tolerability 11...The preclinical activity of AZD5991 has shown that selective targeting of MCL1 induced metabolic dysfunction and abrogated survival of diffuse large B cell lymphoma and ibrutinib-resistant mantle cell lymphoma cell lines in vivo and in vitro.13 Other BH3-mimetics targeting MCL1 include AMG176 and S63845.14-16 In an experimental design testing the effects of AMG-176 on CLL and normal hematopoietic cell death it was demonstrated that AMG-176 is an active agent in inducing CLL cell death while sparing normal blood cells...Anti-CD20 monoclonal antibodies – rituximab, obinutuzumab and ofatumumab – have significantly improved the survival outcomes. The B cell activating factor receptor (BAFF-R) is one of the main pro-survival receptors in B cells.18 In a preclinical study, ianalumab (VAY-736), a humanized defucosylated engineered antibody directed against BAFF-R, antagonized pro-survival effects of BAFF in CLL cells and showed promising activity both as a single agent and in combination with ibrutinib.19 A phase 1 study of dose escalation and dose expansion investigated the combination of ianalumab with ibrutinib in 32 patients with CLL with median one prior line of therapy (range, 0-4)...This study showed promising results not expected with ibrutinib alone.20 Tafasitamab – a Fc-enhanced, humanized, monoclonal antibody to CD19 – in combination with idelalisib or venetoclax in 24 patients has been associated with an ORR of 77% and 91%, respectively...In a phase 1 study involving 26 patients with R/R CLL, cirmtuzumab administered at four biweekly infusions was shown to have a long plasma half-life and did not have dose-limiting toxicity, potentially providing another treatment opportunity for patients with CLL.22 Immune Cell Enabling Therapies...A recent report of a phase 1/2 study of lisocabtagene maraleucel, an autologous CD19-directed CAR T-cell therapy (TRANSCEND CLL 004), confirmed efficacy in patients with R/R CLL.23 In this study, 23 patients with median 4 prior lines of therapy (range 2-11) were enrolled, 10 of whom were considered double exposed/refractory...In total, 65% of patients required administration of tocilizumab and/or corticosteroids.23 In addition to the ongoing phase 2 portion of this study, efforts now focus on innovative CAR T-cell designs as well as combination strategies...A phase 1b/2 ongoing trial is currently examining the safety and tolerability of the product in patients with R/R CLL. The early results suggest that epcoritamab administered subcutaneously is well tolerated in a heavily pretreated patient population with multiple high-risk features and shows clinical activity.25 Furthermore, an ongoing study is demonstrating preliminary efficacy of epcoritamab in patients with Richters transformation, a notoriously difficult-to-treat complication of CLL.26

There were 29 men, 16 women, median age 65.5 years (range 47-86), 43 patients received ibrutinib and 2 acalabrutinib. Our study shows that BTK and/or PLCG2 mutations were found in 64.4% of patients with progression of CLL during BTKi therapy, and in 35.6% of patients the cause of resistance has not yet been identified. Most mutations in our sample were detected in the C481 codon of BTK gene after 2 years of treatment, suggesting that regular screening with simple PCR tests starting from the second year of treatment is a reasonable approach. NGS may expand data in cases with undetectable mutations.

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

Inhibition of BTK by covalent BTK inhibitors (BTKi), such as ibrutinib, acalabrutinib, and zanubrutinib, have revolutionized the management of CLL and other B cell malignancies. BGB-16673 is a potent inhibitor against tumors expressing wildtype and clinical-relevant BTK mutations. In addition, it is superior to ibrutinib and LOXO-305 equivalent for more durable anti-tumor activities and less metastasis. Absolute lymphocyte count, Tumor model, Lymphoma, Mouse model

Pts received one or more of the following cBTKi: ibrutinib (n=44, 90%), acalabrutinib (n=10, 20%), or zanubrutinib (n=1, 2%). Pts who progressed on pirtobrutinib showed clearance of BTK C481 clones and the emergence or outgrowth of non-C481 clones, particularly gatekeeper T474 and kinase-impaired L528W mutations, as well as other VUS. Many acquired BTK mutations were shown to pre-exist at baseline at low VAF, reflecting emergence on prior cBTKi. Importantly, these baseline kinase domain BTK mutations did not preclude pirtobrutinib efficacy.

Pirtobrutinib continues to demonstrate promising, durable efficacy in heavily pretreated R/R CLL/SLL patients who have been treated with a prior covalent BTKi, regardless of prior therapy, reason for prior BTKi discontinuation, age, high-risk TP53 mutations, C481 mutational status, and/or del(17p). Pirtobrutinib was well-tolerated with low rates of discontinuation due to drug-related toxicity.

In pre-clinical safety studies, NX-2127 demonstrates an acceptable safety profile. NX-2127 is currently in phase 1 clinical trials (NCT04830137) for hematological malignancies.