Potential of BGB-11417, a BCL2 inhibitor, in hematological malignancies

KEYWORDS:

• Sonrotoclax
• BGB-11417
• lymphoid malignancies
• myeloid malignancies
• BCL2 inhibitors

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Correction

1. Introduction

Evading apoptosis is a distinctive feature of neoplastic cells. B-cell lymphoma-2 (BCL2), an anti-apoptotic protein, is commonly overexpressed in many neoplasms, including lymphomas and leukemias. This overexpression contributes to the oncogenetic process and is responsible for the development of drug resistance. Venetoclax is a pioneering BCL2 inhibitor employed in the treatment of many hematologic neoplasms. It is currently approved for the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) as well as acute myeloid leukemia (AML) [1,2].

Regrettably, with prolonged treatment, cancer cells can develop many mechanisms of resistance to venetoclax [3].

Sonrotoclax (BGB-11417) is a remarkably potent and selective BCL2 inhibitor, capable of inhibiting both wild-type and G101V-mutated BCL2 in ‘in vitro’ studies. Moreover, sonrotoclax inhibits BCL2 protein activity at significantly lower concentrations compared to venetoclax in both biochemical and cellular assays, demonstrating an exceptional selectivity for BCL2. In mice, the oral administration of sonrotoclax induced rapid and robust apoptosis and displayed a clear pharmacokinetic (PK) and pharmacodynamic (PD) correlation. Moreover, in mouse models xenografted with human acute lymphoblastic leukemia (ALL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL), sonrotoclax exhibited a significantly more potent anti-neoplastic activity than venetoclax [4].

2. Available data

Recently, a Chinese phase 1 study showed the efficacy of sonrotoclax as monotherapy in patients with relapsed/refractory (R/R) B-cell malignancies. The study involved escalating drug dosages (80, 160, 320, or 640 mg/day) with daily or weekly increases up to the expected target dose. Overall, 54 patients were enrolled, including those with DLBCL, follicular lymphomas (FL), marginal zone lymphomas (MZL), transformed non-Hodgkin lymphoma, and R/R CLL/SLL. The study included patients with a median age of 61 years, who had undergone a median of two previous lines of therapy (ranging from 1 to 7). The median duration of the follow-up for these patients was 6.6 months.

Out of the 54 patients, 23 discontinued treatment: 18 due to disease progression, 4 for withdrawal, and 1 for clinical decision. The incidence of treatment-related adverse events (TRAEs) was 92.6%, with 53.7% of them being grade 3 TRAEs. The most common TRAE of all grades was leukopenia (48.1%), and the incidence of grade 3 neutropenia was 25.9%. Dose-limiting toxicity (DLT) occurred in three patients at doses of 80 mg/day and 160 mg/day. None of the patients experienced TRAE leading to death or permanent discontinuation of treatment, and there were no cases of tumor lysis syndrome (TLS) reported.

Among the 39 patients evaluated for response, 5 with NHL and 9 with CLL/SLL achieved a response. All nine patients with R/R CLL/SLL were assessable for minimal residual disease (MRD) evaluation, and three of them showed an undetectable MRD status [5].

In the context of multiple myeloma (MM), sonrotoclax has been explored in combination with dexamethasone for R/R patients with t(11;14). Nineteen patients were enrolled in the dose-escalation cohorts, with three patients each in the 80 mg, 160 mg, and 320 mg groups, and 10 patients in the 640 mg group. The most common AEs reported were insomnia, fatigue, nausea, and arthralgia. Three patients (16%) experienced grade ≥3 TRAEs, including elevated liver enzymes and diarrhea in one patient, decreased lymphocyte count and hypokalemia in another patient, and cataract and retinal detachment in a third patient. With a median treatment duration of 120 days, ORR was 58%, with 11 patients achieving a PR or better [6].

In the same MM setting, a recent phase 1/2 study investigated the safety and efficacy of sonrotoclax as monotherapy, in combination with dexamethasone, or with dexamethasone and carfilzomib. Preliminary data from the study have been recently published [7]. Ten patients were enrolled in dose-escalation cohorts of sonrotoclax with dexamethasone. The median age of the patients was 69 years, and they had received a median of three previous lines of treatment. The median duration of treatment was 3.2 months. None of the patients experienced DLT at any dose level. Three patients died during the study: one due to a complication related to COVID-19 157 days after discontinuation of treatment, another due to COVID-19 during study treatment, and one due to disease progression 50 days after discontinuation of treatment. Notably, none of these deaths were associated with the study treatment. The most common TRAEs included insomnia, fatigue, arthralgia, back pain, lymphopenia, and nausea. Two patients experienced grade ≥3 TRAEs: one had a grade 3 increase in liver enzymes and lymphopenia, and the other had grade 3 lymphopenia [7].

In another phase 1 study involving patients with various B-cell malignancies, sonrotoclax was evaluated, either as monotherapy (at five different dose levels) or in combination with zanubrutinib. At the data cutoff, 2 out of 20 patients with R/R NHL, 1 out of 2 patients with R/R WM, and 4 out of 6 patients with R/R CLL treated with sonrotoclax monotherapy achieved a response. In the combination arm, 16 out of 20 patients achieved a response, including 5 out of 10 patients with relapsed/refractory mantle cell lymphoma (R/R MCL) and 12 out of 19 patients with relapsed/refractory CLL [8].

In a phase 1 study, the potential role of sonrotoclax in R/R MZL patients was investigated. Thirteen patients, with a median age of 73 years and a median number of prior treatments of 1, were enrolled in the study. The most common TRAEs included nausea, pyrexia, diarrhea, and constipation, while the most frequent grade ≥3 TRAEs were neutropenia, febrile neutropenia/neutropenic sepsis, and TLS. Five patients discontinued treatment: three due to progressive disease, one due to infection, and one due to withdrawal. Among the 12 patients assessable for response, the ORR was 67% (n = 8), including four patients (33%) with complete response (CR). In the subset of patients treated at the 640 mg dose level, 9/10 were evaluable for response. The ORR in this subset was 78% (n = 7), including four patients (44%) who achieved a CR [9].

Recently, the combination of sonrotoclax and zanubrutinib has been explored in the setting of treatment-naive (TN) CLL. Ninety-four patients were enrolled, with a median follow-up of 8.5 months. Throughout the study, no deaths occurred, and all patients remained in the trial. The most frequent TRAEs included contusion, neutropenia, and low-grade gastrointestinal toxicity. Neutropenia was the most common grade 3 TRAE, and only one TRAE (cryptococcal meningitis) led to treatment discontinuation. Among the 56 patients assessable for response, the ORR was 100%, and no CLL progression was reported [10].

In the setting of myeloid malignancies, sonrotoclax was explored at different dosages in combination with azacytidine in R/R or TN AML patients who were not suitable for intensive chemotherapy, as well as for patients with myelodysplastic syndromes (MDS), or MDS/myeloproliferative neoplasms. At the time of data cutoff, 51 patients with AML were enrolled in the study. The median follow-up duration was 2.8 months, and the median length of treatment was 1.9 months. Among the 41 patients evaluable for DLTs, one case experienced grade 4 neutropenia and another grade 4 thrombocytopenia at an 80 mg dose level. However, these DLTs did not result in permanent discontinuation of treatment.

Twenty-one (41%) patients discontinued study drugs: 7 due to AEs, 5 due to disease progression, 4 proceeded to transplant, 3 withdrew consent, 1 for clinical decision, 1 started new anti-cancer treatment.

The most common TRAEs were neutropenia, thrombocytopenia, anemia, febrile neutropenia, nausea, and constipation. The most common grade ≥3 TRAEs was neutropenia. The majority of grade ≥3 infections occurred during the first cycle, and the general incidence of febrile neutropenia and infections decreased with subsequent cycles. Four patients died during the study period, but no one for TRAEs.

For patients with R/R AML evaluable for response assessment, 18 patients (50%) achieved a (CR) or CR with partial hematologic recovery (CRh), 9 (25%) a CR, and 9 (25%) attained an MRD negativity. In the case of TN AML patients evaluated for response, 16 cases (59.3%) achieved a CR/CRh, 13 (48.1%) a CR, and, among these latter 7 (53.8%) reached CR at the end of the first cycle of therapy [11]. Available data are summarized in Table 1.

Table 1. Published data exploring Sonrotoclax safety and efficacy.

Disease status	Schedule	Phase study	Number of enrolled cases	DLT	ORR	References
R/R mature B cell malignancies	Sonrotoclax monotherapy 80, 160, 320, or 640 mg once daily	I	54	3	NHL 25% CLL/SLL 45%	[5]
R/R multiple myeloma with t(11;14)	Sonrotoclax 80, 160, 320, or 640 mg once daily with 40 mg of dexamethasone weekly	Ib/II	19	0	58%	[6]
R/R B-cell malignancies	Sonrotoclax 40, 80, 160, 320, or 640 mg once daily with weekly or daily ramp-up to target dose was given as monotherapy or combined with zanubrutinib 320 mg once daily or 160 mg twice daily 8–12 weeks before sonrotoclax	I	58 total 32 monotherapy 26 combination	-	Most patients had a reduction in lymphadenopathy. 2 out of 26 NHL (monotherapy) had responses (1 CR).	[8]
R/R marginal zone lymphoma	Sonrotoclax (dose escalation: 40, 80, 160, 320, or 640 mg once daily) with a 3-day ramp-up, followed by expansions at 640 mg and 320 mg	I/Ib	13	1	67%	[9]
TN-CLL/SLL	Zanubrutinib (320 mg QD or 160 mg BID) 8–12 weeks before starting sonrotoclax in a ramp-up schedule starting from 1 mg to the intended target dosage of 160 mg or 320 mg once daily	I/II	94	-	100%	[10]
AML (TN unfit for intensive chemotherapy or R/R)	Sonrotoclax in a 10-day regimen at 40 mg (cohort 1), 80 mg (cohort 2), or 160 mg (cohort 3) or sonrotoclax 160 mg in a 28-day regimen (cohort 4). All dose levels were given in combination with azacitidine (75 mg/m2 x 7 days).	I/II	51	2	TN 59.3% of evaluable pts R/R 50% of evaluable pts	[11]

R/R: relapsed refractory, TN: treatment naïve, CLL: chronic lymphocytic leukemia, SLL: small lymphocytic lymphoma, WM: Waldenstrom macroglobulinemia, AML: acute myeloid leukemia, DTLs: dose-limiting toxicities, ORR: overall response rate.

3. Ongoing studies

Currently, several studies are evaluating the effectiveness and tolerability of sonrotoclax. A phase 1 study (NCT04883957) is evaluating the safety and efficacy of sonrotoclax monotherapy in malignant B cell neoplasms. A phase 1/2 trial (NCT05471843) aims to assess the use of sonrotoclax in patients with R/R mantle cell lymphoma who have previously received anti-CD20 therapy and a BTK inhibitor (BTKi). A phase 2 study (NCT06073821) is enrolling patients with R/R CLL after exposure to BTKi and immuno-chemotherapy or BTKi alone and not eligible for immuno-chemotherapy (NCT05479994). A phase 3 study compares sonrotoclax and zanubrutinib to venetoclax and obinutuzumab in TN CLL patients.

Similarly, the NCT05952037 trial is investigating sonrotoclax efficacy in patients with R/R WM. Moreover, in myeloid neoplasms, a phase 1/2 trial is recruiting patients to assess the efficacy and safety of sonrotoclax in patients with AML, MDS, or MDS/myeloproliferative disorders (NCT04771130). These ongoing studies aim to provide valuable insights into the potential benefits of sonrotoclax across a range of hematologic malignancies are summarized in Table 2.

Table 2. Ongoing trial exploring sonrotoclax safety and efficacy.

Disease status	Schedule	Primary endpoint	Phase study	Clinical trial registration number
R/R B cell malignancies	Sonorotoclax monotherapy 80, 160, 320, or 640 mg once daily	MTD RP2D	I	NCT04883957
R/R MCL	Sonrotoclax monotherapy	DTLs TRAEs TLS ORR	I/II	NCT05471843
R/R CLL or SLL	Sonrotoclax monotherapy	ORR	II	NCT05479994
R/R WM	Sonrotoclax monotherapy	MRR	II	NCT05952037
TN CLL	Experimental arm: From Cycle 1 a standard dose of zanubrutinib once or twice daily orally and in combination with sonrotoclax starting from Cycle 4 onwards at increasing doses until the target dose is reached and continuing until the end of Cycle 15 (each cycle is 28 days) Comparator arm: obinutuzumab 100mg ev on Day 1 Cycle 1, followed by 900 mg on Day 2 Cycle 1 (or receive 1000 mg intravenously on Day 1), followed by 1000 mg on Days 8 and 15 of Cycle 1 and thereafter on Day 1 of Cycles 2 through 6 (each cycle is 28 days) in combination with venetoclax at increasing doses until target dose is reached from Day 22 Cycle 1 until end of Cycle 12 (each cycle is 28 days)	PFS	III	NCT06073821
AML, MDS or MPN/MDS	Part 1–2 AML: sonrotoclax 40 mg (cohort 1), 80 mg (cohort 2), or 160 mg (cohort 3) for 10, 21, 14 days; or sonrotoclax 160 mg (cohort 4) in a 28-day regimen and azacitidine ev or sc in 28 days cycles Part 1–2 MDS: sonrotoclax for 10 or 21 days on a 28-day cycle and azacitidine ev or sc in 28 days cycles Part 3 AML and MDS: sonrotoclax 40 mg (cohort 1), 80 mg (cohort 2), or 160 mg (cohort 3) for 10, 21, 14, or sonrotoclax 160 mg (cohort 4) in a 28-days regimen and azacitidine ev or sc in 28-day cycles and oral posaconazole for 8 days on a second cycle only. Part 3 AML and MDS: sonrotoclax 160 mg for 28 days on a 28-day cycle.	DLTs TRAEs CR/CRh mOR Pharmacokinetics parameters	I/II	NCT04771130

R/R: relapsed refractory, TN: treatment naïve, MCL: mantle cell lymphoma, CLL: chronic lymphocytic leukemia, SLL: small lymphocytic lymphoma, WM: Waldenstrom macroglobulinemia, AML: acute myeloid leukemia, MDS: myelodysplastic syndromes, MDS/MPN: myelodysplastic/myeloproliferative neoplasms, iv: intravenous, sc: subcutaneous, MTD: maximum tolerated dose, RP2D. recommended phase 2 dose, DTLs: dose-limiting toxicities, TLS: tumor lysis syndrome, ORR: overall response rate, PFR: progression-free survival, CR/CRh: complete remission or complete remission with incomplete hematological recovery, mOR: modified overall response.

4. Expert opinion

During the last few years, the introduction of venetoclax, a first-in-class BCL2 inhibitor, has marked a significant shift in the treatment landscape for both lymphoid and myeloid malignancies. Unfortunately, the prolonged follow-ups have revealed the emergence of several mechanisms of resistance in cancer cells. Notably, in CLL patients, the recurrent G101V mutation in BCL2 has been identified as a mediator of resistance to venetoclax [3]. The recognition of these mechanisms of resistance has underscored the urgent need for more potent BCL2 inhibitors.

Sonrotoclax, identified as a highly potent and selective BCL2 inhibitor, has demonstrated the capability to overcome the development of resistance due to the emergence of G101V mutation [4]. Regrettably, a recent ‘in vitro’ study has indicated the emergence of BAX mutation in neoplastic cells even when exposed to sonrotoclax [12].

In light of these findings, the strategic combination of sonrotoclax with other targeted drugs seems a promising approach. Encouragingly, the synergistic effects resulting from the combination of sonrotoclax and zanubrunitib in TN CLL patients offer moderate optimism. In this setting, the absence of disease progression further emphasizes the potential of such combinations in circumventing resistance and improving treatment outcomes.

This evolving landscape highlights the critical importance of ongoing research efforts to explore innovative therapeutic strategies and address the challenges posed by BCL2 inhibitors’ resistance mechanisms. Further research, both ‘in vitro’ and clinical settings, is needed to refine these approaches.

Article highlights

• While Venetoclax stands as the pioneer BCL2 inhibitor, its effectiveness is hampered by the development of resistance mechanisms. Sonrotoclax, characterized by an increased potency as a BCL2 inhibitor emerges as a promising solution to overcome this resistance.

• Evidence indicates its efficacy in mature B.–cell malignancies and among patients with acute myeloid leukemia.

• Anticipating a promising approach, it is reasonable to consider combining sonrotoclax with other biological therapies like azacitidine for myeloid malignancies and zanubrutinib for Bcell malignancies.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties

Reviewer disclosures

A reviewer on this manuscript has disclosed they have received research funding from Beigene and AbbVie. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Correction Statement

This article was originally published with errors, which have now been corrected in the online version. Please see Correction (http://dx.doi.org/10.1080/13543784.2024.2319956)

Additional information

Funding

This paper was not funded.