BGB-11417 Shows Encouraging Early Efficacy and Tolerability in CLL

The BCL-2 inhibitor BGB-11417, administered alone or in combination with the BTK inhibitor zanubrutinib (Brukinsa), induced promising response rates and was well tolerated patients with chronic lymphocytic leukemia (CLL). Chan Y. Cheah, MD, MBBS, said these results indicate the potential superiority of this agent compared with previously developed BTK plus BCL-2 inhibitor combinations.

Cheah presented early data from the phase 1 BGB-11417-101 trial (NCT04277637) at the 2022 ASH Annual Meeting which showed that relapsed/refractory CLL cohorts experienced an overall response rate (ORR) of 67% with BCB-11417 monotherapy and 95% with the combination regimen. Treatment-naive patients with CLL achieved an ORR of 100% with the combination. The median follow-up was 13.4, 11.1, and 3.5 months respectively. The maximum tolerated dose (MTD) has not been reached at this time.

BCB-11417 administered at a dose of 40 mg reduced absolute lymphocyte counts (ALC) by 90% compared with 200 mg of venetoclax (Venclexta), suggesting greater potency for BCB-11417. Additionally, analysis of treatment-related adverse effects (TEAEs) revealed only 1 case of laboratory tumor lysis syndrome (TLS), which was easily managed.

“The main takeaway for [BGB-11417] is that it’s safe,” Cheah said in an interview with OncLive^®. “[It doesn't show] much TLS or significant toxicity apart from some neutropenia, which is easily managed. It’s readily combinable with zanubrutinib and provides a platform for a novel BCL-2/BTK combination [regimen] which we may be able to bring to patients with CLL in the future.”

Cheah is a clinical professor at the University of Western Australia (WA), a consultant hematologist, lymphoma lead, and fellowship program director at Sir Charles Gairdner Hospital, Pathwest Laboratory Medicine WA, Linear Clinical Research and Hollywood Private Hospital, and the founder of Blood Cancer Research WA, Perth, Western Australia.

OncLive^®: Could you provide some background on the phase 1 trial examining BGB-11417 in patients with CLL?

Cheah: [BGB-11417-101] is a large phase 1 study that includes patients with a range of B-cell malignancies. At [ASH 2022], I presented data on the cohort of patients treated with CLL [who were] treated [with] BGB 11417, an oral, once [daily] BCL-2 inhibitor being explored in a range of different indications.

What is the rationale for targeting BCL-2 within B-cell malignancies?

BCL-2 is a validated pathway for targeting B-cell malignancies. It is essentially an apoptosis protein, so inhibition of BCL-2 causes cells to undergo programmed cell death. [This] induces substantial responses in patients with a range of B-cell malignancies, most notably CLL and acute myeloid leukemia [AML].

BGB-11417 is a small-molecule inhibitor of BCL-2. There is already an approved BCL-2 inhibitor called venetoclax. [However,] BGB-11417 and venetoclax have 2 major differences.

[First, BGB-11417] is more potent [than venetoclax.] Its potency increased…and it has low nanomolar ic50 for both wild-type and G101V mutant BCL-2. The latter properties suggest that it may be active in venetoclax-resistant CLL. Second, [BCB-11417] is more selective; the inhibition of other BCL-2 family proteins such as BCL-XL, BCL-W, and MCL-1 is substantially less than venetoclax, suggesting that there may be less off-target AEs.

Is there anything unique you would like to note regarding the trial design and eligibility criteria?

The key eligibility criteria were fairly standard for a phase 1 study. Patients needed to be over 18 [years of age] and have adequate performance status and organ function—particularly adequate renal function. In the CLL cohort, patients needed to meet the International Workshop on Chronic Lymphocytic Leukemia criteria for the initiation of therapy.

In terms of its design, this is actually quite a complicated study. Because it's a phase 1/1b study, there are up to 5 potential dose levels being explored in monotherapy [arms], ranging from 40 mg to 640 mg. We also explored combination arms with [BGB-11417 plus] the covalent BTK inhibitor zanubrutinib. Zanubrutinib [was administered as a] fixed dose, but BGB-11417 was explored at several dose levels. There have been multiple dose-escalation cohorts within the various malignancies, but this abstract [contained] an aggregate of all the CLL data across both monotherapy and combination cohorts in both the escalation and expansion [phases of the trial].

What important preliminary efficacy data were presented at the 2022 ASH Annual Meeting?

We have treated about 159 patients so far, and about 79 had previously untreated CLL. Of those patients, 8 were treated [with the] monotherapy and 71 received the combination. Preliminary efficacy findings [showed] that the majority of patients achieved a response. Considering the monotherapy cohort, the ORR was [67%, with] about 30% [of patients achieving] complete responses. Response rates were higher in the combination cohorts, as you might expect, [but there was a lower] CR rate. [Responses were about] 95% in the relapsed/refractory cohort and 100% in the treatment-naive cohort.

[Notably,] the combination cohorts had a much shorter median duration of follow-up because [these patients are] younger, and we just haven’t been following [them] as long. When measuring efficacy early on in a study, [it’s important to realize] that it is not going to be as high.

What was learned about the safety of the monotherapy and combination?

The safety of this drug is pretty good. It seems to be clean on BCL-2 and probably has better tolerability than venetoclax. The rates of grade 3 or higher AEs across the whole study were 32%, [which] in my experience, is acceptable. Most of those AEs were uncomplicated neutropenia so that’s fairly easy to manage with granulocyte colony–stimulating factor.

Diarrhea or gastrointestinal [GI] toxicity can be an issue with BCL-2 inhibitors—especially venetoclax [when given] at higher dose levels. We saw a bit of [GI toxicity] in the study, but it was mostly mild. [GI toxicities of] grade 2 or higher were only seen in [12.5%] of patients in the monotherapy arms and [5.6%] of patients in the combination arms. [Based on these data, BGB-11417] does seem to be a well-tolerated agent.

One thing that is always important to [note] when exploring a new BCL-2 inhibitor is the [risk of] TLS. It can be an issue with venetoclax if not appropriately managed. In this study, we did dose escalation in a few different ways. Most patients had a standard weekly ramp-up [of dosage] as you would see with venetoclax, but we explored a daily dose-escalation schedule in a few [cohorts]. [In this approach,] we would actually increase the dose by about 30% each day and then monitor [the patients] closely.

The bottom line is that we didn’t see a whole lot of clinical TLS in this study. There was 1 episode of laboratory TLS, which is where the laboratory tests become abnormal but there are no clinical sequelae for the patient. [Additionally,] there was 1 episode of a DLT in a patient with neutropenic sepsis treated at 80 mg in the CLL cohort. [However,] we didn’t see any other DLTs and there was no maximum tolerated dose reached.

What are the next steps for this research?

This study is ongoing, and enrollment to ongoing expansion cohorts continues. We’ve [also] opened a [new investigational] arm for patients with CLL who have previously been treated with venetoclax.

The pathway forward for this drug is in combination with zanubrutinib because that’s where almost all the patients have been treated. I can see a potential phase 3 strategy looking at this combination in previously untreated patients, randomized against single-agent BTK [inhibitors, for example].

[BGB-11417] is also being explored in a range of other B-cell malignancies, including mantle cell lymphoma, Waldenström macroglobulinemia, and [others]. We will probably see more trials in those BCL-2 inhibitor–sensitive indications as well.

Reference

1. Chan Y. Cheah, Constantine S. Tam, Masa Lasica, et al. A phase 1 study with the novel B-Cell Lymphoma 2 (Bcl-2) inhibitor Bgb-11417 as monotherapy or in combination with zanubrutinib (ZANU) in patients (pts) with CLL/SLL: preliminary data. Blood. 2022;140(suppl 1): 2321–2323. doi:10.1182/blood-2022-169662