BGB-11417 +/- Zanubrutinib Demonstrates Early Efficacy Signals in CLL/SLL

In a phase 1 trial (NCT04277637), treatment with BGB-11417, when given alone or in combination with zanubrutinib (Brukinsa), induced promising responses and minimal residual disease (MRD) negativity rates in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).¹

At a median follow-up of 13.4 months (range, 1.4-21.9), single-agent BGB-11417 elicited an overall response rate (ORR) of 67% (n = 4) among 6 efficacy-evaluable patients with relapsed or refractory disease; this included 2 complete responses (CRs) and 2 partial responses (PRs).

Among 20 efficacy-evaluable patients with relapsed/refractory disease, BGB-11417 plus zanubrutinib elicited an ORR of 95% at a median follow-up of 11.1 months (range, 2.2-18.6); this was comprised of 6 CRs and 13 PRs. In the group of efficacy-evaluable patients who were treatment naïve (n = 11) and who had a median follow-up of 3.5 months (range, 0.4-9.7), the doublet resulted in an ORR of 100%; this included 2 CRs and 9 PRs.

“MRD negativity was observed at doses of 80 mg or higher after 6 months in the monotherapy and combination cohorts,” said lead study author Chan Cheah, MD, of the University of Western Australia, Crawley, in a presentation of the data delivered during the 2022 ASH Annual Meeting. “The undetectable MRD increased with longer follow-up and higher dose. A longer observation time is needed to understand these results better…the MRD data are preliminary but appear promising.”

In the patients with relapsed or refractory disease who received BGB-11417 at 80 mg (n = 4), the MRD negativity rate in the blood was 25%; this rate was 50% in those with relapsed or refractory disease who received BGB-11417 at 160 mg (n = 2). In those with relapsed or refractory disease who received the combination with BGB-11417 given at 40 mg (n = 3), 80 mg (n = 5), 160 mg (n = 6), and 320 mg (n = 2), the blood MRD negativity rates were 0%, 40%, 100%, and 50%, respectively. In treatment-naïve patients who received the combination with BGB-11417 given at a dose of 160 mg (n = 10), the blood MRD negativity rate was 40%.

BCL-2 inhibition is an established mechanism for treating patients with B-cell malignancies such as CLL/SLL. Ibrutinib with venetoclax (Venclexta) has proven to be effective in patients with CLL/SLL but toxicities can limit its use. As such, more tolerable BTK/BCL-2 inhibitor combinations are needed. “BGB-11417 has shown more potent and selective BCL-2 inhibition and better activity against BCL2 mutations than venetoclax in vitro,” Cheah noted.

The first-in-human, multicenter, phase 1 study enrolled a total of 50 patients: 6 were treated with BGB-11417 monotherapy and 44 received BGB-11417 in combination with zanubrutinib. BGB-11417 was administered once daily for ≤30 minutes following a low-fat meal. Patients received escalating doses of BGB-11417 (40, 80, 160, 320, or 640 mg) with a ramp-up to the intended target dose to minimize risk of tumor lysis syndrome (TLS). TLS prophylaxis included hydration, started 24 to 48 hours prior to the first dose, allopurinol started 2 to 3 days prior to first dose, and rasburicase (Elitek) as indicated.

For the combination cohorts, zanubrutinib was given at a twice-daily dose of 160 mg or a once-daily dose of 320 mg, 8 to 12 weeks prior to BGB-11417 was initiated.

To date, 79 patients with CLL have been dosed with study treatment; 8 received BGB-11417 monotherapy and 71 received the combination. Twenty-one patients in the combination group are still receiving zanubrutinib pretreatment. “Overall, all but 1 patient on study remains on treatment with a single instance of Richter transformation,” Cheah said.

In all patients, the median age was 62 years (range, 35-84); the monotherapy cohort was slightly older, with a median age of 68.5 years (range, 55-84) vs 61 years (range, 35-84) in the combination cohort. The median number of prior lines of therapy received was 2 (range, 1-3) in the monotherapy cohort and 1 (range, 1-2) in the combination cohort. Moreover, 58.2% of patients overall were treatment naïve; all these patients were in the combination cohort. Regarding risk status, 16.5% of all patients had del(17p) and 22.8% had TP53-mutated disease.

Any-grade treatment-emergent adverse effects (TEAEs) were experienced by 87% of all patients (n = 79), with 32% of patients experiencing effects that were grade 3 or higher in severity. Eleven percent of patients had serious AEs. No AEs resulted in death.

Thirty-three percent of patients experienced AEs that resulted in a dose hold of BGB-11417, and 2% experienced toxicities that led to a dose reduction of BGB-11417.

There was 1 dose limiting-toxicity, with febrile neutropenia observed in a patient with CLL who received 80 mg of BGB-11417 monotherapy. No maximum tolerated dose was observed. Toxicity did not appear to be dose dependent, Cheah said.

The most frequently observed AEs included neutropenia (62.5%), thrombocytopenia (50.0%), headache (37.5%), COVID-19 (37.5%), and diarrhea (37.5%) in the monotherapy cohort, and contusion (29.6%), COVID-19 (25.3%), diarrhea (22.5%), neutropenia (22.5%), headache (19.7%), and nausea (19.7%) in the combination cohort, which had shorter follow-up.

The incidence of grade 3 or higher neutropenia in the combination cohort was 14.1%. The neutropenia was “readily manageable” with granulocyte colony–stimulating factor, Cheah noted.

A single instance of laboratory TLS occurred in a patient with high tumor burden who was receiving monotherapy. No clinical TLS was reported, and no cases of TLS were observed with daily ramp up. Gastrointestinal toxicity was generally mild, mostly grade 1, with 12.5% of those in monotherapy group and 5.6% of those in the combination group having grade 2 or higher diarrhea, which Cheah described as “mostly self-limiting.”

The absolute lymphocyte count dropped by about 90% after weekly ramp-up to 40 mg of BGB-11417, which is equivalent to about 200 mg of venetoclax in terms of potency, Cheah said.

A venetoclax-treated CLL/SLL cohort is recruiting.

_Reference

_{Cheah CY, Tam CS, Lasica M, 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. Presented at: 2022 ASH Annual Meeting; New Orleans, LA, December 10-13, 2022. Abstract 962}