Novel BTK Degrader Yields Responses in R/R B-Cell Malignancies

“Preliminary results…demonstrate meaningful clinical responses with a short time to response in heavily pretreated patients with a range of B-cell malignancies,” according to John F. Seymour, MBBS, PhD.

Treatment with BGB-16673 elicited quick, meaningful responses and appeared to be tolerable among patients with relapsed/refractory B-cell malignancies, according to data from the phase 1 BGB-16673-101 study (NCT05006716) presented at the 2023 American Society of Hematology (ASH) Annual Meeting and Exposition.

Initial findings from this ongoing trial showed that BGB-16673 produced an overall response rate (ORR) of 57% for all efficacy-evaluable patients (n = 28). Responses consisted of 1 complete response (CR), 13 partial responses (PRs), 1 PR with lymphocytosis (PR-L), and 1 minor response (MR). Five patients achieved stable disease (SD), 5 patients experienced progressive disease (PD), and 2 patients discontinued treatment prior to their first assessment. The disease control rate (DCR) in this population was 75%, with a median time to first response of 2.76 months.

The ORR in high-risk, heavily pretreated patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL) was 70%, and included 6 PRs, 1 PR-L, 2 SDs, and 1 patient who discontinued treatment prior to first assessment. The DCR in this cohort was 90%, and the median time to first response was 2.83 months.

In patients with Waldenström macroglobulinemia (WM), mantle cell lymphoma (MCL), or marginal zone lymphoma (MZL), the ORR was 56%, with 1 CR, 7 PRs, 1 MR, 3 SDs, and 3 PDs, as well as 1 patient who discontinued treatment prior to their first assessment. Patients had a DCR of 75% and a median time to first response of 2.33 months.

“Preliminary results…demonstrate meaningful clinical responses with a short time to response in heavily pretreated patients with a range of B-cell malignancies,” lead author John F. Seymour, MBBS, PhD, a clinical hematologist and associate director of Clinical Research at Peter MacCallum Cancer Centre in Victoria, Australia, and colleagues, wrote in a poster presentation of the data. “Substantial reductions in BTK protein levels in peripheral blood and tumor tissue were also observed, demonstrating proof-of-concept of a strong, on-target effect.”

Both covalent and non-covalent BTK inhibitors currently serve as a standard-of care treatment option across hematologic malignancies, but many patients experience disease progression due to acquired resistance mutations during treatment.

The chimeric degradation activating compound BGB-16673 serves as a promising option for potentially overcoming BTK inhibitor resistance. After binding to BTK and E3 ligase, the agent activates BTK degradation via ubiquination. Preclinical models showed that BGB-16673 degraded both wild-type BTK and known covalent and noncovalent BTK inhibitor–resistant mutant proteins, leading to tumor suppression.

Based on these data, the safety and efficacy of this agent was evaluated in this phase 1, open-label, dose-escalation and -expansion study. Patients with relapsed/refractory CLL/SLL, WM, MCL, MZL, non-germinal center B-cell diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), or Richter transformation (RT) were eligible for enrollment onto the dose escalation portion of the study (part 1a). Patients in this cohort received 1 of 6 doses of BGB-16673 monotherapy ranging from 50 mg to 600 mg once a day.

The safety expansion portion (part 1b) included up to 20 patients with MZL, MCL, CLL/SLL, and WM who were enrolled at cleared doses in part 1a and were recommended for additional evaluation by the safety monitoring committee. An additional safety expansion cohort is planned after part 2 of the study opens and will include up to 40 patients enrolled in up to 3 dose levels, as recommended by the safety monitoring committee.

To be eligible for this study, patients must have received 2 or more prior therapies, at least 1 of which was for RT, and a covalent BTK inhibitor if approved for their disease. Other key eligibility criteria included an ECOG performance status (PS) of 0 to 2, adequate end-organ function, and no history of or current central nervous system involvement by B-cell malignancy.

The study’s primary end points were safety, tolerability, and determining both the maximum tolerated dose and the recommended phase 2 dose of BGB-16673. Key secondary end points included pharmacokinetics, pharmacodynamics, and preliminary antitumor activity.

A total of 51 patients were enrolled onto the study, 50 of whom were treated across all 6 dose levels. Thirty-eight patients remain on study treatment. Patients discontinued study treatment due to disease progression (n = 9), adverse effects (AEs; n = 2), and patient withdrawal (n = 1). The overall median follow-up in this study was 2.55 months (range, 0.2-17.1).

The median age of patients in the overall population was 70.5 years old (range, 25-91). Most patients were male (66%), most had an ECOG PS of 0 or 1 (94%), and most had CLL/SLL (48%). Additionally, 14%, 12%, 12%, 6%, 4%, and 4% of patients had MCL, WM, FL, MZL, DLBCL, and RT, respectively. The median number of prior lines of therapy in this population was 4 (range, 2-10). In total, 80%, 14%, and 56% of patients had received a prior covalent BTK inhibitor, noncovalent BTK inhibitor, and BCL-2 inhibitor, respectively. More than half of patients (56%) had discontinued a prior BTK inhibitor due to disease progression. Most patients (44%) harbored a BCL2 mutation, followed by a BTK mutation (29%) and a PLCG2 mutation (8%). CLL/SLL risk characteristics at baseline included Binet stage C disease, an unmutated IGHV locus, 17p deletions (del[17p]), TP53 mutations, a del(17p) or TP53 mutation, 11q deletions, or a complex karyotype featuring 3 or more genetic abnormalities in 52%, 84%, 33%, 42%, 46%, 8%, and 40% of patients, respectively.

Further analysis of safety deemed the regimen to be tolerable, with 1 incidence of grade 3 maculo-papular rash of the face and legs in a patient who received BGB-16676 at 200 mg serving as the only dose-limiting toxicity reported. Across all dose levels, 92% of patients experienced any treatment-emergent AE (TEAE), including 38% of patients who experienced grade 3 or higher toxicities and 28% of patients who experienced serious AEs. Any-grade treatment-related AEs (TRAEs) were observed in 64% of patients, 22% of which were grade 3 or higher and 10% of which were serious TRAEs. Two TEAEs led to death, although neither death was treatment related. Three TEAEs led to treatment discontinuation, including 1 TRAE; 11 TEAEs led to treatment modification, including 11 dose interruptions and 2 dose reductions.

The most common TEAEs in more than 10% of all patients consisted of contusion (any-grade, 30%; grade ≥ 3, 0%), diarrhea (24%; 0%), fatigue (20%; 0%), increased amylase (16%; 0%), neutropenia (16%; 12%), increased lipase (14%; 4%), pyrexia (14%; 0%), cough (12%; 0%), headache (10%; 0%), thrombocytopenia (10%; 4%), pneumonia (6%; 6%), and COVID-19 pneumonia (4%; 4%). Common grouped TEAEs of interest included bleeding (42%; 4%) and infection (40%; 16%). No atrial fibrillation or hypertension was reported to date.

Assessment of responses according to dose level demonstrated ORRs of 50%, 50%, 89%, 0%, and 100% in patients treated with the 50 mg (n = 4), 100 mg (n = 10), 200 mg (n = 9), 350 mg (n = 4), and 500 mg (n = 1) doses, respectively. The corresponding DCRs were 50%, 80%, 100%, 25%, 100%, and 75%. The median time to first response at each respective dose level was 2.60, 0.95, 2.81. 0, 2.83, and 2.76 months.

“These data support further examination of the clinical activity of BGB-16673 across several B-cell malignancies; phase 2 dose expansions are planned within this study for patients with CLL/SLL and MCL,” investigators concluded in the poster.

Disclosures: Seymour disclosed relationships with F. Hoffmann-La Roche Ltd. Janssen, AstraZeneca, AbbVie, TG Therapeutics, Bristol Meyers Squibb, Beigene, Gilead, and Genor Bio.

Reference

Seymour JF, Cheah CY, Parrondo R, et al. First results from a phase 1, first-in-human study of the Bruton’s tyrosine kinase (BTK) degrader Bgb-16673 in patients (pts) with relapsed or refractory (R/R) B-cell malignancies (BGB-16673-101). Blood. 2023;142(suppl 1):4401. doi:10.1182/blood-2023-180109