Zanubrutinib, a next-generation BTK inhibitor, is demonstrating significant efficacy when combined with BCL2 inhibitors in treating high-risk chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), according to recent clinical trial data presented at the European Hematology Association 2024 Hybrid Congress.
SEQUOIA Trial Results in Treatment-Naïve Patients
The randomized, multicenter, global SEQUOIA phase 3 trial (NCT03336333) investigated zanubrutinib in combination with venetoclax in 66 treatment-naïve patients with CLL/SLL harboring del(17p) and/or TP53 mutations. These genetic alterations represent high-risk features associated with poor treatment outcomes and early relapse.
Patients received zanubrutinib 160 mg twice daily for 3 months, followed by the same zanubrutinib dose combined with venetoclax using ramp-up dosing to 400 mg once daily for 12 to 24 cycles until progressive disease, unacceptable toxicity, or confirmed undetectable minimal residual disease (MRD).
Among 65 response-evaluable patients, the overall response rate (ORR) reached 100%. The complete response (CR) with incomplete hematopoietic recovery (CRi) rate was 48%, comprising 46% CR and 2% CRi. Undetectable MRD was achieved in 59% of patients, and median progression-free survival (PFS) was not reached. The 12- and 24-month PFS estimates were 95% and 94%, respectively.
Safety analysis revealed that 97% of patients experienced at least one treatment-emergent adverse effect (TEAE), with 44% experiencing grade ≥3 non-hematologic TEAEs. The study authors reported no new safety concerns with the combination.
Sonrotoclax Combination Shows Promise in Relapsed/Refractory Setting
The phase 1 BGB-11417-101 study (NCT04277637) evaluated sonrotoclax, a next-generation BCL-2 inhibitor, in combination with zanubrutinib in 47 patients with relapsed/refractory CLL/SLL. Sonrotoclax is described as more selective and pharmacologically potent than venetoclax, with a shorter half-life and no drug accumulation.
At a median follow-up of 19.3 months, the combination achieved a 97% ORR with a CR/CRi rate of 57% across all dose levels. In the 320-mg cohort, which was established as the recommended phase 2 dose, the ORR was 100% with a CR/CRi rate of 73%.
The patient population had challenging characteristics: 53% had 17p deletions and/or TP53 mutations, 68% had unmutated IGHV, and patients had received a median of 1 prior line of therapy. Among patients evaluable for MRD status, 85% achieved undetectable MRD at data cutoff, with responses deepening over time.
Safety Profile and Clinical Implications
The sonrotoclax-zanubrutinib combination demonstrated a manageable safety profile. Among all patients, 94% experienced any-grade TEAEs, 51% had grade 3 or higher TEAEs, and 28% experienced serious TEAEs. The most common adverse events included contusion (32%), neutropenia (27%), COVID-19 (28%), diarrhea (28%), and fatigue (26%). Notably, no cases of tumor lysis syndrome, atrial fibrillation, or febrile neutropenia were observed.
No dose-limiting toxicities occurred with the combination, and the maximum tolerated dose was not reached. Forty-six of 47 patients remained on study treatment at the time of analysis.
Clinical Significance for High-Risk CLL/SLL
CLL/SLL represents the most common adult leukemia in Western populations, comprising 25% to 30% of cases in the United States. Patients with del(17p) and/or TP53 mutations face particularly challenging outcomes, often experiencing treatment resistance or early relapse with standard therapies.
"SEQUOIA has shown that [zanubrutinib] is a highly effective monotherapy treatment for TN CLL patients, including those with high-risk markers like del(17p) and/or TP53 mutation," said Mehrdad Mobasher, MD, MPH, chief medical officer, Hematology at BeiGene. "With one of the largest pools of high-risk patients of any published study to date, SEQUOIA arm D demonstrates how BCL2 inhibitor therapies can complement BRUKINSA as a backbone therapy to achieve deep clinical response even in this patient population."
The findings position zanubrutinib as a potential backbone therapy for combination approaches in high-risk CLL/SLL, with both venetoclax and sonrotoclax showing complementary mechanisms of action that may optimize treatment outcomes while maintaining acceptable safety profiles.
