BeOne Medicines' Oral Beqalzi and Brukinsa Combination Shows Promise in First-Line CLL/SLL

BeOne's Oral Beqalzi-Brukinsa Combo Shows 100% ORR in First-Line CLL/SLL

BeOne Medicines presented promising results for its all-oral combination of Beqalzi (BCL2 inhibitor) and Brukinsa (BTK inhibitor) as a first-line treatment for chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) at the European Hematology Association (EHA) 2026 Congress. The Phase I/Ib BGB-11417-101 trial, which included patients with del(17p) and/or TP53 mutations, reported a 100% overall response rate across 135 efficacy-evaluable patients. In the 320mg Beqalzi cohort (86 patients, median follow-up 34.1 months), the complete response rate was 59.5%, with 100% 24-month progression-free survival. Undetectable measurable residual disease (uMRD4) in this cohort increased from 81.2% at week 24 to 98.2% at week 96. The regimen demonstrated a favorable safety profile with no clinical or laboratory tumor lysis syndrome or TEAE-related deaths.

• The BGB-11417-101 trial showcased exceptional efficacy for BeOne's Beqalzi and Brukinsa combination in treatment-naïve CLL/SLL patients. Across 135 efficacy-evaluable patients, a 100% overall response rate was achieved. Specifically, the 320mg Beqalzi cohort reported a 59.5% complete response rate and a 100% 24-month progression-free survival, indicating deep and durable responses.
• The combination therapy demonstrated high rates of undetectable measurable residual disease (uMRD4), with levels in the 320mg Beqalzi cohort rising from 81.2% at week 24 to 98.2% at week 96. The safety profile was favorable, with 98.8% any-grade and 60.5% grade ≥3 treatment-emergent adverse events, but critically, no clinical or laboratory tumor lysis syndrome or TEAE-related deaths were observed.
• BeOne's wholly owned, all-oral, fixed-duration regimen of Beqalzi plus Brukinsa offers a strategic advantage, aiming to extend the Brukinsa franchise and directly challenge venetoclax-based regimens in the first-line setting. Despite being early Phase I/Ib data, the promising results suggest significant commercial potential, with Beqalzi sales projected to reach almost $1.3 billion and Brukinsa global sales nearly $7 billion by 2032.

EHA 2026: Beqalzi and Jaypirca Deliver Strong CLL/SLL Outcomes

The RESONATE-2 trial (NCT01722487/NCT01724346), a Phase 3 study evaluating single-agent ibrutinib (420 mg/day) versus chlorambucil in treatment-naïve CLL/SLL patients aged ≥65 years without del(17p), reported landmark 10-year follow-up data. With a median follow-up of 9.6 years in the ibrutinib arm, median PFS reached 8.9 years (95% CI, 7.0–NE) versus 1.3 years (95% CI, 0.9–1.6) with chlorambucil. In the high-risk subgroup (unmutated IGHV, del(11q), mutated TP53, or complex karyotype), median PFS was 8.4 years with ibrutinib versus 0.7 years with chlorambucil. Median OS with ibrutinib was not reached, and 27% of patients remained on first-line ibrutinib at study completion. Key any-grade adverse events included diarrhea (52%), fatigue (41%), cough (39%), hypertension (30%), and peripheral edema (31%). Dose reductions due to AEs occurred in 25% of patients (34/136), with 88% of those experiencing subsequent improvement.

The SEQUOIA trial (NCT03336333) assessed zanubrutinib monotherapy versus bendamustine-rituximab (BR) in treatment-naïve CLL/SLL patients without del(17p) who were unsuitable for FCR, including those with TP53 mutations. Zanubrutinib demonstrated superior PFS, with a 3-year investigator-assessed PFS rate of 84.3%; when the population was matched to AMPLIFY by FCR eligibility, this figure rose to 89.2%. In the AMPLIFY trial (NCT03836261), acalabrutinib-venetoclax with or without obinutuzumab was evaluated versus investigator's choice of chemoimmunotherapy (FCR or BR) in treatment-naïve CLL patients without del(17p) or TP53 mutations, yielding a 3-year PFS rate of 78.9%. An anchored matching-adjusted indirect comparison between these two studies favored zanubrutinib monotherapy over acalabrutinib-venetoclax, with an age-adjusted PFS HR of 0.26 (95% CI, 0.13–0.54; P<0.0003).

In the relapsed/refractory setting, a real-world study of venetoclax-rituximab (VR), based on the MURANO regimen, enrolled 37 R/R CLL patients (median age 67 years; 35.1% with prior covalent BTKi exposure) treated between April 2018 and November 2024. Among 24 evaluable patients, ORR was 91.7%, with a complete remission rate of 66.7%. In cBTKi-pretreated patients, ORR was 87.5% and CR rate was 62.5%. Undetectable MRD rates were 78.6% in peripheral blood and 71.4% in bone marrow, with 30-month PFS, time to next treatment, and OS all exceeding 90% for both the overall cohort and cBTKi-pretreated subgroup. The primary safety signal was grade ≥3 neutropenia during the combination phase, which was manageable with G-CSF support. A multilevel network meta-regression incorporating data from ALPINE (N=652), ELEVATE-RR (N=533), and ASCEND (N=310) further demonstrated that zanubrutinib was associated with improved PFS versus both ibrutinib (HR=0.67, 95% CrI=0.52–0.87) and acalabrutinib (HR=0.57, 95% CrI=0.34–0.95) in the general R/R CLL population, with this PFS advantage maintained in the high-risk del(17p)/del(11q) subgroup; OS was similar across all BTK inhibitors with wide credible intervals.

Designing Beqalzi and Jaypirca Trials for CLL/SLL Patients

The CLL/SLL treatment landscape has been shaped by a broad portfolio of clinical trials spanning fixed-duration combination regimens, BTK inhibitor comparisons, chemoimmunotherapy, and cellular therapies. These studies employ diverse design parameters — from phase 2 single-arm studies to large phase 3 randomized controlled trials and network meta-analyses — with progression-free survival and overall survival serving as the predominant primary endpoints across settings.

Navigating the Competitive CLL/SLL Treatment Landscape

The treatment landscape for CLL/SLL has undergone a fundamental paradigm shift, with targeted agents — as monotherapy or in combination — decisively displacing chemoimmunotherapy (CIT) as the standard of care. As reflected in national guidelines updated between 2023 and 2025 (France, Germany, and the US), CIT is now considered appropriate only in exceptional cases. The primary first-line options consist of continuous BTK inhibitor (BTKi) therapy (ibrutinib, zanubrutinib, or acalabrutinib) or fixed-duration regimens combining the BCL2 inhibitor venetoclax with obinutuzumab or a BTKi. Pathway inhibitors (BTKis, PI3K inhibitors, and BCL2 inhibitors) have demonstrated superior efficacy compared to CIT both in the frontline and relapsed/refractory settings, and have shown capacity to mitigate the adverse prognostic impact of high-risk biomarkers such as TP53 aberrations and unmutated IGHV. In the high-risk CLL2-GIVe trial — enrolling previously untreated patients with del(17p) and/or TP53 mutation — the obinutuzumab, ibrutinib, and venetoclax combination yielded a complete response rate of 58.5%, undetectable MRD in peripheral blood in 78.0% of patients, and estimated 24-month progression-free and overall survival rates of 95.1% each, with most adverse events being low grade.

Head-to-head comparative data further substantiate the advantage of next-generation BTKis over earlier standards. In a phase III trial of acalabrutinib versus investigator's choice (idelalisib plus rituximab or bendamustine plus rituximab) in relapsed/refractory CLL, median PFS was not reached with acalabrutinib versus 16.5 months with investigator's choice (HR 0.31; 95% CI, 0.20–0.49; P<0.0001), with an estimated 12-month PFS of 88% versus 68%, respectively. The safety advantage was also notable: serious adverse events occurred in 29% of acalabrutinib-treated patients compared to 56% in the idelalisib-rituximab arm. In treatment-naive CLL, acalabrutinib monotherapy achieved an overall response rate of 97% (90% partial response, 7% complete response) at a median follow-up of 53 months, with a 48-month duration of response rate of 97% and only 6% discontinuation due to adverse events. Matching-adjusted indirect comparisons further confirmed a favorable safety profile for acalabrutinib with or without obinutuzumab relative to ibrutinib and venetoclax-based regimens, with the exception of an increased neutropenia risk when combined with obinutuzumab.

For patients with multiply relapsed or "double refractory" disease — having progressed on both BTKi and BCL2 inhibitor-based regimens — novel investigational approaches are demonstrating meaningful activity. Noncovalent BTKis, particularly pirtobrutinib, have shown substantial efficacy in patients who have progressed on covalent BTKis. CAR T-cell therapy with lisocabtagene maraleucel (liso-cel), now FDA-approved for double-refractory CLL/SLL, achieved overall and complete response rates of 82% and 45%, respectively, with undetectable MRD in blood and marrow in 75% and 65% of evaluable patients in the TRANSCEND CLL 004 study — a population with a median of four prior lines of therapy and 83% bearing high-risk features. Bispecific antibodies represent an additional emerging modality with high response rates in heavily pretreated patients. Fixed-duration combination regimens from pivotal trials (CLL14, GLOW, CAPTIVATE, AMPLIFY, MURANO) continue to support extended treatment-free intervals, though outcomes remain suboptimal in high-risk genomic subgroups, and cardiovascular toxicity — particularly with ibrutinib-venetoclax — remains a clinically relevant concern.

Beqalzi-Brukinsa: A New Benchmark for First-Line CLL?

The recent presentation of Beqalzi and Brukinsa's Phase I/Ib data at EHA 2026 represents a significant moment for the chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) treatment landscape. For patients, particularly those with high-risk features like del(17p) and/or TP53 mutations, who historically faced poor outcomes with traditional chemoimmunotherapy, these results offer substantial hope. The all-oral combination demonstrated an unprecedented 100% overall response rate and, critically, 100% 24-month progression-free survival in the 320mg Beqalzi cohort.

What truly stands out is the depth of response, evidenced by undetectable measurable residual disease (uMRD4) rates climbing from 81.2% at week 24 to an impressive 98.2% at week 96. This level of deep remission is a key indicator of durable disease control and aligns with the evolving goal of achieving functional cures in CLL. The favorable safety profile, notably the absence of clinical or laboratory tumor lysis syndrome and treatment-emergent adverse event-related deaths, is also a crucial factor, especially for a first-line regimen where tolerability is paramount.

Strategically, this combination could reshape the first-line treatment paradigm, potentially setting a new benchmark for efficacy and safety. The high uMRD rates strongly suggest the feasibility of a time-limited, chemotherapy-free approach, which is a highly desirable patient outcome and a significant competitive advantage. However, it is important to acknowledge that these are early-phase results. While promising, the relatively small patient cohort and the need for longer-term follow-up in larger Phase III trials are critical considerations. The dynamic competitive landscape, with ongoing advancements in BTK and BCL2 inhibitors, also means continuous innovation will be essential to maintain a leading position. Nevertheless, these data provide a compelling rationale for the continued development of this potent combination, potentially offering a new, highly effective, and well-tolerated option for patients with newly diagnosed CLL/SLL.