Zanubrutinib shows significant activity in high-risk treatment-naïve patients with del(17p) CLL/SLL in a global phase III trial

Although rare in treatment-naïve patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), chromosome 17p deletion (del(17p)) is associated with rapid disease progression and poor response to treatment.¹ The treatment of choice for this high-risk disease group is the Bruton’s tyrosine kinase inhibitor (BTKi) ibrutinib; however, off-target toxicities are common. Zanubrutinib is a highly potent and selective second-generation BTKi. With greater selectivity than ibrutinib, it is anticipated that zanubrutinib may have an improved safety profile. In an article recently published in Haematologica, Constantine Tam, a member of our Scientific Advisory Board, and colleagues, presented 18-month follow-up data from Arm C of the phase III SEQUOIA study (NCT03336333) of zanubrutinib monotherapy in treatment-naïve CLL/SLL patients with del(17p).²

Study design

• A nonrandomized arm of the multicenter, open-label, phase III SEQUOIA clinical trial that included adult patients with del(17p) CLL/SLL, without prior BTKi treatment
• Patient eligibility criteria:
  • Confirmed CLL/SLL requiring treatment, as defined by the International Workshop on Chronic Lymphocytic Leukemia (iwCLL)
  • Central confirmation of del(17p) by fluorescence in situ hybridization (> 7% aberrant nuclei present)
  • Treatment-naïve patients aged ≥ 65 years, or incompatible with chemoimmunotherapeutic agents (fludarabine, cyclophosphamide, and rituximab) and an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• Zanubrutinib was evaluated for safety and tolerability (dose 160 mg, oral, twice daily until intolerance or progressive disease [PD])
• After the first dose, patient responses were assessed quarterly for 24 months and then every 6 months, until PD or initiation of new treatment
• Bone marrow examination was performed at baseline and for assessment of complete response (CR)
• Study endpoints included overall response rate (ORR), progression-free survival (PFS), duration of response (DOR), and safety (frequency and severity of all adverse events [AEs]). Best ORR and PFS were reported for both del(17p), in the following disease categories: high, ≥ 20% del(17p)-positive nuclei; and low, > 7% to < 20% del(17p)-positive nuclei

Results

• A total of 109 patients were enrolled from 13 countries (including USA, UK, Europe, Australia, New Zealand, and Russia), between February 3, 2018, and February 20, 2019
• The median duration of the study follow-up was 18.2 months (range, 5.0–26.3)
• At study entry, the median patient age was 70.0 years (range, 42–86)
• Reported symptoms during enrolment, as per iwCLL criteria, included

• • progressive bone marrow failure; lymphadenopathy (both, 41.3%)
  • night sweats (32.1%); progressive lymphocytosis (28.4%); splenomegaly (23.9%); weight loss (14.7%)

• Most patients had other high-risk disease characteristics, in addition to del(17p):

• • Binet stage C (40.4%); bulky disease (38.5%); elevated β2-microglobulin (78.8%); unmutated IGHV (65.0%); complex karyotypes (37.2%)

• Key efficacy data were as follows:

• • An ORR of 94.5%, including three patients (2.8%) with CR
  • One patient (0.9%) achieved CR with incomplete hematologic recovery
  • A partial response was achieved in 95 patients (87.2%), and four patients (3.7%) achieved partial response with lymphocytosis
  • The 18-month estimates of PFS and OS were 88.6% (95% CI, 79.0–94.0) and 95.1% (95% CI, 88.4–98.0), respectively. Median PFS and OS were not reached
  • A 12-month DOR was reported in 92.8% of patients; median DOR was not reached
  • High category del(17p) disease: Best ORR = 98%; 18-month PFS = 89%
  • Low category del(17p) disease: Best ORR = 92%; 18-month PFS = 88%

• Five patients (4.6%) had stable disease, and nine patients (8.3%) progressed, four of whom had histologically confirmed Richter transformation
• At data cutoff (April 15, 2020), treatment was discontinued by seven patients due to PD, four patients due to AEs, and one patient due to withdrawal of consent
• Two patients had new lesions, confirmed with computed tomography/positron emission tomography (CT/PET)
• Although short-term lymphocytosis was detected, target lesion size significantly reduced during response assessments
• Sustained hematologic improvement was observed, as shown in Table 1

Table 1. Hematologic improvement in patients with cytopenias at baseline²

Baseline cytopenia (n)	Sustained improvements by parameter (%)
Anemia (8)	Hemoglobin level (86.0)
Neutropenia (43)	Absolute neutrophil count, (75.0)
Thrombocytopenia (28)	Platelet count (85.7)

• Table 2 shows the most commonly reported AEs
• Grade ≥ 3 AEs and serious AEs were observed in 48.6% and 36.7% of patients, respectively
• Major bleeding (Grade ≥ 3, any serious AE, or bleeding affecting the central nervous system) occurred in just six patients (5.4%)
• Only three patients had treatment-emergent atrial fibrillation, two were grade ≥ 3
• Five fatalities were reported, due to either PD (n = 2) or AEs (renal failure, n = 1; septic shock, n = 1; Grade 5 pneumonia, n = 1)

Table 2. Most common AEs of any grade, and Grade ≥ 3 AEs²

AE, adverse event.
Most common AE (≥ 10%), any grade	%
Arthralgia	11.0
Back pain	12.8
Constipation	13.8
Contusion	20.2
Cough	11.9
Diarrhea	16.5
Fatigue	10.1
Nausea	14.7
Upper respiratory tract infection	19.3
Rash	13.8
Grade ≥3 AE	%
Atrial fibrillation/flutter	1.8
Infections	13.8
Major bleeding	4.6
Neutropenia/decreased neutrophil count	12.9
Pneumonia	3.7

Conclusion

The results of this arm of the phase III global SEQUOIA trial showed that zanubrutinib monotherapy is active and well tolerated in a previously untreated cohort of high-risk patients with del(17p) CLL/SLL. Despite recruiting an older patient population with chronic comorbidities, major bleeding (resulting from Grade ≥ 3 AEs or serious AEs) was low (5.6%), and no central nervous system event was reported. The high selectivity of zanubrutinib for BTK inhibition was demonstrated by a low incidence (< 1%) of Grade ≥ 3 AEs, such as diarrhea, joint stiffness, muscle pain or muscle injuries. Study limitations included a single-arm study design and a relatively short duration of follow-up.

In summary, zanubrutinib holds promise for treating patients with high-risk, del(17p) CLL/SLL. However, similarly to other BTKi therapies, single-agent zanubrutinib is unlikely to promote deep responses. Enrolment of patients with del(17p) CLL/SLL into Arm D of the SEQUOIA trial, evaluating zanubrutinib combined with the BCL-2 inhibitor venetoclax, is underway.