Zanubrutinib Induces Sustained PFS Benefit in Relapsed/Refractory CLL/SLL

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Treatment with zanubrutinib (Brukinsa), compared with ibrutinib (Imbruvica), demonstrated sustained progression-free survival (PFS) benefit in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), according to extended follow-up from the phase 3 ALPINE trial (NCT03734016) presented at the 2023 American Society of Hematology Annual Meeting.¹

“ALPINE is the only study to demonstrate PFS superiority in a head-to-head comparison of BTK inhibitors,” Jennifer R. Brown, MD, PhD, director of the CLL Center of the Division of Hematologic Malignancies at Dana-Farber Cancer Institute and the Worthington and Margaret Collette Professor of Medicine in the Field of Hematologic Oncology at Harvard Medical School, Boston, said during a presentation of the data.

“With over 3 years of follow-up, these data reconfirm zanubrutinib improved efficacy over ibrutinib and a more favorable safety profile in patients with relapsed/refractory CLL/SLL.”

After a median follow-up of 39.0 months, zanubrutinib sustained PFS benefit over ibrutinib, reducing the risk for disease progression by 32% (HR, 0.68; 95% CI, 0.53-0.86; P = .0011). Brown noted that this benefit was seen across all subgroups, including age, sex, prior lines of therapy, baseline 17p deletion and/or TP53 mutation status, bulky disease, baseline IGHV mutation status, disease stage, and complex karyotype.

Among patients with a 17p deletion and/or TP53 mutation, zanubrutinib reduced the risk for disease progression by 48% (HR, 0.52; 95% CI, 0.33-0.83; P = .0047). The 36-month PFS rates with zanubrutinib and ibrutinib were 58.6% and 41.3%, respectively. This benefit was seen, regardless of 17p deletion and/or TP53 mutation status during the extended follow-up, with zanubrutinib reducing the risk for disease progression by 23% (HR, 0.77; 95% CI, 0.59-1.01).

Additionally, PFS benefit with zanubrutinib was confirmed in a sensitivity analysis, designed to include only progression and death events that occurred on active treatment (HR, 0.69; 95% CI, 0.49-0.97; P = .031).

In addition, overall response rate (ORR) remained higher with zanubrutinib compared with ibrutinib (85.0% vs 74.8%, respectively; P = .001), according to the abstract.

Brown highlighted that responses with complete remission (CR)/complete remission with incomplete count recovery (CRi) to zanubrutinib and ibrutinib deepened (10.4% vs 7.1%, respectively) at 48 months.

The 36-month overall survival rates with zanubrutinib and ibrutinib were 82.5% and 79.6%, respectively, reducing the risk for death by 25% with zanubrutinib (HR, 0.75; 95% CI, 0.54-1.05; P = .098).

Median treatment with zanubrutinib was 38.3 months (range, 0.4-54.9), compared with 35.0 months (range, 0.1-58.4) with ibrutinib.

Grade 3 to 5 adverse events (AEs) occurred in 72.5% and 77.5% of the zanubrutinib and ibrutinib arms, respectively, while grade 5 AEs were seen in 12.7% and 12.3%. Overall, 50.9% of the zanubrutinib arm and 59.0% of the ibrutinib arm experienced a serious AE.

AEs that led to dose reductions occurred in 14.5% of the zanubrutinib arm and 18.2% of the ibrutinib arm, dose interruptions in 60.5% and 62.0%, respectively, treatment discontinuation in 19.8% and 26.2%, and hospitalization in 46.3% and 55.6%.

Further, Brown noted that, despite similar hypertension rates in both arms, the change in systolic blood pressure was lower with zanubrutinib, while the cardiac safety profile was also more favorable with the agent (cardiac AEs, 24.7% vs 34.6%, respectively). Serious cardiac AEs were lower with zanubrutinib over ibrutinib (3.4% vs 9.6%, respectively)–including atrial fibrillation/flutter (3 vs 13), ventricular fibrillation (0 vs 2), and acute coronary syndrome (3 vs 3)–as well as fewer fatal cardiac events (0 vs 6). Cardiac events leading to treatment discontinuation occurred in 3 patients in the zanubrutinib arm and 15 patients in the ibrutinib arm.

ALPINE Study

In the randomized, multinational phase 3 ALPINE trial, 652 patients with relapsed/refractory CLL/SLL after 1 or more prior treatment were randomized to receive either 160 mg zanubrutinib twice daily or 420 mg ibrutinib daily until disease progression or unacceptable toxicity.²

Patients were stratified by age, geographic, region, refractoriness, and 17p deletion and/or TP53 mutation.

Key inclusion criteria included relapsed/refractory disease to 1 or more prior systemic treatment for CLL/SLL, measurable lymphadenopathy by CT or MRI, and treatment per iwCLL. Patients were excluded if they had prior Bruton tyrosine kinase therapy and treatment with warfarin or other vitamin K antagonists.

Demographic and clinical characteristics were balanced at baseline across both groups. Median age was 67 years (range, 35-90) in the zanubrutinib arm and 68 years (range, 35-89) in the ibrutinib arm, while the majority were White (81%). Overall, 44.3% and 45.8% of patients, respectively, had bulky disease, 73.4% and 74.2% had unmutated immunoglobulin IGHV status, and 22.9% and 23.1% had a chromosome 17p deletion, a TP53 mutation, or both. Patients received a median of 1 prior line of therapy (range, 1-12), with 7.3% and 9.2% of patients in the zanubrutinib and ibrutinib arms, respectively, having received more than 3 lines of therapy.

Further, 80% of the zanubrutinib arm and 76% of the ibrutinib arm had previously received chemoimmunotherapy.

After a median follow-up of 29.6 months, zanubrutinib demonstrated superior PFS, compared with ibrutinib, reducing the risk for disease progression by 35% (HR, 0.65; 95% CI, 0.49-0.86; P = .0024). The 24-month PFS rates were 78.4% and 65.9%, respectively.

Among patients with a 17p deletion and/or TP53 mutation, zanubrutinib also showed superior PFS, compared with ibrutinib, reducing the risk for disease progression by 47% (HR, 0.53; 95% CI, 0.31-0.88).

At extended follow-up, 194 patients (59%) were ongoing with treatment with zanubrutinib, compared with 152 (47%) with ibrutinib, after median follow-ups of 40.3 months and 38.7 months, respectively. In the zanubrutinib arm, 130 patients discontinued treatment because of AEs (n = 69), progressive disease (PD; n = 51), withdrawal (n = 7), and lost to follow-up or other (n = 3), compared with 172 lost in the ibrutinib arm because of AEs (n = 88), PD (n = 62), withdrawal (n = 15), physician decision (n = 6), and lost to follow-up or other (n = 1).¹

REFERENCES:

1. Brown JR, Eichhorst BF, Lamanna N, et al. Extended Follow-up of ALPINE Randomized Phase 3 Study Confirms Sustained Superior Progression-Free Survival of Zanubrutinib Versus Ibrutinib for Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma (R/R CLL/SLL). Blood. 2023;142(1):202. doi:10.1182/blood-2023-174289.

2. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. New Eng J Med. 2023;388:319-332. doi:10.1056/NEJMoa2211582.