Zanubrutinib Provides ORR, PFS Benefits Over Ibrutinib in Relapsed/Refractory CLL/SLL

Zanubrutinib (Brukinsa) elicited significantly higher response rates and survival benefits compared with ibrutinib (Imbruvica) in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), according to findings from the preplanned interim analysis of the phase 3 ALPINE trial (NCT03734016) presented at the 10th Annual Meeting of the Society of Hematologic Oncology.

After a median follow-up of 15 months, patients who received zanubrutinib (n = 207) achieved an overall response rate (ORR) of 78.3% (95% CI, 72.0%-83.7%) vs 62.5% (95% CI, 55.5%-69.1%) for patients given ibrutinib (n = 208; 2-sided P = .0006; pre-specified α = .0099). In the zanubrutinib arm, the complete response/complete response with incomplete bone marrow recovery (CR/CRi) rate was 1.9%, the partial response (PR) rate was 75.8%, and the nodular PR (nPR) rate was 0.5%, compared with CR/CRi, PR, and nPR rates of 1.4%, 61.1%, and 0, respectively, in the ibrutinib arm.

Additionally, the rates of PR with lymphocytosis, stable disease, and disease progression in the zanubrutinib arm were 10.1%, 8.2%, and 0.5%, respectively. Those rates were 18.8%, 13.5%, and 1.0%, respectively, in the ibrutinib arm.

“In recent years, treatment of CLL/SLL has been transformed with the advent of effective inhibitors of B-cell receptor signaling, such as the BTK inhibitor, ibrutinib,” lead study author Jennifer R. Brown, MD, PhD, director of the CLL Center at Dana-Farber Cancer Institute and the Worthington and Margaret Collette Professor of Medicine in the Field of Hematologic Oncology at Harvard Medical School, and colleagues, wrote in a poster presentation of the data.

The clinical course of CLL usually includes disease progression, and patients with 17p deletions and TP53 mutations tend to have poorer outcomes and suboptimal responses to chemoimmunotherapy.

The off-target effects of ibrutinib, a BTK inhibitor, contribute to its toxicity profile, which includes an increased risk for cardiovascular diseases such as atrial fibrillation, hypertension, and hemorrhage. Additionally, the cardiovascular adverse effects (AEs), rash, and diarrhea observed in patients who received ibrutinib have been associated with the off target-inhibition of kinases like EGFR, HER, and TEC.

Zanubrutinib, a next-generation BTK inhibitor, has demonstrated lower rates of atrial fibrillation compared with ibrutinib. High response rates have been reported in previously untreated patients with 17p deletions who received zanubrutinib.

The randomized, international, open-label ALPINE study investigated zanubrutinib vs ibrutinib in patients with relapsed/refractory CLL/SLL.

Eligible patients included those at least 18 years of age with relapsed/refractory CLL/SLL following at least 1 prior systemic therapy. Patients also needed to have measurable lymphadenopathy by CT scan or MRI, and an ECOG performance status of 0 to 2. Relapsed disease was defined as disease that relapsed over 6 months after the last CLL/SLL treatment and subsequently progressed. Refractory disease was defined as disease with no objective response or progression within 6 months of the last CLL/SLL treatment.

Patients were excluded if they had current or past Richter’s transformation, prior treatment with BTK inhibitors, or treatment with vitamin K antagonists, such as warfarin.

Between November 5, 2018, and December 20, 2019, 415 patients were randomly assigned 1:1 to receive either zanubrutinib at 160 mg twice daily or ibrutinib at 420 mg once daily until disease progression or withdrawal of consent. Of the 207 and 208 patients in the zanubrutinib and ibrutinib arms, 204 and 207, respectively, received their assigned treatment.

The primary end point of this trial was investigator-assessed ORR, including CR/CRi, PR, or nPR. Non-inferiority between the treatment arms was assessed, and, if non-inferiority was demonstrated, a hierarchical approach would test the superiority of zanubrutinib over ibrutinib in ORR.

Key secondary end points included progression-free survival (PFS), defined as the time from randomization to disease progression or death, and the presence of any-grade atrial fibrillation or flutter. Other secondary end points included duration of response, overall survival (OS), rate of PR with lymphocytosis or higher, and safety.

The treatment arms were well balanced for demographics and disease characteristics. In total, 62.3% and 68.6% of the zanubrutinib arm and 61.5% and 75.0% of the ibrutinib arm were at least 65 years old and male, respectively. Additionally, 7.3% and 10.1% of the zanubrutinib and ibrutinib arms, respectively, received more than 3 prior lines of therapy. Additionally, 58.9% of patients in the zanubrutinib arm and 59.6% in the ibrutinib arm had Ann Arbor stage I/II disease.

Regarding mutation status, 11.6% of patients in the zanubrutinib arm and 12.5% in the ibrutinib arm had 17p deletions, and 14.0% of the zanubrutinib arm and 11.5% of the ibrutinib arm had TP53 mutations. In addition, 29.5% and 26.4% of patients the zanubrutinib and ibrutinib arms, respectively, had 11q deletions. In total, 51.2% and 50.5% of patients in the zanubrutinib and ibrutinib arms, respectively, had bulky disease, defined as disease measuring at least 5 cm.

The data cutoff for this interim analysis was approximately 12 months after 415 patients were randomized. The data used in this analysis were for these first 415 patients.

At a median follow-up of 15.3 months (range, 0.1-23.1) in the zanubrutinib arm and 15.4 months (range, 0.1-26.0) in the ibrutinib arm, 87.4% and 75.5% of the zanubrutinib and ibrutinib arms, respectively, were still receiving treatment. The most common reason for treatment discontinuation was AEs. Of the 11.1% of patients in the zanubrutinib arm who discontinued treatment, 1.9% had progressive disease (PD), 1.4% withdrew, and 7.7% had an AE. Of the 24.0% of patients in the ibrutinib arm who discontinued treatment, 6.7% had PD, 2.9% withdrew, 13.0% had an AE, 1.0% discontinued at the investigator’s discretion, and 1 patient was lost to follow-up. In addition, 2.9% of patients in the zanubrutinib arm and 4.3% of those in the ibrutinib arm discontinued treatment or started a new therapy prior to the first ORR assessment.

The ORR benefit with zanubrutinib over ibrutinib was consistent across most patient subgroups, including age, sex, disease stage, number of prior lines of therapy, mutation status, and bulky disease. In the subset of patients with 17p deletions, the ORR was 83.3% in the zanubrutinib arm vs 53.8% in the ibrutinib arm.

At a median follow-up 14 months, the investigator-assessed 12-month PFS rates were 94.9% and 84% in the zanubrutinib and ibrutinib arms, respectively (HR, 0.40; 95% CI, 0.23-0.69; 2-sided P = .0007). The 12-month OS rate was 97.0% in the zanubrutinib arm vs 92.7% in the ibrutinib arm (HR, 0.54; 95% CI, 0.23-1.16; 2-sided P = .1081).

Regarding safety, 95.6% and 99.0% of patients in the zanubrutinib and ibrutinib arms, respectively, experienced an AE of any grade. Grade 3 or higher AEs were observed in 55.9% and 51.2% of the zanubrutinib and ibrutinib arms, respectively. Additionally, 27.5% and 32.4% of the zanubrutinib and ibrutinib arms, respectively, experienced serious AEs, and 3.9% and 5.8% experienced fatal AEs.

In total, 11.3%, 39.7%, and 7.8% of patients in the zanubrutinib arm and 12.1%, 40.6%, and 13.0% of those in the ibrutinib arm had AEs leading to dose reduction, dose interruption, and treatment discontinuation, respectively.

The most frequent AEs of any grade in the zanubrutinib and ibrutinib arms, respectively, were diarrhea (16.7% vs 19.3%), neutropenia (19.6% vs 15.5%), anemia (13.2% vs 15.0%), upper respiratory tract infection (21.6% vs 14.0%), arthralgia (9.3% vs 14.0%), hypertension (15.7% vs 13.0%), muscle spasms (2.9% vs 11.1%), contusion (10.3% vs 8.7%), urinary tract infection (10.8% vs 8.2%), and cough (12.7% vs 6.3).

AEs of special interest in the zanubrutinib and ibrutinib arms, respectively, included cardiac disorders (any grade, 13.7% vs 25.1%; grade ≥ 3, 2.5% vs 6.8%); hemorrhage (any grade, 35.8% vs 2.9%; grade ≥ 3, 2.9% vs 2.9%), including major hemorrhage (any grade, 2.9% vs 3.9%; grade ≥ 3, 2.9% vs 2.9%); hypertension (any grade, 16.7% vs 16.4%; grade ≥ 3, 10.8% vs 10.6%); infections (any grade, 59.8% vs 63.3%; grade ≥ 3, 12.7% vs 17.9%); neutropenia (any grade, 28.4% vs 21.7%; grade ≥ 3, 18.6% vs 15.0%); thrombocytopenia (any grade, 9.3% vs 12.6%; grade ≥ 3, 3.4% vs 3.4%); and secondary primary malignancies (any grade, 8.3% vs 6.3%; grade ≥ 3, 4.9% vs 1.9%), including skin cancers (any grade, 3.4% vs 4.8%; grade ≥ 3, 1.5% vs 1.0%).

Additionally, the rates of any-grade atrial fibrillation and flutter were consistently higher in the ibrutinib arm, at 10.1% vs 2.5% in the zanubrutinib arm (2-sided P = .0014). Atrial fibrillation and flutter of grade 3 or higher was seen in 1.0% of patients in the zanubrutinib arm and 1.9% of the ibrutinib arm.

“These data support that more selective BTK inhibition, with more complete and sustained BTK occupancy, results in improved efficacy and safety outcomes,” the study authors concluded.

Reference

Brown JR, Hillmen P, Eichhorst B, et al. First interim analysis of ALPINE study: results of a phase 3 randomized study of zanubrutinib vs ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Presented at: 2022 SOHO Annual Meeting; September 28-October 1, 2022; Houston, TX. Poster CLL-115.