Extended Follow-Up Supports Frontline Zanubrutinib as Standard Option in CLL/SLL

Zanubrutinib (Brukinsa) demonstrated long-term improved efficacy vs bendamustine plus rituximab (Rituxan [BR]) at 5-year follow-up in patients with treatment-naive chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), according to findings presented at the 2024 ASH Annual Meeting.¹

In cohort 1 of the phase 3, open-label SEQUOIA trial (NCT03336333), patients who were randomly assigned to zanubrutinib (n = 241) experienced improved progression-free survival (PFS) regardless of disease risk status and COVID-19 impact compared with patients randomly assigned to BR (n = 238). Zanubrutinib also showed better overall response rate (ORR) and adverse event (AE) incidence.

Zanubrutinib demonstrated sustained PFS vs bendamustine/rituximab at 5 years in treatment-naive CLL/SLL.

Bruton tyrosine kinase (BTK) inhibitors offer improved outcomes for patients with CLL/SLL, and the next-generation BTK inhibitors such as zanubrutinib are designed for even better efficacy and tolerability through increased potency, greater BTK specificity, and more exposure coverage.

“With a median study follow-up of 61.2 months, zanubrutinib has been shown to offer a sustained superior PFS over BR in [patients with] treatment-naive CLL with 71% reduction of the risk of progression or death,” Mazyar Shadman, MD, MPH, medical director of cellular immunotherapy at Fred Hutchinson Cancer Center, said in his presentation of the data.

Median PFS was not reached in patients given zanubrutinib vs 44.1 months (95% CI, 38.4-55.6) in those given BR (HR, 0.29; 95% CI, 0.21-0.40; P < .0001). The 54- and 60-month PFS rates were 80.1% and 75.8% with zanubrutinib vs 44.6% and 40.1% with BR, respectively.

Additionally, the degree of PFS difference was similar when the investigators adjusted for the impact of COVID-19 on the treatment outcomes (HR, 0.25; 95% CI, 0.17-0.35; P < .0001), with 83.2% vs 45.2% 54-month PFS rates and 78.7% vs 40.6% 60-month PFS rates for zanubrutinib vs BR, respectively.

Regardless of IGHV status, zanubrutinib showed consistent PFS benefit (HR for mutated vs unmutated, 1.35; 95% CI, 0.76-2.40; P = .5194). However, treatment with BR displayed lower PFS rates which were affected by IGHV status. Shadman noted that in prior reports from cohort 2 of the SEQUIOA trial, patients with deletion 17p (del[17p]) and TP53 mutations showed similar PFS rates in those without the high-risk features. “This suggests that the treatment with zanubrutinib may overcome negative prognostic factors such as IGHV [mutation], del(17p), or TP53 mutation,” he said.

The ORR with long-term follow-up was 97.5% (95% CI, 94.7%-99.1%) with zanubrutinib vs 88.7% (95% CI, 83.9%-92.4%) with BR. With zanubrutinib, the complete response (CR)/CR with incomplete bone marrow recovery (CRi) rates was 20.7% (95% CI, 15.8%-26.4%) compared with BR at 23.5% (95% CI, 18.3%-29.4%). The CR/CRi rate is the highest reported with an inhibitor monotherapy, according to Shadman.

In total, 34 deaths occurred in each arm at the time of follow-up. The estimated overall survival (OS) rates at 54 and 60 months with zanubrutinib were 87.7% and 85.5%, respectively; after adjusting for COVID-19, it was 91.3% and 89.4%. For treatment with BR, the estimated 54- and 60-month OS rates were 86.0% and 85.0%; then with COVID-19 adjustment, 87.8% and 86.8%.

In terms of toxicity, zanubrutinib was well tolerated over the extended treatment period in these patients with CLL/SLL. The most common grade 3 or higher treatment-emergent and post-treatment AEs included COVID-19 (zanubrutinib, 9% vs BR, 2%), hypertension (12% vs 6%), and neutropenia (10% vs 41%).

There were “low rates of atrial fibrillation/flutter [afib/flutter], infections, or AEs that limit daily living activities like [gastrointestinal] toxicities,” Shadman explained. The exposure-adjusted incidence rates for AEs of interest included afib/flutter at 0.13 with zanubrutinib vs 0.09 with BR, hemorrhage at 1.66 vs 0.35, major hemorrhage at 0.18 vs 0.05, and hypertension at 0.50 vs 0.38. However, the cumulative incidence of afib/flutter and hypertension remained low and were comparable to background incidence seen in the BR arm, according to the investigators.

In the original readout of the SEQUOIA trial, zanubrutinib showed statistically significant and clinically meaningful improvement in PFS over BR in patients with CLL/SLL without del(17p) at 26.2 months median follow-up.²

Zanubrutinib was given at 160 mg twice daily until disease progression or intolerable toxicity and BR was given for a maximum of 6 cycles. The primary end point was PFS, with ORR and CR rate as the key secondary end points. Crossover was allowed after progression and prior to starting any other therapy for CLL/SLL.

At baseline, patient characteristics were similar between the zanubrutinib and BR arms. The median age was 70 years, with 82% of patients above the age of 65 in each arm. A majority of patients were male, and 72% were from Europe. Approximately 30% had Binet stage C disease and disease bulk of 5 cm or larger, respectively. There were 53% of patients in each arm with unmutated IGHV, and 6% with a TP53 mutation.

The median treatment duration with zanubrutinib at the 61.2-month follow-up was 60.5 months (95% CI, 0.5-77.9), with 163 patients (67.6%) still receiving treatment. For BR, 79% completed all 6 cycles of treatment and 13% discontinued early due to AEs. Fifty-nine patients overall crossed over from BR to zanubrutinib after experiencing disease progression.

“The result of this extended follow-up support the use of zanubrutinib as the standard first-line treatment option for patients, regardless of the disease risk factors,” Shadman concluded.

References:

1. Shadman M, Munir T, Robak T, et al. Sustained superiority of zanubrutinib vs bendamustine + rituximab in treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma: 5-year follow-up of cohort 1 from the SEQUOIA study. Blood. 2024;144(suppl 1):3249. doi:10.1182/blood-2024-194864

2. Tam CS, Brown JR, Kahl BS, et al. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022;23(8):1031-1043. doi:10.1016/S1470-2045(22)00293-5