Zanubrutinib (Brukinsa) demonstrated durable progression-free survival (PFS) and a manageable safety profile in treatment-naive patients with
At a median follow-up of 78.75 months, findings showed that among the subgroup of patients at least 80 years of age treated with zanubrutinib (n = 38), the investigator-assessed PFS estimate was 89.3% (95% CI, 74.0%-95.9%) at 36 months and 63.8% (95% CI, 44.6%-77.8%) at 72 months. The overall response rates (ORRs) reached 100% for this subgroup of patients, including a complete response (CR) rate of 18.4%.
Additionally, 15.8% of patients in the older subgroup received a subsequent therapy, and 26.3% of patients had died without beginning a subsequent therapy. At 36 months and 72 months, 94.5% (95% CI, 79.8%-98.6%) and 87.7% (95% CI, 70.2%-95.3%) of patients, respectively, had not initiated subsequent therapy.
The respective 36- and 72-month overall survival (OS) rates were 86.8% (95% CI, 71.2%-75.8%) and 75.8% (95% CI, 58.6%-86.6%).
“In this [older] population, which was enriched for high-risk genomic features, such as 17p deletion [del(17p)] and/or TP53 mutations, zanubrutinib demonstrated durable clinical benefit, with high PFS rates at 72 months,” lead study author Alessandrea Tedeschi, MD, of ASST Grande Ospedale Metropolitano Niguarda in Milan, Italy, and colleagues wrote in a poster presentation of the data. “These findings support zanubrutinib as an effective treatment option for treatment-naive CLL/SLL across age groups, including [older] patients.”
In January 2023,
Although CLL/SLL primarily affects older adult patients, patients 80 years of age and above have historically been underrepresented in clinical trials, the study authors noted.1 In SEQUOIA, the randomized arm A—which evaluated zanubrutinib monotherapy—included 241 patients, of whom 28 were at least 80 years of age. In the nonrandomized arm C, which evaluated zanubrutinib in patients harboring del(17p), 10 of the 111 patients were at least 80 years of age.
The goal of the subgroup analysis was to better characterize the outcomes with zanubrutinib for this older population.
SEQUOIA was a global, randomized, open-label phase 3 study that enrolled treatment-naive patients with CLL/SLL who had measurable disease and met International Working Group in CLL criteria for treatment; patients needed to be considered unsuitable for fludarabine, cyclophosphamide, and rituximab (Rituxan).
In arms A and B, patients without del(17p) were randomly assigned 1:1 to receive zanubrutinib at 160 mg per day until disease progression, unacceptable toxicity, or end of study; or bendamustine plus rituximab for a maximum of 6 cycles. Patients with del(17p) were assigned to arm C, where they all received zanubrutinib on the same schedule.
In the older subgroup of patients treated with zanubrutinib in arm A or C, patients had a median age of 81 years (range, 80-87), and 60.5% of patients were male. Notably, 36.8% of patients had del(17p) and/or TP53 mutations, and 57.9% of patients had unmutated IGHV. Additionally, 10.5% of patients had at least 3 copy number aberrations, and complex karyotype data were missing for 36.8% of patients. As of data cutoff, 36.8% of patients remained on treatment.
At a median follow-up of 79.15 months (95% CI, 0.3-96.0) for arm A (n = 241) and 82.73 months (95% CI, 5.0-92.9) for arm C (n = 111), the ITT analysis showed that the estimated 72-month PFS rate was 74.4% (95% CI, 68.1%-79.6%) for arm A and 66.3% (95% CI, 56.2%-74.5%) for arm C. After adjustment for the effect of COVID-19, the 72-month PFS rates were 77.3% (95% CI, 71.1%-82.3%) and 67.0% (95% CI, 57.0%-75.3%) for arms A and C, respectively.
The ORR was 97.5% in arm A and 97.3% in arm C, with respective CR/CR with incomplete marrow recovery (CRi) rates of 27.0% and 21.8% in Arm C.
In the older subgroup, any-grade treatment-emergent adverse effects (TEAEs) of interest included hypertension (28.9%), major hemorrhage (21.1%), atrial fibrillation or flutter (15.8%), and second primary malignancies excluding non-melanoma skin cancer (15.8%). Grade 3 or higher infections were also reported in 36.8% of patients.
Among first-onset TEAEs that emerged within the initial 3 years of treatment, hypertension was reported in 21.1% of patients with an exposure-adjusted incidence rate (EAIR) of 0.56 per 100 person-months. Grade 3or higher infections in 21.1% of patients (EAIR, 0.68), major hemorrhage in 7.9% of patients (EAIR, 0.36), and atrial fibrillation or flutter in 5.3% of patients (EAIR, 0.26) were also reported in first-onset TEAEs in the first 3 years of treatment. Only 3 patients (7.9%) discontinued treatment due to a TEAE in the first 3 years of therapy.
“The tolerability profile observed in this subgroup was consistent with expectations for a very elderly population and aligned with the established safety profile of zanubrutinib. Rates of discontinuation due to AEs were low during the first 3 years of treatment,” the study authors concluded.
