KEY TAKEAWAYS
- SEQUOIA is a phase 3, multicentre, open-label, randomized, active-controlled study comparing zanubrutinib with bendamustine-rituximab in patients with untreated CLL or SLL.
- The study’s primary endpoint was progression-free survival per the independent review committee in the intention-to-treat population.
- The results showed a statistically significant improvement in progression-free survival with zanubrutinib compared to bendamustine-rituximab.
- The most common grade 3 or worse adverse event was neutropenia, with serious AEs occurring in 88 (37%) of 240 patients in group A and 113 (50%) of 227 patients in group B.
Zanubrutinib effectively treats relapsed chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma(SLL). It is a next-generation, selective Bruton tyrosine kinase inhibitor. To evaluate the efficacy of zanubrutinib as first-line therapy for patients with CLL or SLL, we compared it to the standard of care, bendamustine-rituximab.
We conducted phase 3 open-label, multicenter research at 153 centers in 14 nations and regions. Patients who met International Workshop on CLL criteria for untreated CLL or SLL, who were 65 or older, or 18 or older with comorbidities, and who had an Eastern Cooperative Oncology Group performance status score of 0-2 were considered eligible. Patients without del(17)(p131) were randomly assigned to receive either zanubrutinib (group A) or bendamustine-rituximab (group B) through a centralized interactive web response system (permutated blocks with a random block size of four). Zanubrutinib was given to patients in group C who had del(17)(p131). Oral zanubrutinib 160 mg twice daily (28-day cycles); intravenous bendamustine 90 mg/m2 of body surface area on days 1 and 2 for six cycles; and intravenous 375 mg/m2 of body surface area of rituximab the day before or on day 1 of cycle 1, and 500 mg/m2 of body surface area on day 1 of cycles 2-6. Progression-free survival was used as the primary endpoint, with a two-sided significance level α of 0.05 required to show superiority between Groups A and B in the Intent-to-Treat population. All patients given at least one dosage of the study medication were evaluated for safety.
590 participants were enrolled between October 31, 2017, and July 22, 2019, with those without del(17)(p13·1) receiving either zanubrutinib (group A; n=241) or bendamustine-rituximab (group B; n=238). Median progression-free survival was not achieved in either group at a median follow-up of 26.2 months (IQR 23.7-29.6) (95% CI not estimable [NE] to NE; group B 28.1% to NE). Group A had a much better progression-free survival rate than Group B (HR 0·42 [95% CI 0·28 to 0·63]; two-sided p<0·0001). Neutropenia was the most common adverse event of grade 3 or worse, affecting 27 (11%) of 240 patients in group A, 116 (51% of 227) in group B, and 17 (15%) of 111 patients in group C. Eighty-eight (37%) of 240 patients in group A experienced serious adverse events, 113 (50%) of 227 patients in group B experienced adverse events, and 45 (41%) of 111 patients in group C experienced adverse events. Eleven (5%) of 240 patients in group A died due to an adverse event, whereas 12 (5%) of 227 patients in group B died due to an adverse event, and three (3%) of 111 patients in group C died due to an adverse event. The most common causes of death were COVID-19 (four [2%] of 240 patients in group A), diarrhea, aspiration pneumonia (two [1%] of 227 patients in group B), and other infectious diseases.
Source: https://pubmed.ncbi.nlm.nih.gov/35810754/
Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT03336333
Tam CS, Brown JR, Kahl BS, Ghia P, Giannopoulos K, Jurczak W, Šimkovič M, Shadman M, Österborg A, Laurenti L, Walker P, Opat S, Chan H, Ciepluch H, Greil R, Tani M, Trněný M, Brander DM, Flinn IW, Grosicki S, Verner E, Tedeschi A, Li J, Tian T, Zhou L, Marimpietri C, Paik JC, Cohen A, Huang J, Robak T, Hillmen P. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukemia and small lymphocytic lymphoma (SEQUOIA): a randomized, controlled, phase 3 trial. Lancet Oncol. 2022 Aug;23(8):1031-1043. doi: 10.1016/S1470-2045(22)00293-5. Epub 2022 Jul 7. Erratum in: Lancet Oncol. 2023 Mar;24(3):e106. PMID: 35810754.
