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Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. SEQUOIA (ClinicalTrials.gov identifier: NCT03336333) is a phase III, randomized, open-label trial that compared the oral Bruton tyrosine kinase inhibitor zanubrutinib to bendamustine plus rituximab (BR) in treatment-naïve patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The initial prespecified analysis (median follow-up, 26.2 months) and subsequent analysis (43.7 months) found superior progression-free survival (PFS; the primary end point) in patients who received zanubrutinib compared with BR. At a median follow-up of 61.2 months, median PFS was not reached in zanubrutinib-treated patients; median PFS was 44.1 months in BR-treated patients (hazard ratio [HR], 0.29; one-sided P = .0001). Prolonged PFS was seen with zanubrutinib versus BR in patients with mutated immunoglobulin heavy-chain variable region (IGHV) genes (HR, 0.40; one-sided P = .0003) and unmutated IGHV genes (HR, 0.21 [95% CI, 0.14 to 0.33]; one-sided P < .0001). Median overall survival (OS) was not reached in either treatment arm; estimated 60-month OS rates were 85.8% and 85.0% in zanubrutinib- and BR-treated patients, respectively. No new safety signals were detected. Adverse events were as expected with zanubrutinib; rate of atrial fibrillation was 7.1%. At a median follow-up of 61.2 months, the results supported the initial SEQUOIA findings and suggested that zanubrutinib was a favorable treatment option for untreated patients with CLL/SLL.

Axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor T-cell therapy, was approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL) based on the results from pivotal Cohorts 1+2 of ZUMA-1 (NCT02348216). ZUMA-1 was expanded to investigate safety management strategies aimed at reducing the incidence and severity of cytokine release syndrome (CRS) and neurologic events (NEs). Prospective safety expansion Cohort 5 evaluated the impact of debulking therapy, including rituximab-containing immunochemotherapy regimens and radiotherapy, in axi-cel-treated patients; the CRS and NE management strategy paralleled those in Cohorts 1+2. Among the 50 patients in Cohort 5 who received axi-cel, 40% received ≥3 prior lines of chemotherapy, and 40% had disease that progressed while on the most recent chemotherapy. Forty-eight patients (96%) received debulking therapy, 14 (28%) radiotherapy only, and 34 (71%) systemic immunochemotherapy. Median decrease in tumor burden (per sum of product of diameters of target lesions) relative to screening was 17.4% with R-ICE/R-GDP, 4.3% with other debulking chemotherapies, and 6.3% with radiotherapy only. All patients were followed for ≥8 months. CRS was reported in 43 patients (86%), with 1 patient (2%) experiencing grade ≥3. NEs were reported in 28 patients (56%), with 6 (12%) experiencing grade ≥3. Cytopenias were the most frequent grade ≥3 adverse event (AE); 19 (38%) and 18 (36%) treated patients had any and grade ≥3 prolonged thrombocytopenia, respectively, and 25 (50%) and 24 (48%) patients had any and grade ≥3 prolonged neutropenia, respectively. Overall, patients who received debulking chemotherapy had higher incidences of serious treatment-emergent AEs than those who received radiotherapy only. At the 24-month analysis, objective response rate was 72%, and complete response rate was 56%. Median duration of response, progression-free survival, and overall survival were 25.8, 3.1, and 20.6 months, respectively. These results from exploratory Cohort 5 demonstrate the feasibility of debulking prior to axi-cel, and together with current real-world evidence, suggest that debulking regimens may help minimize the frequency and severity of CRS and NEs in patients with R/R LBCL. The incidence of other AEs observed in Cohort 5 suggest the risk/benefit profile was not improved via the debulking regimens studied here., Competing Interests: TvM: honoraria from Kite, a Gilead Company, Gilead Sciences, Celgene/Bristol Myers Squibb; consulting/advisory role for Janssen, Lilly, and Kite; and research funding from Celgene/Bristol Myers Squibb, Siemens, and Genentech. JK: honoraria from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Gilead Sciences, Incyte, Janssen, Karyopharm, Merck, Novartis, Pfizer, Roche, and Seattle Genetics; consulting/advisory role for AbbVie, Antengene, Bristol Myers Squibb, Gilead Sciences, Karyopharm, Medison Ventures, Merck, Roche, and Seattle Genetics; research funding from AstraZeneca, Merck, and Roche; and other relationship with DSMB, Karyopharm, and Chair of Scientific Advisory Board Lymphoma Canada. KWS: honoraria from Amgen, Bristol Myers Squibb, Janssen, and Kite, a Gilead Company. CT: consulting or advisory role for Amgen, Bristol Myers Squibb, Incyte, Kite, a Gilead Company, Novartis, Roche, and Takeda; research funding from Roche; and travel, accommodations, and expenses from Bristol Myers Squibb, Incyte, Kite, Novartis, Roche, and Takeda. MCM: consulting or advisory role for Bristol Myers Squibb, CDR-life, GSK, and Janssen-Cilag (institution); speaker’s bureau participation for WebMD (institution); and research funding from BeiGene (institution). EF: consulting or advisory role for Novartis; speakers’ bureau participation for Alexion, Astellas, Gilead Sciences, GSK, Novartis, and Sanofi; and travel support from Alexion, Gilead Sciences, MSD, and Novartis. SDG: honoraria from and consulting/advisory role for AbbVie, Gilead Sciences, and Janssen. MJK: honoraria from and consulting/advisory role for Adicet Bio, Celgene/Bristol Myers Squibb, Kite, a Gilead Company, Miltenyi Biotec, Novartis, and Roche; research funding from Kite (all to institution); and travel support from Kite, Miltenyi Biotec, Novartis, and Roche. PGNJM: no relevant financial relationships to disclose. MW: honoraria from AstraZeneca, Bristol Myers Squibb, Merck, Novartis, and Pfizer; consulting/advisory role for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Genmab, Kite, a Gilead Company, Merck, Novartis, and Pfizer; and travel support from AstraZeneca, Bristol Myers Squibb, and Novartis. YZ: employment with Kite, a Gilead Company; and stock or other ownership in Gilead Sciences. AX: Stock or other ownership in Amgen, Biogen, and Kite, a Gilead Company. JNW: employment with and research funding from Kite, a Gilead Company, and stock or other ownership in Gilead. JN: employment with and stock or other ownership in Kite, a Gilead Company. RRS: employment with and stock or other ownership in Kite, a Gilead Company; and patents, royalties, and other intellectual property from Atara and Kite. CS: employment with Kite, a Gilead Company; and stock or other ownership in Gilead Sciences. FN: employment with Kite, a Gilead Company; and stock or other ownership in Gilead Sciences. JJK: employment with and stock or other ownership in Kite, a Gilead Company. MST: consulting/advisory role for AstraZeneca, Bristol Myers Squibb, Genmab, Kite, a Gilead Company, and Roche; research funding from Kite, Regeneron, Roche, and Takeda; and travel support from Janssen and Kite., (AJCR Copyright © 2024.)