The ELEVATE-TN (NCT02475681) trial demonstrated superior efficacy with acalabrutinib ± obinutuzumab versus obinutuzumab/chlorambucil (median follow-up: ≤58.2 months) in patients with treatment-naive chronic lymphocytic leukemia (CLL). Updated results at 74.5 months of follow-up were presented at the 2023 American Society of Hematology annual meeting and summarized here.
In the ELEVATE-TN trial, eligible patients received acalabrutinib monotherapy, acalabrutinib/obinutuzumab, or obinutuzumab/chlorambucil; crossover to acalabrutinib monotherapy was allowed in patients who progressed on obinutuzumab/chlorambucil. The primary end point was investigator-assessed progression-free survival (PFS) (acalabrutinib/obinutuzumab vs obinutuzumab/chlorambucil). Investigator-assessed overall response rate (ORR), overall survival (OS), and safety were also evaluated. Date of data cutoff was March 3, 2023.
A total of 535 patients were enrolled and randomized to receive acalabrutinib monotherapy (n=179), acalabrutinib/obinutuzumab (n=179), or obinutuzumab/chlorambucil (n=177). The median age was 70 years, nearly 60% of patients had unmutated immunoglobulin heavy chain variable region genes (uIGHV), 8% of patients had del(17p), and 13%-14% had either del(17p) and/or TP53 mutation (TP53mut).
At a median follow-up of 74.5 months, PFS was significantly prolonged with acalabrutinib monotherapy versus obinutuzumab/chlorambucil (not reached [NR] vs 27.8 months; hazard ratio [HR], 0.24; P<.0001) and acalabrutinib/obinutuzumab (NR vs 27.8 months; HR, 0.14; P<.0001) versus obinutuzumab/chlorambucil; and significantly prolonged with acalabrutinib/obinutuzumab versus acalabrutinib monotherapy (HR, 0.58; P=.0229). The estimated 72-month PFS rates were 78% for acalabrutinib/obinutuzumab, 62% for acalabrutinib, and 17% obinutuzumab/chlorambucil. For the 79 patients who crossed over from obinutuzumab/chlorambucil to acalabrutinib monotherapy, median PFS2 (time to second disease progression or death) was NR; estimated 72-months PFS2 rate was 54%.
Median OS was NR in the 2 treatment arms; a significant 38% reduction in risk of death was associated with acalabrutinib/obinutuzumab versus obinutuzumab/chlorambucil (HR: 0.62; P=.0349); estimated 72-months OS rates were 87% for acalabrutinib/obinutuzumab, 79% for acalabrutinib, and 80% for obinutuzumab/chlorambucil cohorts.
In the uIGHV cohort (n=337), median PFS was significantly longer in both the acalabrutinib/obinutuzumab (NR vs 22.2 months; HR, 0.08; P<.0001) and acalabrutinib arms (NR vs 22.2 months; HR, 0.12; P<.0001) compared to obinutuzumab/chlorambucil; estimated 72-months PFS rates were 75%, 60%, and 5%, respectively. In the del(17p) and/or TP53mut cohort (n=73), median PFS was significantly longer in both the acalabrutinib/obinutuzumab (73.1 months vs 17.5 months; HR, 0.28; P≤.0009) and acalabrutinib arms (NR vs 17.5 months; HR, 0.23; P≤.0002) compared to obinutuzumab/chlorambucil; estimated 72-months PFS rates were 56%, 56%, and 18%, respectively.
ORR and complete response (CR) rates were significantly higher with acalabrutinib/obinutuzumab and acalabrutinib monotherapy compared to obinutuzumab/chlorambucil (P≤.0499 for both arms). ORR and CR rates were also significantly higher with acalabrutinib/obinutuzumab compared to acalabrutinib alone (ORR difference 6.1%, CR difference 17.9%; P=.022 for both comparisons). Additionally, acalabrutinib-treated patients who achieved a CR had longer PFS (HR, 0.23; P<.0001).
The most common grade ≥3 adverse events (AEs), occurring in ≥5% of patients, for acalabrutinib/obinutuzumab and acalabrutinib were neutropenia (31% and 12%), thrombocytopenia (8% and 3%), diarrhea (6% and 1%), COVID-19 (9% and 7%), pneumonia (7% and 6%), syncope (5% and 2%), and hypertension (4% and 5%). Grade ≥3 atrial fibrillation was reported in 1.7% of patients, hypertension in 4.5%, and secondary primary malignances in 7.3% of patients treated with acalabrutinib/obinutuzumab; and in 1.7%, 5%, and 5% of patients treated with acalabrutinib, respectively.
Treatment is ongoing in 54% of acalabrutinib/obinutuzumab-treated patients (n=96) and 47% of acalabrutinib-treated patients (n=84). Treatment discontinuation due to AEs were reported in 21% (n=38) of acalabrutinib/obinutuzumab-treated patients, and 18% (n=32) of acalabrutinib -treated patients. Among patients who crossed over from obinutuzumab/chlorambucil to acalabrutinib (n=32) 12% discontinued acalabrutinib due to AEs (n=10).
Extended follow-up results of the Elevate-TN trial (median follow-up of 74.5 months) confirmed sustained efficacy and safety of acalabrutinib/obinutuzumab and acalabrutinib monotherapy compared to obinutuzumab/chlorambucil in patients with treatment-naive CLL, including in patients with high-risk genetic features.
Source:
Sharman J, Egyed M, Jurczak W, et al. Acalabrutinib ± obinutuzumab vs obinutuzumab + chlorambucil in treatment-naive chronic lymphocytic leukemia: 6-year follow-up of Elevate-TN. Presented at the 65th American Society of Hematology (ASH) Annual Meeting & Exposition, December 9-12, 2023; San Diego, CA: Abstract 636.
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