ELEVATE-TN: acalabrutinib, alone or with obinutuzumab, against chemo-immunotherapy in untreated CLL
In ELEVATE-TN, acalabrutinib, a second-generation BTK inhibitor, with or without an antibody, cut the risk of progression by 80-90% compared with chlorambucil-obinutuzumab in older or unfit patients with CLL.
ELEVATE-TN was a three-arm phase 3 trial of 535 treatment-naive patients aged 65 or older, or younger with comorbidities. Patients were randomised to acalabrutinib plus obinutuzumab, acalabrutinib monotherapy, or chlorambucil plus obinutuzumab; the primary endpoint was PFS for the combination versus chemo-immunotherapy. At a median follow-up of 28.3 months median PFS was not reached in either acalabrutinib arm versus 22.6 months with chemo-immunotherapy, with hazard ratios of 0.10 for the combination and 0.20 for monotherapy. Acalabrutinib caused less atrial fibrillation and bleeding than reported with ibrutinib, and the trial supported its front-line approval.
- 535 patients; acalabrutinib + obinutuzumab (179), acalabrutinib (179), chlorambucil + obinutuzumab (177).
- Median PFS not reached in both acalabrutinib arms vs 22.6 months; hazard ratio 0.10 (combination) and 0.20 (monotherapy).
- Estimated 24-month PFS about 93% (combination), 87% (monotherapy) and 47% (chemo-immunotherapy).
- Headache and diarrhoea were the commonest acalabrutinib adverse events; atrial fibrillation was uncommon.
- Adding obinutuzumab to acalabrutinib improved PFS further in longer follow-up but was not the primary comparison.
ELEVATE-TN put a more selective BTK inhibitor into first-line CLL and, with the head-to-head ELEVATE-RR trial, showed it is as effective as ibrutinib with fewer cardiac side effects. Continuous acalabrutinib became one of the two main front-line options alongside fixed-duration venetoclax combinations. The trade-off is indefinite therapy and cost versus a time-limited course.
- The comparator, chlorambucil-obinutuzumab, was already being superseded when the trial reported.
- Continuous therapy until progression; no MRD-guided stopping.
- Cross-trial comparisons with venetoclax regimens are indirect.
- Overall survival was not significantly different at early follow-up.
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