From the World Congress of Oncology (ASCO), which closed yesterday, comes one last piece of good news regarding relapsed and refractory patients at high risk and a sustained long-term benefit even at the forefront. In fact, the final results of two phase 3 studies, Elevate-RR and Elevate-Tn acalabrutinib, have been presented which bode well. Acalabrutinib received European Medicines Agency (EMA) approval last year for the treatment of chronic lymphocytic leukemia across multiple lines of treatment.
Progression-free survival and atrial fibrillation
With a median follow-up of 40.9 months, the ELEVATE-RR study met the primary endpoint of non-inferiority of progression-free survival (PFS) compared to ibrutinib with a median PFS of 38.4 months in both arms. . Patients treated with acalabrutinib had a significantly lower incidence of atrial fibrillation, a key secondary endpoint, compared to patients treated with ibrutinib (9.4% versus 16.0%). Atrial fibrillation is an irregular heart rate that can increase the risk of stroke, heart failure, and other heart-related complications – complications that are particularly risky for the chronic lymphocytic leukemia population. “One of the major obstacles to treating patients with chronic lymphocytic leukemia, patients who are generally diagnosed after age 70 and often have one or more comorbidities, is finding effective and tolerated treatment options for long-term disease management without having to interrupt the therapeutic process “, he declares Paolo Ghia, Professor of Medical Oncology at the Vita-Salute San Raffaele University, Coordinator of the Strategic Research Program on LLC of the San Raffaele Hospital and Principal Investigator for Italy of these studies.
“The results of the ELEVATE-RR study – continues Ghia – confirm the potential of acalabrutinib in terms of disease control for patients with chronic lymphatic leukemia who have already faced a first line of treatment, with a better cardiovascular safety profile – an element important to take into account. Having an effective and better tolerated therapeutic option is excellent news for clinicians and for the more than 3,000 patients in Italy who receive this type of diagnosis every year ”.
The comparison study in relapsed or refractory CLL
Elevate-RR is the first Phase III study to compare two Bruton tyrosine kinase (BTK) inhibitors in patients with previously treated CLL in the presence of deletion 17p or deletion 11q. The study met the PFS-defined non-inferiority study endpoint for acalabrutinib (n = 268) versus ibrutinib (n = 265) in patients with previously treated CLL with certain high-risk prognostic factors. Patients treated with acalabrutinib had a statistically significantly lower incidence of atrial fibrillation of all grades, a key secondary endpoint, compared to patients treated with ibrutinib (9.4% [n=25/266] compared to 16.0% [n=42/263]; p= 0.02).
Adverse events
A lower frequency of adverse events (AEs) was observed with acalabrutinib compared to ibrutinib, including lower common adverse events, grade 3 or higher adverse events, serious adverse events, treatment discontinuation due to adverse events, and overall cardiac events. The safety profile and tolerability of acalabrutinib in the ELEVATE-RR study were consistent with those of previous studies. Adverse events led to treatment discontinuation in 14.7% of acalabrutinib-treated patients and 21.3% of ibrutinib-treated patients. Adverse events of clinical interest for acalabrutinib compared to ibrutinib included cardiac events, haemorrhagic events, hypertension, infections, interstitial lung disease / pneumonia, and second primary malignancies excluding non-melanoma skin cancer. Serious adverse events (of any grade) occurred in 53.8% of patients treated with acalabrutinib compared with 58.6% of patients treated with ibrutinib. Median overall survival (OS) was not achieved in either arm, with 63 (23.5%) patients in the acalabrutinib arm and 73 (27.5%) patients in the ibrutinib arm experiencing an event (HR of 0 , 82, 95% CI 0.59-1.15).
Four-year follow-up data
ELEVATE-TN is a randomized, multicentre, open-label Phase III study evaluating the safety and efficacy of acalabrutinib in combination with obinutuzumab or alone versus chlorambucil in combination with obinutuzumab in previously untreated patients with CLL. The study met its primary endpoint (IRC-assessed PFS with acalabrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab) at data cut-off for the interim analysis after a median follow-up of 28.3 months. With a median follow-up of 46.9 months, the ELEVATE-TN Phase III study showed that acalabrutinib in addition to obinutuzumab reduced the risk of disease progression or death by 90% and as monotherapy by 81% (compared with to chlorambucil plus obinutuzumab. The estimated 48-month PFS rates for acalabrutinib plus obinutuzumab or monotherapy were 87% and 78%, respectively, compared with 25% for chlorambucil plus obinutuzumab. PFS results were consistent between the high-risk subgroups.
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