Results from the phase III ELEVATE TN trial in patients with treatment-naïve chronic lymphocytic leukemia

Acalabrutinib is a highly selective Bruton tyrosine kinase inhibitor (BTKi) that has demonstrated durable responses and a favorable safety profile when combined with obinutuzumab in treatment-naïve (TN) chronic lymphocytic leukemia (CLL).

At the 61^st American Society of Hematology (ASH) Annual Meeting & Exposition, Jeff Sharman, Willamette Valley Cancer Institute and Research Center & US Oncology Network, Eugene, OR, presented results from the multicenter, open-label phase III ELEVATE TN trial of acalabrutinib combined with obinutuzumab (O) vs acalabrutinib alone vs O plus chlorambucil (Clb) in patients with TN CLL.¹

Study design

• Study participants (N= 535) with TN CLL aged ≥ 65 years or < 65 years with coexisting conditions were recruited
• Patients were stratified according to deletion(17p) status, ECOG status, and geographic region
• Randomization was 1:1:1 to receive oral acalabrutinib alone (n= 179), or acalabrutinib combined with intravenous O (n= 179), or O plus oral Clb (n= 177; standard frontline chemoimmunotherapy for CLL)
• The primary endpoint was progression-free survival (PFS) with acalabrutinib + O vs O + Clb
• Key secondary endpoints included PFS with acalabrutinib vs O + Clb, overall response rate (ORR), overall survival (OS), and safety
• Crossover from the O + Clb arm to acalabrutinib was allowed after confirmation of progression

Results

PFS

• At a median follow-up of 28.3 months, PFS in the acalabrutinib + O arm (hazard ratio [HR]= 0.10; 95% CI, 0.06–0.17; p< 0.0001) and in the acalabrutinib alone arm (HR= 0.20; 95% CI, 0.13–0.30; p< 0.0001) was not reached (NR) vs 22.6 months for O + Clb
• Estimated 24-month PFS was 93%, 87%, and 47% for acalabrutinib + O, acalabrutinib alone, and O + Clb, respectively
• Subgroup analysis showed that PFS improvement for acalabrutinib + O and acalabrutinib alone arms were consistent across all subgroups examined (age, sex, Rai stage, ECOG status, bulky disease, cytogenetic risk group, IGHD mutation status, and karyotype)
• The study allowed crossover, and 45 patients out of 82 that experienced disease progression in the O + Clb arm crossed over to the acalabrutinib monotherapy arm

ORR

• ORR was 93.9% with acalabrutinib + O (partial response [PR] 81%; complete response [CR] 13%), 85.5% with acalabrutinib monotherapy (PR 85%; CR 1%), and 78.5% in the O + Clb arm (PR 74%; CR 5%). The higher ORR rate of acalabrutinib + O was statistically significant compared to the O + Clb arm (p< 0.0001)

OS

• Estimated 24-month OS rates were 95%, 95%, and 92% in acalabrutinib + O, acalabrutinib, and O + Clb arms, respectively

Adverse events

• Serious Adverse Events (SAEs) were reported in 38.8%, 31.8%, and 21.9% of subjects in acalabrutinib + O, acalabrutinib, and O + Clb arms, respectively. The most common SAEs were represented by pneumonia, infusion-related reactions, anemia, neutropenia, and tumor lysis syndrome
• AEs of clinical interest included:
  • Atrial fibrillation (any grade: acalabrutinib + O, 3.4%; acalabrutinib, 3.9%; O + Clb, 0.6%)
  • Bleeding (any grade: acalabrutinib + O, 42.7%; acalabrutinib, 39.1%; O + Clb, 11.8%)
  • Hypertension (Grade ≥3: acalabrutinib + O, 2.8%; acalabrutinib, 2.2%; O + Clb, 3%)
• The higher percentage of SAEs and AEs observed in the acalabrutinib arms vs the O + Clb arm may be due to differences in the length of treatment period. The median exposure was 27.7 months for acalabrutinib with or without O (range, 2.3–40.3 months and 0.3–40.2 months, respectively) and only 5.6 months (range, 0.9–7.4 months) for O + Clb

Conclusions

• A significant PFS improvement was observed in the acalabrutinib arms in comparison with the O + Clb arm, and this PFS improvement was consistent across all subgroups examined
• ORR was higher in both acalabrutinib arms vs O + Clb, with CR rates higher with acalabrutinib + O vs O + Clb
• Acalabrutinib showed tolerable safety in patients with TN CLL, but differences in the length of treatment period could be a limitation of the study