Acalabrutinib maintains efficacy over 4 years in treatment-naïve CLL

Acalabrutinib with or without obinutuzumab maintains significant progression-free survival (PFS) benefit over the chemoimmunotherapy combination of obinutuzumab plus chlorambucil (O + Clb) through 4 years in treatment-naïve chronic lymphocytic leukaemia (CLL) patients, according to the phase III ELEVATE-TN study presented at EHA 2021.   

These findings thus suggest the potential of acalabrutinib, either alone or in combination with obinutuzumab, as a new chemotherapy-free treatment option for these patients.

Acalabrutinib is a target therapy that is a potent and highly selective inhibitor of Bruton tyrosine kinase (BTK). Previously reported interim analysis has shown that acalabrutinib with or without obinutuzumab significantly improved PFS during a median follow-up of 28.3 months, with acceptable safety profile.

The current data presented at EHA 2021 was an updated analysis after a median follow-up of almost 4 years (46.9 months). [EHA 2021, abstract S148]

Compared with the O + Clb arm, median PFS was significantly longer in patients treated with acalabrutinib monotherapy or in combination with obinutuzumab (not reached [NR] and NR vs 27.8 months; p<0.0001 for both).

At 48 months, the estimated PFS rates were 87 percent and 78 percent for acalabrutinib with or without obinutuzumab, respective, compared with 25 percent for O+Clb (hazard ratios [HRs], 0.19 and 0.10).

Furthermore, the PFS benefit was consistent across high-risk genetic subgroups, including those with unmutated immunoglobulin heavy chain gene (IgHV) or del(17p) status. Among patients with unmutated IgHV, the median PFS was not reached with acalabrutinib with or without obinutuzumab vs 22.2 months with O + Clb (p<0.0001 for both). The corresponding median PFS was NR vs 17.7 months among patients with del(17p) status (p<0.005).

The median overall survival (OS) has yet to reach in all treatment arms. At 48 months, 93 percent, 88 percent, and 88 percent of patients were still alive in the acalabrutinib monotherapy or combined obinutuzumab arms and the O + Clb arm, respectively.

“Fewer deaths occurred in patients who received acalabrutinib + obinutuzumab, although statistical significance was not reached,” reported the researchers, who pointed out that the numerically lower death rate persisted through 60 months. 

The global, phase III, open-label study included 535 treatment-naïve patients (median age 70 years) with CLL in a 1:1:1 ratio to receive acalabrutinib with or without obinutuzumab or Clb + O in 28-day cycles.

Acalabrutinib + obinutuzumab led to a significantly higher objective response rate (ORR) compared with O + Clb (96.1 percent vs 82.5 percent; p<0.0001) — including complete response/complete response with incomplete haematologic recovery (CR/CRi) rates of 26.8/3.9 percent vs 12.4/0.6 percent.

Similarly, ORR was also significantly higher with acalabrutinib alone (89.9 percent; p=0.035) vs O + Clb, with 10.6 percent and 0.6 percent of patients who achieved CR and CRi, respectively with acalabrutinib monotherapy.

Common AEs were mostly consistent with the previous interim report.

“Safety of acalabrutinib, both alone and in combination with obinutuzumab, was maintained despite longer time on treatment,” noted the researchers. “Most AEs in the acalabrutinib-containing arms occurred predominantly during the first year of treatment.”

AEs that occurred more frequently with the acalabrutinib-containing regimen than with O + Clb included diarrhoea, headache, arthralgia, fatigue, cough, and upper respiratory tract infection. On the other hand, nausea, neutropenia, and infusion-related reaction were more common in the O + Clb arm.

“Acalabrutinib with or without obinutuzumab demonstrates durable disease control, … with an increase in CR since the interim analysis and low rates of discontinuation [in treatment-naïve CLL patients],” the researchers concluded.