Frontline Acalabrutinib Improves Quality-Adjusted Survival in CLL

Jeff P. Sharman, MDS

Acalabrutinib (Calquence), whether used as a single agent or in combination with obinutuzumab (Gazyva), led to an improvement in survival adjusted for quality over chlorambucil and obinutuzumab in patients with treatment- naive chronic lymphocytic leukemia (CLL). The results were from a post hoc quality-adjusted time without symptoms of disease and toxicity (Q-TWiST) analysis of patient-level data from the randomized, open-label phase 3 ELEVATE-TN trial (NCT02475681).¹

A Q-TWiST analysis assesses the balance of risk (toxicity) and benefit (prolonged survival without symptoms of progression or adverse events) of oncologic treatments. It incorporates both the benefits and risks of the drug’s effect, capturing the toxicity and mortality effects of treatment over the follow-up of a clinical trial.

The findings were presented at the 2021 International Workshop on Chronic Lymphocytic Leukemia by Jeff P. Sharman, MD, director of research at Willamette Valley Cancer Institute and Research Center and medical director of hematology research for The US Oncology Network, and colleagues.

Patients treated with acalabrutinib monotherapy had a significantly longer mean duration of time spent without toxicity compared with those treated with chlorambucil plus obinutuzumab at 24.94 months vs 19.53 months, respectively (P < .0001). They also experienced a significantly shorter duration of relapse (1.39 vs 5.64 months; P < .0001). Additionally, the acalabrutinib- monotherapy arm had a numerically shorter time with toxicity at 1.11 vs 1.65 months with chlorambucil plus obinutuzumab (P = .126). Overall, Q-TWiST duration was significantly longer with acalabrutinib monotherapy compared with chlorambucil plus obinutuzumab at 26.20 vs 23.18 months, respectively (P < .0001).

Patients treated with the acalabrutinib plus obinutuzumab combination, compared with chlorambucil plus obinutuzumab, had a significantly longer duration of TWiST at 25.10 vs 19.53 months, respectively (P < .0001) and a significantly shorter time spent in relapse (0.14 vs 5.64 months; P < .0001). They also had a significantly longer Q-TWiST duration (26.14 vs 23.18 months; P < .0001) and a numerically longer duration of time spent with toxicity (1.94 vs 1.65 months; P = .4847).

“The relative gain in Q-TWiST is equivalent to 11.3% and 11.0% of OS [overall survival] time in acalabrutinib monotherapy and acalabrutinib plus obinutuzumab, respectively; the gains were considered clinically important as they met the criterion of 10% used to determine clinically important Q-TWiST improvement,” the study authors wrote.

Previously in ELEVATE-TN, acalabrutinib plus obinutuzumab and acalabrutinib monotherapy significantly improved progression-free survival (PFS) compared with obinutuzumab plus chlorambucil, with tolerable safety in patients with treatment-naïve CLL.²

Patients in the study were randomized 1:1:1 to receive oral acalabrutinib (100 mg twice daily continuously) alone or combined with intravenous obinutuzumab (1000 mg on days 1, 2, 8, and 15 of cycle 2, and day 1 of subsequent 28-day cycles for a total of 6 cycles), or obinutuzumab plus oral chlorambucil (0.5 mg/kg on days 1 and 15 of each 28-day cycle for 6 cycles). Crossover to acalabrutinib was allowed for patients who progressed on obinutuzumab plus chlorambucil.

At a median follow-up of 28.3 months (range, 25.6-33.1), the median PFS was not reached with acalabrutinib or acalabrutinib plus obinutuzumab compared with 22.6 months for chlorambucil plus obinutuzumab (HR, 0.1; 95% CI, 0.06-0.17; P < .0001). A lower or similar incidence of grade 3/4 adverse events was also reported for the acalabrutinib- based combination as compared with the chlorambucil-based regimen. The PFS rate at 2 years was estimated to be 93% (95% CI, 87%-96%) with acalabrutinib plus obinutuzumab, 87% (95% CI, 81%-92%) with single-agent acalabrutinib, and 47% (95% CI, 39%-55%) with obinutuzumab plus chlorambucil.

With the acalabrutinib and obinutuzumab combination, the most common grade 3 or higher adverse event was neutropenia in 30% of patients, and infections were reported in 21%. For the Q-TWiST analysis, the restricted mean duration for each health state was derived from the area under the Kaplan- Meier survival curve.

A limitation of the analysis was the use of immature clinical trial data, according to the investigators. “Given the indolent nature of CLL and acalabrutinib as a chronic treatment, maturity of clinical trial data can be achieved in long-term follow-up only; therefore, an updated analysis from ELEVATE-TN with longer-term follow-up [median of 47 months] is planned to validate the findings presented herein,” they wrote.

_REFERENCES:

_{1. Sharman JP, Emeribe U, Cai L, Gaitonde P. A quality-adjusted survival (Q-TWiST) analysis of acalabrutinib with or without obinutuzumab in patients with treatment-naïve chronic lymphocytic leukemia (CLL). Poster presented at: 2021 International Workshop on CLL; September 17-20, 2021; Virtual. Abstract 1083755.}

_{2. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naïve chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278- 1291. doi:10.1016/S0140-6736(20)30262-2}