Acalabrutinib, Alone or With Obinutuzumab, Improves Quality-Adjusted Survival in Frontline CLL

Treatment with acalabrutinib (Calquence) as monotherapy or in combination with obinutuzumab (Gazyva) improved quality-adjusted survival compared with chlorambucil plus obinutuzumab in patients with treatment-naïve chronic lymphocytic leukemia (CLL), according to results presented at the 2021 International Workshop on CLL.¹

The findings come from a post-hoc Q-TWiST analysis of patient level data from the randomized, open-label phase ELEVATE-TN trial comparing the 2 treatment regimens, which were presented as a poster by Jeff P. Sharman, MD, director of research from Willamette Valley Cancer Institute and Research Center, and colleagues.

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

Patients treated with acalabrutinib monotherapy had a significantly longer mean duration of time spent without toxicity (TWiST) compared with those treated with chlorambucil plus obinutuzumab at 24.94 months vs 19.53 months, respectively (P < .0001), while also experiencing a significantly shorter duration of relapse (1.39 vs 5.64 months; P < .0001). The acalabrutinib-monotherapy arm also had a numerically shorter time with toxicity at 1.11 vs 1.65 months with chlorambucil/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), a significantly shorter time spent in relapse (0.14 vs 5.64 months; P < .0001), and 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 authors wrote.

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

At a median follow-up of 28.3 months, 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), and a lower or similar incidence of grade 3/4 adverse events.

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). Presented at: 2021 ESMO Congress; September 16-21, 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 leukemia (ELEVATE TN): a randomized, controlled phase 3 trial. Lancet. 2020;395(10232):1278-1291. doi:10.1016/S0140-6736(20)30262-2