Acalabrutinib, alone or combined with obinutuzumab, led to greater improvements in progression-free survival (PFS), compared with obinutuzumab plus chlorambucil, in patients with treatment-naïve chronic lymphocytic leukemia (CLL), according to findings from the ELEVATE-TN study.1 The results from this trial supported the FDA’s approval of acalabrutinib for adults with CLL or small lymphocytic lymphoma on November 21, 2019.
Lead investigator Jeff P. Sharman, MD, of Willamette Valley Cancer Institute and Research Center, in Oregon, presented the interim findings from this trial at the 2019 ASH Annual Meeting. In his presentation, Dr. Sharman noted that the PFS benefits were experienced while maintaining “a favorable tolerability and safety profile.”
Dr. Sharman and an international team of researchers enrolled patients with previously untreated CLL who were 65 or older, or who were younger than 65 but presented with a chronic inflammatory response syndrome score >6 and creatinine clearance <70 mL/min.
The 535 enrolled patients (median age 70 years; range 41-91 years) were randomized 1:1:1 to receive:
- acalabrutinib 100 mg twice-daily (n=179)
- acalabrutinib 100 mg twice-daily plus intravenous obinutuzumab (1,000 mg on days 1 and 2 [split 100/900], 8, and 15 of cycle 2, and day 1 of subsequent 28-day cycles for 6 cycles; n=179)
- obinutuzumab plus oral chlorambucil (0.5 mg/kg on days 1 and 15 of each 28-day cycle for a total of 6 cycles; n=177)
Participants also were stratified according to del17p status, Eastern Cooperative Oncology Group score (ECOG; ≤1 vs. 2), and geographic region.
Per study protocol, patients who achieved an investigator-assessed complete response (CR) or CR with incomplete marrow recovery were evaluated for measurable residual disease. Patients randomized to obinutuzumab plus chlorambucil who experienced disease progression were allowed to cross over to the single-agent acalabrutinib arm.
As of data presentation, 178 patients in the acalabrutinib group, 179 in the acalabrutinib plus obinutuzumab group, and 169 in the obinutuzumab plus chlorambucil group had been treated according to their protocol assignment.
Median treatment exposures in each group were as follows:
- 27.7 months (range = 0.3-40.2) for acalabrutinib alone
- 27.7 months (range = 2.3-40.3) for acalabrutinib plus obinutuzumab
- 5.6 months (range = 0.9-7.4) for obinutuzumab plus chlorambucil
After a median follow-up of 28.3 months (range not provided), PFS (the study’s primary endpoint) was significantly longer in the acalabrutinib plus obinutuzumab arm compared with the obinutuzumab plus chlorambucil arm: not reached versus 22.6 months, respectively. This translated to a 90% reduction in the risk of disease progression or death with the acalabrutinib-containing regimen (hazard ratio [HR] = 0.10; 95% CI 0.06-0.17; p<0.0001).
Patients treated with acalabrutinib monotherapy also had a lower risk of disease progression or death, compared with patients treated with obinutuzumab plus chlorambucil (HR=0.20; 95% CI 0.13-0.30; p<0.0001).
In addition, the 30-month PFS rates were highest in the groups treated with acalabrutinib plus obinutuzumab and acalabrutinib monotherapy (90% and 82%, respectively) compared with obinutuzumab plus chlorambucil (34%; p values for comparison not provided).
The acalabrutinib combination also appeared to outperform the single-agent acalabrutinib arm in terms of PFS (HR=0.49; 95% CI 0.26-0.95; p value not reported), however, Dr. Sharman noted that the study was not designed or powered to detect a PFS effect between these 2 arms.
In subgroup analyses, the researchers reported that the PFS benefit with acalabrutinib was seen across different subgroups, independent of age group, sex, Rai stage, or ECOG score. Dr. Sharman highlighted the improvement in PFS seen with acalabrutinib treatment in patients with high-risk mutations, including del17p (HR for acalabrutinib + obinutuzumab = 0.13 [95% CI 0.04-0.46] and HR for acalabrutinib monotherapy = 0.20 [95% CI 0.06-0.64]) and IGHV (HR=0.15 [9%% CI 0.04-0.52] and 0.69 [95% C 0.31-1.56], respectively).
During study follow-up, 9 patients in the acalabrutinib plus obinutuzumab arm died, 11 in the acalabrutinib monotherapy arm, and 17 in the obinutuzumab plus chlorambucil arm. The median overall survival (OS), a secondary endpoint, was not reached in any of the treatment groups. Although the HRs for death again appeared to favor the acalabrutinib arms, the findings did not reach statistical significance.
At the end of study follow-up, approximately 55% of patients in the obinutuzumab and chlorambucil arm crossed over to the acalabrutinib monotherapy group. The researchers added that a higher proportion of patients randomized to the obinutuzumab and chlorambucil combination regimen received a next therapy, compared with those who were initially treated with acalabrutinib alone or with obinutuzumab (31% vs. 6% vs. 3%, respectively).
In reporting the safety data from ELEVATE-TN, Dr. Sharman said that, “due to the study design, in which continuous Bruton tyrosine kinase (BTK) inhibitor therapy was compared with fixed-duration chemoimmunotherapy, there was an imbalance in reporting of adverse events that occurred within 30 days of the last dose, with a longer reporting period in the BTK inhibitor-containing arms.”
While similar proportions of patients experienced at least 1 any-grade adverse event (AE), more patients in the acalabrutinib combination or monotherapy arms experienced a serious AE, compared with the obinutuzumab plus chlorambucil group: 38.8%, 31.8%, and 21.9%, respectively.
There were no differences in AEs observed between the acalabrutinib treatment arms. However, a higher proportion of infusion-related reactions were seen in the obinutuzumab plus chlorambucil than the acalabrutinib plus obinutuzumab group (39.6% vs. 13.5%, respectively). More patients in the acalabrutinib combination and monotherapy groups also developed second primary malignancies (5.6% and 2.8% vs. 1.8%), but Dr. Sharman said that this could be attributed to substantially longer follow-up in the BTK inhibitor-containing arms. Other common AEs of interest are reported in the TABLE.
AEs leading to treatment discontinuations were observed in 11% of patients who received acalabrutinib plus obinutuzumab, 9% of patients who received acalabrutinib monotherapy, and 14% of patients who received obinutuzumab plus chlorambucil. After more than 2 years, most patients in the acalabrutinib-containing arms (79.3%) are still treated with single-agent acalabrutinib, the authors reported.
Several investigators criticized the use of chlorambucil in the control arm of the trial. However, Michael Hallek, MD, of the University of Cologne and the University of Bonn in Germany and leader of the German CLL Study Group, pointed out that chlorambucil and obinutuzumab was a standard regimen for CLL at the time the ELEVATE-TN study was designed, based on results of the CLL 11 study published in the New England Journal of Medicine in 2014.2 Dr. Hallek also noted that chlorambucil in combination with obinutuzumab is still used in clinical practice in some countries, particularly in older patients with comorbid conditions. Dr. Sharman pointed out that obinutuzumab monotherapy is not considered acceptable by regulators as a control arm and that chlorambucil-based control arms in CLL will likely no longer be used after several other fully enrolled studies report out in the near future.
Although the findings of ELEVATE-TN point to substantial improvements with acalabrutinib treatment, the authors noted that longer follow-up is needed to evaluate improvements in OS. The imbalance in follow-up between the acalabrutinib-containing arms and the chemoimmunotherapy arm also may have confounded reporting of certain AEs.
Several study authors reported relationships with Acerta Pharma, which sponsored the trial.
- Sharman JP, Banerji V, Fogliatto LM, et al. ELEVATE TN: Phase 3 study of acalabrutinib combined with obinutuzumab (O) or alone vs O plus chlorambucil (clb) in patients (pts) with treatment-naïve chronic lymphocytic leukemia (CLL). Abstract #31. Presented at the 2019 ASH Annual Meeting, December 7, 2019; Orlando, FL.
- Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370:1101-1110.