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. The results from this trial supported the U.S. Food and Drug Administration’s approval of acalabrutinib for adults with CLL or small lymphocytic lymphoma on November 21.
Lead investigator Jeff P. Sharman, MD, of the Willamette Valley Cancer Institute and Research Center and the US Oncology Network, 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 either:
- 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=178)
- 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=169)
Participants also were stratified according to del17p status, Eastern Cooperative Oncology Group score (≤1 vs. 2), and geographic region.
Per study protocol, patients who achieved an investigator-assessed complete response (CR) or CR with incomplete marrow recovery (CRi), were evaluated for minimal residual disease. Patients randomized to obinutuzumab plus chlorambucil who experienced disease progression were allowed to cross over to the single-agent acalabrutinib arm.
Median durations of treatment were as follows:
- 7 months (range = 0.3-40.2) for acalabrutinib alone
- 7 months (range = 2.3-40.3) for acalabrutinib plus obinutuzumab
- 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 authors noted that the PFS benefit with acalabrutinib was seen across different subgroups, including those with del17p mutation (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]).
In terms of overall survival (OS), a secondary endpoint, the median OS was not reached in any of the treatment groups, with similar 30-month OS rates in the acalabrutinib plus obinutuzumab, acalabrutinib monotherapy, and obinutuzumab plus chlorambucil arms (95%, 94%, and 90%, respectively).
At the end of study follow-up, approximately 25% 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).
No differences in adverse events (AEs) were observed between the acalabrutinib treatment arms; however, a higher proportion of infusion reactions were observed in the obinutuzumab plus chlorambucil than the acalabrutinib plus obinutuzumab group (39.6% vs. 13.5%, respectively). 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 two years of follow-up, most patients in the acalabrutinib-containing arms (79.3%) are still treated with single-agent acalabrutinib, the authors reported.
Although these findings point to significant improvements with acalabrutinib treatment, the authors noted that longer follow-up is needed to evaluate improvements in OS.
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-naive chronic lymphocytic leukemia (CLL). Abstract #31. Presented at the 2019 ASH Annual Meeting, December 7, 2019; Orlando, FL.
TABLE. Common Adverse Events of Interest
|Acalabrutinib + obinutuzumab (n=178)||Acalabrutinib (n=179)||Obinutuzumab + chlorambucil (n=169)|
|All grade (%)||Grade ≥3 (%)||All grade (%)||Grade ≥3 (%)||All grade (%)||Grade ≥3 (%)|
|Neutropenia||56 (31.5)||53 (29.8)||19 (10.6)||17 (9.5)||76 (45.0)||70 (41.4)|
|Arthralgia||39 (21.9)||2 (1.1)||28 (15.6)||1 (0.6)||8 (4.7)||2 (1.2)|
|Upper respiratory tract infection||38 (21.3)||4 (2.2)||33 (18.4)||0||14 (8.3)||1 (0.6)|
|Infusion-related reaction||24 (13.5)||4 (2.2)||0||0||67 (39.6)||9 (5.3)|
|Pyrexia||23 (12.9)||0||12 (6.7)||1 (0.6)||35 (20.7)||1 (0.6)|