Acalabrutinib, alone or in combination with obinutuzumab, demonstrated superior efficacy and an acceptable safety profile in patients with treatment-naïve chronic lymphocytic leukemia.
Acalabrutinib (Calquence), alone or in combination with obinutuzumab (Gazyva), demonstrated superior efficacy and an acceptable safety profile in patients with treatment-naïve chronic lymphocytic leukemia (CLL), according to long-term results from the pivotal, phase 3 ELEVATE-TN study (NCT02475681) that were presented during the 2021 Pan Pacific Lymphoma Conference.1
The updated results showed that, at a median follow-up of 46.9 months (range, 0.0-59.4), the acalabrutinib-containing arms improved the median progression-free survival (PFS) compared with obinutuzumab plus chlorambucil in this patient population. Specifically, the median PFS was not reached in the acalabrutinib/obinutuzumab arm compared with 27.8 months for the control arm (HR, 0.10; 95% CI, 0.07-0.17; P <.0001). The median PFS in the acalabrutinib-monotherapy arm was also not reached (HR, 0.19; 95% CI, 0.13-0.28; P <.001).
The estimated 4-year PFS rates were 87% with the combination, 78% with single-agent acalabrutinib, and 25% with the control arm.
Jeff Sharman, MD, who is director of research at Willamette Valley Cancer Institute in Eugene, Oregon, and medical director of hematology research of The US Oncology Network, presented the findings in a poster at the meeting.
“Median progression-free survival was significantly longer for acalabrutinib-containing treatment arms vs obinutuzumab/chlorambucil,” he said. “PFS benefit was consistent across high-risk genetic subgroups. Fewer deaths were observed in the acalabrutinib with obinutuzumab arm; however, this was not statistically significant.”
In patients with 17p deletion and/or TP53 mutation (n = 25), the median PFS was not reached in the acalabrutinib/obinutuzumab arm compared with 17.5 months in the control arm HR, 0;17; 95% CI, 0.07-0.42; P<.0001). The median PFS with acalabrutinib monotherapy in this patient subset was also not reached (HR, 0.18; 95% CI, 0.07-0.46; P <.0001).
The 4-year PFS rates were 76% in the combination arm, 75% with single-agent acalabrutinib, and 18% in the control arm.
Obinutuzumab plus chlorambucil was a standard frontline option for patients with CLL prior to the introduction of the BTK inhibitor ibrutinib (Imbruvica). In November 2019, the FDA approved acalabrutinib as a treatment for patients with CLL or small lymphocytic lymphoma, partly based on data from the ELEVATE-TN trial, as well as the ASCEND trial (NCT02970318), which evaluated the BTK inhibitor against either rituximab (Rituxan) or idelalisib (Zydelig) in previously treated patients with CLL.
In the randomized, multicenter, open-label ELEVATE-TN trial, investigators evaluated the safety and efficacy of acalabrutinib alone or in combination with obinutuzumab vs obinutuzumab/chlorambucil in 535 treatment-naïve patients with CLL. Investigators randomly assigned patients to obinutuzumab/chlorambucil (n = 177); 100 mg of twice-daily acalabrutinib in combination with obinutuzumab until disease progression or unacceptable toxicity (n = 179); or single-agent twice-daily acalabrutinib at 100 mg until disease progression or unacceptable toxicity (n = 179). Patients were stratified by 17p deletion status, ECOG performance status of 0 to 1 or 2, and geographic region.
Crossover from the obinutuzumab/chlorambucil arm was permitted after an independent review committee (IRC)-confirmed disease progression. Sixty-nine patients crossed over from the control arm to receive acalabrutinib monotherapy.
Additional data showed that the investigator-assessed overall response rate (ORR) was 96.1% in the combination arm, with a complete response (CR) rate of 30.7%. The ORR in the monotherapy arm was 81.0% with a CR rate of 11.2%. In the control arm, the ORR and CR rates were 69.5% and 13.0%, respectively.
The median overall survival (OS) was not reached in any treatment arm. The 4-year OS rate was 93% in the combination arm (HR, 0.50; 95% CI, 0.25-1.02; P = .0604) and 88% in both the monotherapy (HR, 0.95; 95% CI, 0.52-1.74; P = .9164) and control arms.
Regarding safety, the most common grade 3 or higher adverse event (AE) in all treatment groups was neutropenia. The condition, as grade 3 or higher, was most common in the control arm (41.4%), followed by the combination arm (30.9%) and the monotherapy arm (11.2%). No other grade 3 or higher AE appeared in more than 6% of patients in any group.
“Overall, these results are consistent with the established safety profile of these agents and no new toxicity signals were observed,” Sharman said.
In previous findings presented at a median follow-up of 28.3 months, the combination of the BTK inhibitor with obinutuzumab led to a 90% reduction in the risk of disease progression or death compared with obinutuzumab/chlorambucil (HR, 0.10; 95% CI, 0.06-0.17; P <.0001).2 When used as monotherapy, acalabrutinib also showed a statistically significant benefit in PFS (HR, 0.20; 95% CI, 0.13-0.30; P <.0001).