Acalabrutinib Alone or in Combination Improves PFS in Frontline CLL

Jeff P. Sharman, MD

Acalabrutinib (Calquence) as a single agent or in combination with obinutuzumab (Gazyva) led to a statistically significant improvement in progression-free survival (PFS) compared with obinutuzumab plus chlorambucil in treatment-naïve patients with chronic lymphocytic leukemia (CLL), according to results from the phase III ELEVATE-TN trial presented at the 2019 ASH Annual Meeting.

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). When used as monotherapy, acalabrutinib also showed a statistically significant benefit in PFS (HR, 0.20; 95% CI, 0.13-0.30; P <.0001).

“Acalabrutinib has demonstrated efficacy and a consistent safety profile in treatment-naïve and relapsed/refractory patients, and is now an approved treatment option for patients with CLL,” said lead study author Jeff P. Sharman, MD, director of research at Willamette Valley Cancer Institute and medical director of hematology research for The US Oncology Network, in a presentation during the meeting.

Obinutuzumab combined with 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 granted approval to acalabrutinib for the treatment of patients with CLL or small lymphocytic lymphoma, partly based on data from the ELEVATE-TN trial, as well as the ASCEND trial, which evaluated the BTK inhibitor compared with either rituximab (Rituxan) or idelalisib (Zydelig) in previously treated patients with CLL.

“Acalabrutinib is a more selective BTK inhibitor, with less off-target kinase inhibition in vitro compared with ibrutinib and a favorable safety profile, prompting this evaluation as a frontline therapy with or without obinutuzumab,” Sharman said.

In the randomized, multicenter, open-label, phase III ELEVATE-TN (ACE-CL-007) trial, investigators evaluated the safety and efficacy of acalabrutinib alone or in combination with obinutuzumab versus chlorambucil/obinutuzumab in 535 treatment-naïve patients with CLL. Patients were randomized 1:1:1 into 3 arms: chlorambucil plus obinutuzumab (n = 177); 100 mg of acalabrutinib twice daily in combination with obinutuzumab until disease progression or unacceptable toxicity (n = 179); or single-agent acalabrutinib at 100 mg twice daily 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 independent review committee (IRC)-confirmed disease progression; therefore, these patients were not included in the PFS data that were presented during the 2019 ASH Annual Meeting.

An interim analysis was planned based on events, which was after the occurrence of ~111 IRC-assessed PFS in the combination arms, or after 24 months if the required number of events was not met by this time.

Baseline characteristics were similar across the 3 treatment arms. The median patient age for the trial was 70.5 years, 63% of patients had an unmutated IGVH, 47% had Rai stage III or IV disease, 18% had 11q deletion, and 14% had 17p deletion or TP53 mutation. Most patients (93.6%) had an ECOG performance status between 0 and 1. High-risk features were evenly distributed.

The treatment discontinuation rates were 20.7%, 20.1%, and 18.1% in the acalabrutinib/obinutuzumab, acalabrutinib-alone, and obinutuzumab/chlorambucil arms, respectively. The most common reason patients discontinued treatment was due to adverse events (AEs), which occurred in 11.2%, 8.9%, and 14.1% of patients, respectively. Two deaths were reported on the acalabrutinib combination arm, 3 deaths on the single-agent acalabrutinib arm, and 1 death in the chemoimmunotherapy group. The median duration of treatment in the acalabrutinib arms was 27.7 months and 5.6 months in the chlorambucil/obinutuzumab arm, and 79.3% of patients were still continuing on treatment.

The primary endpoint was PFS in the acalabrutinib/obinutuzumab arm compared with the chlorambucil/obinutuzumab arm, as assessed by IRC. Secondary endpoints included IRC-assessed PFS in the acalabrutinib-alone arm versus chlorambucil/obinutuzumab, as well as objective response rate (ORR), time to next treatment, overall survival (OS), and safety.

Results by IRC assessment showed that the median PFS was not reached with either acalabrutinib arm, compared with 22.6 months (95% CI, 20.2-27.6) with chlorambucil/obinutuzumab. The 2-year PFS rates were 93%, 87%, and 47% for acalabrutinib/obinutuzumab, single-agent acalabrutinib, and chemoimmunotherapy, respectively.

Although the trial was not powered or designed to compare the PFS outcomes between the 2 acalabrutinib arms, Sharman noted that an exploratory posthoc analysis showed that acalabrutinib plus obinutuzumab was superior to acalabrutinib alone (HR, 0.49; 95% CI, 0.26-0.95).

The IRC-assessed PFS benefit with the acalabrutinib regimens was found to be consistent across prespecified subgroups, irrespective of high-risk disease characteristics.

“In contrast with several recent studies, treatment with the combination of acalabrutinib/obinutuzumab yielded an overall PFS benefit compared with the control in both unmutated and mutated IGHV subgroups,” Sharman explained.

OS favored both the acalabrutinib/obinutuzumab arm (HR, 0.47; 95% CI, 0.21-1.06; P = .0577) and the single-agent acalabrutinib arm (HR, 0.60; 95% CI, 0.28-1.27; P = .1556); however, this benefit was not found to be statistically significant. The estimated 2-year OS rates were 95%, 95%, and 92% with acalabrutinib/obinutuzumab, acalabrutinib alone, and chemoimmunotherapy, respectively.

Thirty-one percent of patients who were randomized to chemoimmunotherapy experienced disease progression, and 82% of this subgroup crossed over to receive the BTK inhibitor alone.

“Despite crossover for disease progression in the obinutuzumab/chlorambucil arm, fewer deaths were seen with acalabrutinib/obinutuzumab and acalabrutinib monotherapy, though longer follow-up is needed to detect a difference in OS,” Sharman said.

Additionally, the IRC-assessed ORR was 93.9% (95% CI, 89.3-96.5) with acalabrutinib/obinutuzumab and was 78.5% (95% CI, 71.6-89.9) with chemoimmunotherapy (P <.0001), a difference that was found to be statistically significant. The acalabrutinib combination ORR comprised a 13% complete response (CR) rate and an 81% partial response (PR) rate; 2% of patients achieved stable disease (SD).

In the single-agent acalabrutinib arm, the ORR was 85.5% (95% CI, 79.6-89.9) with a 1% CR rate, a 85% PR rate, and a 5% SD rate; compared with the chlorambucil/obinutuzumab ORR, this difference was not found to be statistically significant, according to Sharman. The obinutuzumab/chlorambucil arm consisted of a 5% CR rate, 74% PR rate, and a 9% SD rate.

Due to the study design in which continuous BTK inhibitor therapy was compared with fixed-duration chemoimmunotherapy, Sharman noted that there was an imbalance of reporting AEs that occurred within 30 days of the last dose, with a longer reporting period in the BTK inhibitor—containing arms.

Regarding safety, no new or unexpected patterns were observed. At least 1 all-grade AE(s) were observed in all 3 arms; more serious AEs were observed with acalabrutinib/obinutuzumab (38.8%) compared with acalabrutinib alone (31.8%) or obinutuzumab/chlorambucil (21.9%). The rates of grade ≥3 AEs were 70.2%, 49.7%, and 69.8%, respectively. Twelve grade 5 AEs were observed in the chemoimmunotherapy arm, 7 in the acalabrutinib monotherapy arm, and 5 in the acalabrutinib combination arm; these were pulled from the entire treatment-emergent and non—treatment-emergent period.

The most common all-grade AEs (≥15%) in the acalabrutinib/obinutuzumab and single-agent acalabrutinib arms were headache (39.9% vs 36.9%, respectively), diarrhea (38.8% vs 34.6%), neutropenia (31.5% vs 10.6%), fatigue (28.1% vs 18.4%), contusion (23.6% vs 15.1%), arthralgia (21.9% vs 15.6%), cough (21.9% vs 18.4%), upper respiratory tract infection (21.3 vs 18.4%), nausea (20.2% vs 22.3%), and dizziness (18.0% vs 11.7%). Grade ≥3 neutropenia was highest with obinutuzumab/chlorambucil (41.4%) versus acalabrutinib/obinutuzumab (29.8%) and acalabrutinib alone (9.5%).

The most common (≥2%) serious AEs with acalabrutinib/obinutuzumab, acalabrutinib, and obinutuzumab/chlorambucil were pneumonia (6.7% vs 2.8% vs 1.8%, respectively), infusion-related event (2.2% vs 0% vs 1.2%), anemia (1.7% vs 2.2% vs 0%), febrile neutropenia (1.7% vs 1.1% vs 4.1%), and tumor lysis syndrome (0.6% vs 0% vs 4.7%). These events were consistent with the previously established safety profile of this class of agents, Sharman said.

Specific AEs were of clinical interest for acalabrutinib. Any-grade atrial fibrillation was observed in 6 (3.4%) patients on acalabrutinib/obinutuzumab, 1 of which was grade ≥3. Seven cases of atrial fibrillation were observed on the acalabrutinib arm. Hypertension, bleeding, infections, and second primary malignancies, excluding nonmelanoma skin cancer, were also AEs of interest with the BTK inhibitor.

Sharman JP, Banerji V, Fogliatto LM, et al. Phase 3 study of acalabrutinib combined with obinutuzumab or alone versus obinutuzumab plus chlorambucil in patients with treatment-naïve chronic lymphocytic leukemia: results from ELEVATE-TN. Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, Florida. Abstract 31. bit.ly/33ST9NS.

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