Jennifer A. Woyach, MD

At 3 years of follow-up, the combination of acalabrutinib (Calquence) and obinutuzumab (Gazyva) continued to show benefit in patients with both newly diagnosed chronic lymphocytic leukemia (CLL) and relapsed or refractory (R/R) disease.

In updated findings of the phase Ib/II ACE-CL-003 trial presented at the 2019 European Hematology Association (EHA) Congress,1high response rates were seen with the combination in both patient populations.

“Treatment with acalabrutinib plus obinutuzumab yielded high response rates that were durable and deepened over time in both R/R and treatment-naïve patients with CLL irrespective ofTP53status,” the study authors, led by Jennifer A. Woyach, MD, of The Ohio State University Comprehensive Cancer Center, wrote in their poster presented at the EHA meeting.

The ACE-CL-003 trial enrolled 19 treatment-naïve patients aged≥65 years or who were <65 years and were ineligible to receive chemoimmunotherapy plus 26 patients who had previously received ≥1 treatment regimen for CLL or small lymphocytic leukemia (SLL). All patients had an ECOG performance status of up to 2, and patients in the R/R group were allowed to have received prior BTK inhibition if they had not progressed while on treatment.

Patients were given 100 mg twice daily or 200 mg daily of acalabrutinib in 28-day cycles until disease progression along with obinutuzumab on days 1, 2, 8, and 15 of the second cycle at increasing doses followed by 1000 mg intravenously on day 1 for cycles 3 through 7. The primary endpoints for the study were overall response rate (ORR) and safety.

Of the 45 total patients, only 1 patient in the treatment-naïve group had SLL. The median patient age was 61 years (range, 42-75) in the treatment-naïve group and 63 years (range, 42-76) in the R/R group. Seventy-one percent of patients were male. Almost half of the patients (49%) had a complex karyotype; additionally, del(17p) was noted in 9 patients, del(11q) in 14, and unmutatedIGHVin 26.

Patients were followed for a median of about 3.5 years with 78% of patients still on treatment as of data cutoff. Ten patients, 2 in the treatment-naïve group and 8 in the R/R group, had discontinued acalabrutinib and all patients had discontinued obinutuzumab, mostly due to completing the treatment cycles.

In line with earlier reports, the ORR was high in both groups at 95% in the treatment-naïve group and 92% in the previously treated group. Complete responses were seen in 31.6% of the treatment-naïve patients and in 7.7% of the R/R patients. The investigators noted that responses deepened over time.

The median time to response was 2.8 months in each group and the median time to a complete response was 18.4 months in the treatment-naïve group versus 12.9 months in the previously treated group. The median duration of response was not reached in each patient population.

In the group of newly diagnosed patients, the progression-free survival (PFS) rate at 39 months was 94.4% (95% CI, 66.6%-99.2%). The rate of PFS at 42 months in the previously treated group was 72.7% (95% CI, 43.8%-88.4%).

Minimal residual disease (MRD) negativity rates in the bone marrow were higher in the treatment-naïve group (26%) compared with the R/R group (15%). MRD responses in the peripheral blood were maintained over time.

TP53mutation, loss of copy number, or del(17p) occurred in 5 treatment-naïve patients and 8 previously treated patients. “No enrichment ofTP53loss (mutation or chromosome deletion) [were observed] in any response category or with MRD status,” Woyach and colleagues wrote in their poster.

The most common adverse events (AEs; any grade) observed in ≥40% of all patients were upper respiratory tract infection, weight increase, maculopapular rash, cough, diarrhea, headache, nausea, arthralgia, dizziness, constipation, contusion, fall, infusion-related reaction, sinusitis, vomiting, fatigue, hypertension, and skin lesions.

The most common grade ≥3 AEs were neutrophil count decrease (24%), syncope (11%), platelet count decrease (9%), cellulitis (9%), weight increase (9%), hypertension (7%), and hypophosphatemia (7%). Serious AEs occurred in 33% of patients, including most commonly cellulitis in 4 patients and diarrhea, dyspnea, pneumonia, pyrexia, and syncope in 2 patients each.

AEs leading to discontinuation in the treatment-naïve group included 1 case of grade 3 metastatic squamous cell carcinoma; in the R/R group, events included grade 1 vomiting, grade 3 maculopapular rash, grade 3 diarrhea, and grade 3 lung adenocarcinoma.

Richter transformation occurred in 3 patients, 1 in the treatment-naïve group and 2 in the previously treated group. All 3 of these patients had complex karyotype, and 1 from each arm also had del(17p) and unmutatedIGHV.

Of clinical interest, bleeding events occurred in 71% of patients but no cases of atrial fibrillation were noted. Hypertension of any grade occurred in 40% of patients.

Further Research With Acalabrutinib, Combinations

Going forward, 2 additional cohorts of the study are evaluating the combination of acalabrutinib and obinutuzumab plus venetoclax (Venclexta) in newly diagnosed patients or acalabrutinib, venetoclax, and rituximab (Rituxan) for R/R patients.

Additionally, the ongoing phase III ACE-CL-007/ELEVATE-TN trial (NCT02475681) is investigating the frontline acalabrutinib/obinutuzumab combination in comparison with obinutuzumab/chlorambucil or acalabrutinib monotherapy in patients with CLL.2

The multicenter, open-label trial randomized 535 treatment-naïve patients with CLL in a 1:1:1. In both acalabrutinib arms, the BTK inhibitor was administered at 100 mg twice daily until disease progression.

The primary endpoint is PFS in the acalabrutinib/obinutuzumab arm compared with the chlorambucil/obinutuzumab arm as assessed by an independent review committee (IRC). A key secondary endpoint is IRC-assessed PFS with single-agent acalabrutinib compared with chlorambucil plus obinutuzumab. ORR, time to next treatment, and overall survival are additional secondary endpoints of the study.

Recently, AstraZeneca, the company developing acalabrutinib, announced that the trial met its primary endpoint, demonstrating that the acalabrutinib and obinutuzumab combination induced a statistically significant and clinically meaningful improvement in PFS compared with obinutuzumab/chlorambucil.2

Acalabrutinib monotherapy also demonstrated a statistically significant and clinically meaningful improvement in PFS compared with obinutuzumab combined with chlorambucil in topline results of the trial. The safety and tolerability findings were also consistent with prior reports for the BTK inhibitor.

Full findings from the trial are expected to be presented at an upcoming medical meeting.

References