Acalabrutinib Plus Venetoclax and Obinutuzumab Achieves High Bone Marrow uMRD Rate in CLL

Matthew Davids, MD, MMSc

In patients with chronic lymphocytic leukemia (CLL) and undetectable minimal residual disease (MRD) in the bone marrow, the frontline combination of acalabrutinib (Calquence), venetoclax (Venclexta), and obinutuzumab (Gazyva) were highly active and well-tolerated, according to phase 3 study results published in The Lancet Oncology.¹

“These are 3 of the most active new drugs approved for patients with CLL, and our trial is the first published study to examine the efficacy of this triplet as initial treatment for CLL. Prior experience with chemoimmunotherapy demonstrated that putting our best drugs together first was the most effective strategy in this disease, and our study is one of the first to evaluate whether the same may be true with novel agent only based treatment, said Matthew Davids, MD, MMSc, the lead investigator and director, Clinical Research, Division of Lymphoma and physician at Dana-Farber Cancer Institute and an associate professor of Medicine at Harvard Medical School, in an interview with Targeted Oncology™.

Preclinical studies in CLL have specifically shown that Bruton’s tyrosine kinase (BTK) inhibitors and BCL-2 inhibitors have synergy. The first-generation BTK inhibitor, ibrutinib (Imbruvica), in combination with venetoclax, in particular, achieved deep response in CLL models with undetectable MRD in the peripheral blood and/or bone marrow.

Considering that acalabrutinib was shown to have non-inferior efficacy compared with ibrutinib in the phase 3 ELEVATE RR clinical trial (NCT02477696) of patients with high-risk CLL, with less cardiotoxicity, investigators hypothesized that utilizing acalabrutinib with BCL-2 inhibition would be beneficial in the MRD-negative CLL subgroup, including in those with higher-risk disease.²

The single-arm, open-label, investigator-sponsored, phase 2 study (NCT03836261) was conducted at both the Dana-Farber Cancer Institute and Beth Israel Deaconess Medical Center. A total of 37 patients were enrolled. Patients were required to 18 years of age or older with an ECOG performance status of 0 to 2, and measurable disease. At baseline, patients were also required to have a total bilirubin 1.5 × the upper limit of normal (ULN) or lower; aspartate aminotransferase and alanine aminotransferase 2.5 × the ULN or lower; creatinine clearance of 50 mL/min or higher, absolute neutrophil count of 750 cells per mm³ or higher, and a platelet count of 50000 per mm³ or higher.¹

In 28-day cycles, patients were treated with acalabrutinib 100 mg orally twice daily cycle 1. Then on the first day of cycle 2, patients received obinutuzumab 100 mg followed by 900 mg on day 2, 1000 mg on day 8, and 1000 mg on day 15. Obinutuzumab was administered intravenously (IV) with continuous acalabrutinib. On day 1 of cycles 3 to 7, obinutuzumab treatment at 1000 mg IV was continued. Oral venetoclax was added to the study treatment on day 1 of cycle 4 and was administered on an accelerated dose schedule. Specifically, venetoclax 20 mg was administered on day 1, then patients received 50 mg of venetoclax on days 2–7, 100 mg on gays 8–14, 200 mg on days 15–21, and 400 mg on days 22.

The protocol required that patients who were at high risk for tumor lysis syndrome (TLS) to initiate venetoclax therapy at 20 mg and 50 mg while inpatient during cycle 4. Those with low or medium risk for TLS could start their venetoclax therapy inpatient or outpatient, according to the discretion of the clinicians. Following the obinutuzumab during cycle 7, all patients continued acalabrutinib 100 mg twice daily and venetoclax 400 mg once daily until 15 cycles were completed. Acalabrutinib plus venetoclax was continued until disease progression or unacceptable toxicity. However, patients had the option to discontinue if they achieved a complete remission.

The rate of CR with undetectable MRD in the bone marrow at the start of cycle 16 was the study’s primary end point. The study was powered to detect a 60% CR with undetectable MRD in the bone marrow, assuming the null hypothesis rate was 40%. The secondary end point explored in the study included CR and undetectable MRD in the bone marrow at the start of cycles 8 and 25, partial remission (PR) rate and Cr rate defined by the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria at the start of cycle 16, in addition to undetectable MRD in the peripheral blood and bone marrow at the start of cycles 8.16,, and 25, best overall response rates, best rate of CR, best overall rate of undetectable MRD in the bone marrow and peripheral blood, and the association between established prognostic indicators and responses to acalabrutinib plus venetoclax and obinutuzumab.

Secondary safety/tolerability end points including, the rate of adverse events (AEs) of special interest, the rate of any-grade atrial fibrillation, the rate of grade 3 or worse bleeding events, and the rate for clinical and laboratory TLS were also evaluated during the study.

At baseline, the median patient age was 63 years (range, 57-70), and most patients with male (73%) and identified as non-Hispanic White (89%). No patient had an ECOG performance status of 2, and 54% had a score of 1 while the remaining 46% of patients had a score of 2. The largest percentage of patients (35%) had a Rai stage of 2 at the time therapy started in the study, and 30% had a score of 3, 24% had a score of 4, and 11% had a score of 1.

In terms of cytogenetics at baseline, 13q deletions were most common (49%), and 6q deletion were least common (5%). There were also patients with 17p deletions (27%), 11q deletions (35%), Trisomy 12 (14%), and complex karyotype (19%). Most of the patient population did not have IGHV-mutated disease (73%), and 49% had were negative for ZAP-70. In terms of high-risk factors, 27% of the population had both a TP53 mutation and 17p deletion, and 19% had a NOTCH1 mutation.

All patients received at least 1 dose of each therapy in the study. Thirty-six of the patients were evaluable for the secondary end points. At a median follow-up of 27.6 months (interquartile range, 25.1-28.2), there were no cases of clinical progression and all patients remained alive at data cut off.

The rate of CR with undetectable MRD at the start of cycle 16 was 38% (95% CI, 22-55), missing the primary end point of the study. But, notably, the CR rate increased from 14% at cycle 8% to 35% at cycle 16% and was still 38% by cycle 25. It was also notable, according to the study authors, that those who achieved a CR by cycle 8 all had IGHV-unmutated disease and 5 of them has a TP53 aberration.

Acalabrutinib with venetoclax and obinutuzumab did achieve a 100% ORR in the study with the best CR rate being 46%, and this result was irrespective of IGHV mutation status or the presence of TP53 aberrations.

In the subgroup of patients with undetectable MRD in both the peripheral blood and bone marrow, response status did not appear to impact the rate of undetectability, which was 92% in the peripheral blood, and 86% in the bone marrow. Further, across mutational subgroups, the rate of MRD undetectability in the blood and bone marrow were similar.

AEs were observed in all study patients but were predominantly low-grade. No AEs were considered treatment-related and there were no deaths as a result of AEs. One patient in the study discontinued treatment due to a higher grade AE.

Grade 1/2 hematologic AEs were most commonly neutropenia (41%), thrombocytopenia (54%), and anemia (54%). Low-grade non-hematological AEs were most commonly fatigue (86%), headache (73%), and bruising (59%).

The most common grade 3/4 hematological AE was neutropenia, which occurred in 43% of patients. the most common non-hematologic AEs included hyperglycemia and hypophosphatemia, which occurred in 8% of patients each.

“We have learned since we first designed the study that attaining undetectable MRD is a better predictor of long term PFS than whether a patient achieves a CR, so in retrospect, the primary end point was not optimal. Our triplet therapy achieved one of the highest bone marrow uMRD rates ever reported [86%] despite the fact that our population was enriched for patients with high-risk TP53-aberrant CLL,” Davids explained. “This suggests that the responses with this time-limited therapy are likely to be highly durable. Moreover, the tolerability of this triplet therapy was excellent, suggesting that it may be a regimen that could be used across a broad population of patients with CLL, including those who are older and/or have other medical comorbidities”

The combination of acalabrutinib, venetoclax, and obinutuzumab or AVO will be explored further in a phase 3 ACE-CL-311 clinical trial (NCT03836261) against the comparator of either AV or chemoimmunotherapy consisting of fludarabine, cyclophosphamide, and rituximab (Rituxan) in approximately 780 patients with previously untreated CLL. The primary end point of the study is progression-free survival.

“The phase 3 CL-311 study comparing AVO versus AV versus chemoimmunotherapy is now fully accrued. This registrational study is potentially label-enabling for the AVO triplet and/or the AV doublet. We are also about to open a global phase 3 study called “MAJIC”, which will compare the AV doublet to VO, with both arms having MRD-guided therapy duration. MAJIC will help to define the optimal combination partner for venetoclax for the initial treatment of CLL,” Davids stated.

_Reference:

_{1. Davids MS, Lampson BL, Tyekucheva S, et al. Acalabrutinib, venetoclax, and obinutuzumab as frontline treatment for chronic lymphocytic leukaemia: a single-arm, open-label, phase 2 study. Lancet Oncol. 2021;22(10):1391-1402. doi: 10.1016/S1470-2045(21)00455-1}

_{2. Byrd JC, Hillmen P, Ghia P, et al. First results of a head-to-head trial of acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia. J Clin Oncol. 2021;39(suppl 15):7500. doi: 10.1200/JCO.2021.39.15_suppl.7500}