Phase II trial supports efficacy, safety of oral acalabrutinib-based therapy

A triple-therapy drug combo for chronic lymphocytic leukemia was the subject of this article, which BreakingMED published Nov. 17, 2021, and is being re-published now as part of our year-end review. Click here to view the original article and obtain CME/CE credit.

A triple-agent front-line treatment was active and well tolerated in patients with chronic lymphocytic leukemia (CLL), although the phase II study did not meet its primary endpoint, researchers reported.

In a single-arm, open-label trial of acalabrutinib, venetoclax, and obinutuzumab therapy, 38% (n=14/37) of participants with CLL had complete remission (CR) with undetectable minimal residual disease (MRD) in the bone marrow at cycle 16/day 1 (28-day cycles), according to Matthew S. Davids, MD, MMSc, of the Dana-Farber Cancer Institute in Boston, and co-authors.

While the “rate of complete remission with undetectable MRD in the bone marrow, the primary endpoint of our study, did not meet the prespecified goal of 60%,” they noted in The Lancet, this “was due mainly to patients who had good quality partial remissions with undetectable MRD in the bone marrow.”

They acknowledged that the primary endpoint of CR based on International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 criteria, along with undetectable MRD in the bone marrow, was “suboptimal because we now know from the CLL14 study that undetectable MRD in the bone marrow alone is a better predictor of progression-free survival with a venetoclax-obinutuzumab based regimen than complete remission by iwCLL criteria.”

Still, the phase II results were solid enough for a phase III trial to move forward that will evaluate acalabrutinib-venetoclax, with and without obinutuzumab, versus chemoimmunotherapy for previously untreated CLL.

Acalabrutinib is a covalent Bruton tyrosine kinase (BTK) inhibitor utilized as continuous therapy for CLL. Venetoclax, a B-cell lymphoma 2 (BCL-2) protein inhibitor, and obinutuzumab, a monoclonal antibody that binds to B-lymphocyte antigen CD20, are used as fixed-duration CLL therapy.

Acalabrutinib was FDA-approved in 2019 for use in adults with CLL or small lymphocytic lymphoma (SLL) based on progression-free survival findings from the ELEVATE-TN and ASCEND trials.

ELEVATE-TN data were presented at the 2020 European Hematology Association (EHA) congress, and four-year follow-up data were shared at the 2021 American Society of Clinical Oncology meeting. It was a head-to-head trial of acalabrutinib versus ibrutinib in previously treated CLL.

“What we’ve learned from this study is that a second-generation BTK inhibitor, acalabrutinib, is at least as good as ibrutinib…survival was favorable, and it’s much better tolerated by patients. This enables potentially better combination approaches for CLL patients with this second-generation molecule,” ELEVATE-TN co-investigator John Byrd, MD, of the Ohio State University College of Medicine in Columbus, told eCancer TV.

ELEVATE-TN co-investigator Jeff Sharman, MD, of the Willamette Valley Cancer Institute in Eugene, Oregon, told eCancer TV at EHA that “BTK inhibitors have become perhaps one of the most important drug classes in the management of chronic lymphocytic leukemia. These oral medications combine some of the highest efficacy rates that we’ve seen in the published literature in this disease and, at the same time, have a considerably improved toxicity profile relative to the historical chemotherapy regimens that we used.”

As for ASCEND, that phase III trial looked at acalabrutinib versus idelalisib plus rituximab, or bendamustine plus rituximab, in relapsed or refractory CLL. Data were presented at the 2020 American Society of Hematology virtual meeting and published in the Journal of Clinical Oncology. In terms of adverse events (AEs) in ASCEND, “acalabrutinib appeared to be the safest. The typical adverse event with acalabrutinib was headache… it’s something that happens after the first [dose] and it lasts only a couple of weeks…and it’s usually mild, grade 1 or 2,” explained ASCEND investigator Paolo Ghia, MD, PhD, of the Università Vita-Salute San Raffaele in Milan, Italy, in a CLL Society interview.

In the current trial, acalabrutinib’s safety profile was reinforced. Davids’ group reported that one patient needed a dose reduction because of grade 3 headache but was “successfully increased back to full dose 1 month later.” Serious AEs occurred in 24% of all patients, with neutropenia being the most common (8%).

The open-label study enrolled treatment-naïve patients with CLL or SLL, according to iwCLL 2018 criteria, from August 2018 to May 2019. They had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2. Median follow-up was 27.6 months. The median age of the 37-patient cohort was 63, and 89% were non-Hispanic White, while 73% were male. More than half had an ECOG 1 PS. Over a quarter were TP53-aberrant with high-risk features of both TP53 mutation and 17p deletion, and 24% of patients expressed mutated IGHV status.

The agents were combined into a triplet of 28-day therapy cycles in an effort to induce durable remissions in the cohort, Davids and co-authors explained. The protocol consisted of:

  • Acalabrutinib oral monotherapy twice daily for cycle 1.
  • Acalabrutinib combined at cycle 2 with IV obinutuzumab at varying dosages for six cycles.
  • Introduction of venetoclax at the start of cycle 4 and then ramp-up from 20 mg on day 1 to 400 mg by day 22.
  • Continuation of 400-mg venetoclax dose for remainder of treatment.
  • Continuation of acalabrutinib-venetoclax until day 1 of cycle 16 or day 1 of cycle 25.

“If the patient had undetectable MRD in the bone marrow they were given the option to discontinue therapy at the start of cycle 16 (if also in complete remission) or at the start of cycle 25 (if at least in partial remission),” the authors wrote.

CT scans were performed at baseline and five times at the beginning of various therapy cycles. Bone marrow biopsy was optional at the beginning of cycle 4 but was mandatory at the beginning of therapy cycles 8, 16, and 25. Patients who had MRD in their bone marrow had peripheral blood monitored for MRD every three months after therapy cessation, according to Davids’ group.

All trial patients received at least one dose of any study drug. One patient discontinued the study due to an AE during therapy cycle 5, while the remaining 36 continued on to at least the end of cycle 15.

The authors reported that 32/37 patients discontinued the study drugs at various time points, specifically:

  • Twelve patients discontinued acalabrutinib-venetoclax after CR after 15 cycles.
  • One patient discontinued acalabrutinib-venetoclax due to autoimmune cytopenia while in CR with incomplete bone marrow recovery with undetectable bone marrow MRD during cycle 18.
  • Nineteen patients discontinued acalabrutinib-venetoclax after having undetectable bone marrow MRD after 24 cycles.

As of data cutoff on May 11, 2021, four patients were still on acalabrutinib-venetoclax therapy.

“The rate of complete remission with undetectable MRD increased from 14% (five of 37) at the start of cycle 8 to 38% (14 of 37) at the start of cycle 16 and remained at 38% (14 of 37) at the start of cycle 25,” the authors noted. “…The best overall rate of undetectable MRD in the peripheral blood was 92% (34 out of 37) and in the bone marrow was 86% (32 out of 37).”

In addition, five patients who had CR with undetectable MRD at the start of cycle 8 had IGHV-unmutated disease, and one had TP53-aberrant disease. CR proportions among patients with IGHV-mutated or TP53-aberrant disease were similar to that of the total population, they said.

Study limitations were a relatively short follow-up time for a first-line therapy study and a small cohort size. In addition, the authors conceded that “a crucial question in [CLL] therapy is whether the addition of obinutuzumab enhances efficacy. Without a doublet therapy comparator group, we cannot directly address what benefit obinutuzumab is adding to acalabrutinib and venetoclax.”

Hopefully, the ongoing phase III ACE-CL-311 trial (2027 estimated study completion date) will offer that answer, they added.

Shalmali Pal, Contributing Writer, BreakingMED™

The study was funded by AstraZeneca and a Dana-Farber Cancer Institute Collaborative Award. Acalabrutinib was supplied for the study by AstraZeneca. Obinutuzumab and venetoclax were supplied for the study by Genentech.

Davids reported support from, and/or relationships with, the Leukemia and Lymphoma Society, Ascentage Pharma, AstraZeneca, Genentech, MEI Pharma, Novartis, Pharmacyclics, Surface Oncology, TG Therapeutics, Verastem, AbbVie, Adaptive Biotechnologies, BeiGene, Bristol-Myers Squibb, Celgene, Eli Lilly, Genentech, Janssen, Merck, Pharmacyclics, Research to Practice, Syros Pharmaceuticals, Takeda, TG Therapeutics, and Zentalis.

Co-authors reported support from the NIH and relationships with multiple entities including AstraZeneca and Genentech.

Cat ID: 466

Topic ID: 78,466,730,466,192,925