Posted: Thursday, May 14, 2020
Based on data from two phase III clinical trials, acalabrutinib has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with treatment-naive or relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).1 This approval signifies another step forward in the treatment landscape for CLL, which has recently been dramatically altered with the development of drugs targeting a variety of kinases in the B-cell receptor (BCR) signaling pathway.2
Acalabrutinib is a next-generation selective inhibitor of Bruton’s tyrosine kinase (BTK). It had already been granted accelerated approval by the FDA for adults with mantle cell lymphoma who have received at least one prior therapy.
Acalabrutinib Versus Ibrutinib
BTK plays a key role in the B-cell receptor signaling pathway; acalabrutinib binds irreversibly to BTK and inhibits its activity. The drug was designed as a potentially more selective BTK inhibitor, in an attempt to mitigate some of the treatment-limiting toxicities often seen with ibrutinib. According to Dr. Brown, “Acalabrutinib is the BTK inhibitor of choice for people with comorbidities, particularly cardiac issues.”
The efficacy data look similar between acalabrutinib and ibrutinib, although follow-up is longer with ibrutinib, Dr. Brown continued. Therefore, the key difference between the drugs lies in their side-effect profiles. Ibrutinib tends to be more poorly tolerated in older patients and is associated with high rates of atrial fibrillation and hypertension. “Acalabrutinib is much better-tolerated [than ibrutinib], so I use it preferentially, particularly in my older patients,” she said.
The drug’s approval in CLL, granted in November 2019, was based on safety and efficacy data from interim analyses of the ELEVATE-TN trial of patients with previously untreated CLL3 and the ASCEND trial of patients with relapsed or refractory CLL.4 In both trials, acalabrutinib demonstrated superior progression-free survival compared with standard therapy, and a favorable tolerability profile. In the ELEVATE-TN trial, specifically, acalabrutinib combined with obinutuzumab and as monotherapy reduced the risk of disease progression or death by 90% and 80%, respectively.
“Tolerability remains an issue in the current treatment landscape of CLL, which may require ongoing therapy for many years,” stated Jeff Sharman, MD, Director of Research at Willamette Valley Cancer Institute, Medical Director of Hematology Research for The US Oncology Network, and lead author of the ELEVATE-TN trial, in a press release. “In the ELEVATE-TN and ASCEND trials comparing [acalabrutinib] to commonly used treatment regimens, [acalabrutinib] demonstrated a clinically meaningful improvement in progression-free survival in patients across multiple settings, while maintaining its favorable tolerability and safety profile.”5
Generally, the main comorbidities to consider when using BTK inhibitors are cardiac. “Hypertension is a problem with ibrutinib over time, as people stay on it indefinitely until disease progression or an adverse event, but it seems to be less of a problem with acalabrutinib,” Dr. Brown noted. “Patients who need anticoagulation are still a bit of an issue; there is bleeding with both drugs, albeit probably less with acalabrutinib in my experience, although major bleeding looks about the same in trials.”
Hypertension is a problem with ibrutinib over time, as people stay on it indefinitely until disease progression or an adverse event, but it seems to be less of a problem with acalabrutinib.
Acalabrutinib tends to have fewer off-target effects. “For example, ibrutinib inhibits EGFR, and that can contribute to rash and diarrhea, which we don’t see with acalabrutinib nearly as much,” Dr. Brown told JNCCN 360. “With ibrutinib, there are also substantial risks of atrial fibrillation and other cardiac events, including ventricular arrhythmia, with ibrutinib, which do not appear to be as significant with acalabrutinib.”
Although head-to-head data do not yet exist, the ongoing ELEVATE-RR trial is comparing ibrutinib and acalabrutinib in patients with previously treated high-risk CLL. “This might shed some light on whether there’s differential efficacy, and it will obviously shed light on toxicity,” Dr. Brown shared.
Patients treated with ibrutinib also tend to experience “low-grade, irritating side effects” much more often than patients treated with acalabrutinib, according to Dr. Brown. Patients often find these side effects difficult to describe, but they may include gastrointestinal irritation, joint and muscle aches, and general unwellness. “It’s hard to capture in the studies, but it’s definitely true,” she added. “When someone has to stay on the same drug for years, they really add up.”
Other Clinical Challenges With Acalabrutinib
Allison Dean, MS, APRN-CNP, a nurse practitioner at The James Cancer Hospital at The Ohio State University, has worked with patients on clinical trials of acalabrutinib. One of the most common side effects she has seen, especially when patients first start the drug, is headache.
It can range from mild to severe, but it is common enough that patients should be made aware “and know how to manage it prior to starting treatment,” suggested Ms. Dean. “It’s usually not something so severe that we need to stop the medication; we just manage it with supportive measures, and the headaches usually improve within a couple of days to weeks. We always make sure patients know that even if they do experience these severe headaches, they will improve and most likely go away.”
To manage headaches, she tells patients to increase their hydration at home if their headache is mild or with IV fluids, if necessary. Patients can also take acetaminophen as needed. Additionally, “If patients are able to tolerate it,” she added, “sometimes just drinking a cup of coffee in the morning will help.”
However, generally the side effects associated with acalabrutinib are manageable, and most patients tolerate it well, Ms. Dean told JNCCN 360. Most of the time, side effects of acalabrutinib can be managed with supportive measures (ie, gentle stretching for joint pain).
Most of the time, side effects of acalabrutinib can be managed with supportive measures.
“If patients experience severe mouth sores, for example, we might consider a consult with a specialist in oral pathology,” she noted. “However, with this drug, we see these severe side effects infrequently and don’t need to involve other specialties as often.”
ELEVATE-TN Trial in Newly Diagnosed Disease
The randomized, multicenter, open-label phase III ELEVATE-TN trial reported a statistically significant and clinically meaningful improvement in progression-free survival for patients treated with acalabrutinib, either in combination with obinutuzumab or as monotherapy, when compared with chemoimmunotherapy with chlorambucil/obinutuzumab.3 The trial evaluated the safety and efficacy of acalabrutinib in treatment-naive patients with CLL who were older than age 65 or younger patients (aged 18–65) with comorbid medical conditions. Patients were randomly assigned to receive chemoimmunotherapy with chlorambucil in combination with obinutuzumab, or acalabrutinib as monotherapy or in combination with obinutuzumab until disease progression or unacceptable toxicity.
In the acalabrutinib-obinutuzumab arm, the investigators observed a 90% reduction in the relative risk of disease progression or death, with a similar risk reduction of 80% in the monotherapy arm. Acalabrutinib delivered consistent progression-free survival results across all risk groups.
According to Dr. Brown, this is the first trial to suggest a possible benefit of adding an anti-CD20 antibody to a BTK inhibitor. “We’ll see if this holds up over longer follow-up,” she said. “It does look convincing, although the study wasn’t powered for this comparison.”
After a median follow-up of 28.3 months, median progression-free survival has not been reached in the acalabrutinib-obinutuzumab arm, compared with 22.6 months in the control arm. Median overall survival has not been reached in any arm.
Ms. Dean noted that cytopenias tend to be seen more often in patients treated with acalabrutinib/obinutuzumab than in patients treated with acalabrutinib monotherapy. “We’ll often check labs in between cycles of obinutuzumab to make sure there is no unsafe decrease in neutrophil [counts], and if there are, we’re watching closely for infection,” she told JNCCN 360. “We watch their counts closely when they first start acalabrutinib monotherapy too, but eventually that tapers off after a few months. We’ll usually check labs every 2 to 4 weeks while patients are receiving obinutuzumab infusions.”
According to Ms. Dean, most patients experience an increase in lymphocytosis when they first start acalabrutinib. “It’s important to make sure patients know this and it actually means the drug is working,” she added.
ASCEND TRIAL in Relapsed or Refractory CLL
Treatment with acalabrutinib led to superior progression-free survival compared with investigator’s choice in the randomized, phase III ASCEND trial.4 The study enrolled patients with CLL who had received at least one prior systemic therapy. Patients were randomly assigned to acalabrutinib as monotherapy until disease progression or unacceptable toxicity, or investigator’s choice of rituximab in combination with the phosphoinositide 3-kinase (PI3K) inhibitor idelalisib or chemoimmunotherapy with rituximab and bendamustine.
After a median follow-up of approximately 16 months, treatment with acalabrutinib resulted in a 69% relative risk reduction in disease progression or death compared with idelalisib/rituximab or bendamustine/rituximab. The overall response rate was not significantly different; 81% with acalabrutinib monotherapy versus 75% with investigator’s choice. However, the median overall survival was not reached in either arm. The rate of adverse events that led to discontinuation of treatment in patients receiving acalabrutinib was 11%.
Adherence to Oral Therapy
According to Dr. Brown, poor medication adherence is less of an issue for patients taking acalabrutinib than ibrutinib, due to milder and fewer side effects. However, communicating that treatment with acalabrutinib will continue until disease progression can still be a challenging conversation.
“Some patients are fine with it, and if they don’t have side effects, they view it like taking a blood pressure or cholesterol-lowering medicine,” she explained. “Other patients don’t like it and would much rather have time-limited therapy. That’s where a conversation about a venetoclax/obinutuzumab regimen comes in, limited to 1 year, or also possibly chemoimmunotherapy.”
Ms. Dean agreed that because typically these patients are older and most of them are dealing with at least one comorbidity that requires chronic treatment, the idea of treating until disease progression tends to be acceptable. “We tell them this is usually an indefinite treatment,” she said. “It is something they’re going to take for as long as they tolerate it and we know it is working.”
Patients at The James Cancer Hospital meet with their pharmacist prior to starting on acalabrutinib, commented Ms. Dean. Together, they will often work out a plan to maintain adherence (often using a timer or pillbox). “Remembering to take two doses per day can be an issue for patients who aren’t used to that schedule,” she noted.
Ms. Dean sees her patients on acalabrutinib once a week for the first 4 weeks and then monthly for the next few months to ensure it is well tolerated. “We want to see them to do a physical exam, check lab work, and make sure there aren’t any side effects they neglected to mention or thought weren’t important,” she told JNCCN 360.
Ongoing Clinical Trials
Several phase III clinical trials in CLL are ongoing. They include the ASCEND and ELEVATE-TN trials, as well as ELEVATE-RR (ACE-CL-006), which is evaluating acalabrutinib versus ibrutinib in patients with previously treated high-risk CLL (ClinicalTrials.gov identifier NCT02477696). Finally, the ACE-CL-311 trial (NCT038626; for which Dr. Brown is principal investigator) is studying acalabrutinib in combination with venetoclax with or without obinutuzumab versus chemoimmunotherapy in patients with previously untreated CLL without 17p deletion or TP53 mutation.
Jennifer Brown, MD, PhD, has served as a consultant for AbbVie, Acerta, AstraZeneca, BeiGene, Catapult, Dynamo Therapeutics, Eli Lilly, Juno/Celgene, MEI Pharma, Nextcea, Novartis, Octapharma, Pfizer, and Verastem; has received research funding from Gilead Sciences, Loxo, Sun, and Verastem; and has served on a data safety monitoring committee for Invectys.
Allison Dean, MS, APRN-CNP, reported no conflicts of interest.
- S. Food and Drug Administration. Project Orbis: FDA approves acalabrutinib for CLL and SLL. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/project-orbis-fda-approves-acalabrutinib-cll-and-sll. Accessed April 29, 2020.
- Isaac K, Mato AR. Acalabrutinib and its therapeutic potential in the treatment of chronic lymphocytic leukemia: a short review on emerging data. Cancer Manag Res 2020;12;12:2079–2085.
- Sharman JP, Banerji V, Fogliatto LM, et al. ELEVATE-TN: Phase 3 study of acalabrutinib combined with obinutuzumab or alone vs obinutuzumab plus chlorambucil in patients with treatment-naive chronic lymphocytic leukemia. Blood 2019;134(suppl 1):31.
- Ghia P, Pluta A, Wach M, et al. ASCEND phase 3 study of acalabrutinib vs investigator’s choice of rituximab plus idelalisib or bendamustine in patients with relapsed/refractory chronic lymphocytic leukemia. 2019 European Hematology Association Congress; Amsterdam, The Netherlands. Abstract LB2606.
- AstraZeneca Press Release. Calquence approved in the US for adult patients with chronic lymphocytic leukaemia. Available at https://www.astrazeneca.com/media-centre/press-releases/2019/calquence-approved-in-the-us-for-adult-patients-with-chronic-lymphocytic-leukaemia-21112019.html. Accessed April 29, 2020.