The next-generation, selective BTK inhibitor acalabrutinib demonstrated noninferiority to ibrutinib in terms of progression-free survival in patients with previously treated chronic lymphocytic leukemia in the phase 3 ELEVATE-RR trial.
The next-generation, selective BTK inhibitor acalabrutinib (Calquence) demonstrated noninferiority to ibrutinib (Imbruvica) in terms of progression-free survival (PFS) in patients with previously treated chronic lymphocytic leukemia (CLL) in the phase 3 ELEVATE-RR trial (NCT02477696). However, the agent was linked with reduced occurrences of common adverse effects (AEs), such as atrial fibrillation in this patient population, according to Peter Hillmen, MD, PhD.
Results from the study, which were presented at the European Hematology Association 2021 Virtual Congress, showed that at a median follow-up of 40.9 months (range, 0.0-59.1), the median PFS was 38.4 months for both acalabrutinib and ibrutinib (HR, 1.00; 95% CI, 0.79-1.27). However, incidence of any-grade atrial fibrillation, which was a key secondary endpoint, was significantly lower with acalabrutinib vs ibrutinib, at rates of 9.4% vs 16%, respectively.
“There is no difference in terms of PFS from this trial, so either [agent is] effective,” Hillmen said. “There are lower levels of discontinuation with acalabrutinib because of the improved tolerability, and the major tolerability is around the cardiovascular AEs, which is important going forward if a patient is staying on treatment for a long period of time.”
In an interview with OncLive, Hillmen, a consultant in Clinical Haematology at Leeds Teaching Hospitals NHS Trust, as well as an honorary professor of haematology at the University of Leeds in the United Kingdom, discussed the results of the head-to-head trial comparing acalabrutinib and ibrutinib, as well as future directions for BTK inhibitors in CLL.
Hillmen: BTK inhibition has really revolutionized the treatment of [patients with] CLL over the last 10 years, and it has now become a standard of care in both the frontline and relapsed setting. [This was] mainly led by ibrutinib, which was the first of the first-generation BTK inhibitors. It is an irreversible inhibitor which not only inhibits BTK, but [also] inhibits irreversibly several tyrosine kinases, which is thought to account for some of the AEs of the drug.
For many patients, one of the issues for ibrutinib is tolerability. There are AEs that are either clinically significant, [such as] cardiac events, high blood pressure, etc., or [there are] other ones AEs, [such as] arthralgia, bruising, and fatigue.
Some years ago, the second-generation BTK inhibitors were developed, which are the reversible ones [and] are more selective. This trial was designed to compare ibrutinib and acalabrutinib in a relapsed/refractory group of patients. We selected patients who we consider to be, at the time, [at] the highest risk, which [were those with] del(17p) or del(11q). It was quite a brave trial to do, to go against a very effective therapy such as ibrutinib. The design of the trial was noninferiority in terms of PFS, so it was a very long study, because ibrutinib is a very effective drug. We recruited 533 patients who were randomized head-to-head to receive either agent.
The primary end point, which was noninferiority with PFS, was met, meaning there was no difference between the 2 BTK inhibitors in terms of PFS. [That] is obviously important. In terms of the secondary end points, which were analyzed in a hierarchical way, the incidence of atrial fibrillation, or atrial flutter, was reduced in the acalabrutinib arm compared with the ibrutinib arm. The rates were 16% at the follow-up of the trial for ibrutinib, compared with 9.4% for acalabrutinib. The hazard ratio was just above 0.5 in favor of acalabrutinib. [Additionally,] if you excluded the patients with previous atrial fibrillation, the difference [in reduction] is even more marked for acalabrutinib.
There was also a significant reduction in hypertension, and hypertension is [an AE] that continues to build up over time and can be correlated with the medication, [as well as] late complications. Less than half of the patients developed hypertension with acalabrutinib compared with ibrutinib. There were very low levels, which is encouraging. In addition, [there were] some of the nuisance [AEs, such as] arthralgia, bruising, and bleeding. [Acalabrutinib] was best tolerated from that perspective, [however] there was no difference in overall survival.
We need to have further follow up. This trial was a select group of relapsed/refractory patients, and in retrospect, knowing what we do now, we may have broadened that to all relapsed patients. [Although,] at the time, it was a sensible restriction on those patients. The next question is: what about patients in the frontline setting? Does this change the practice?
If we are going to select a BTK inhibitor, will we go with the second-generation inhibitors, such as acalabrutinib? In that group of patients, because progression is less frequent in the frontline setting and they will likely stay on treatment longer, tolerability is more important. We can interpret the data in that way, and we do have that the frontline data with acalabrutinib which is positive against chemoimmunotherapy. Moving forward, the next [batch] of trials is looking at combinations, and [whether we can] stop therapy with BTK inhibitors. That is where we are moving in CLL for all patients.
Generally, yes. When we think of the trials that we do in CLL or any disease, the main result we like to get is the approval of drugs, which is obviously critical to allow us to use them more broadly, [as well as] globally. [However,] that is usually in a highly selective group of patients, and we then try to interpret the use of those drugs into a wider group of patients that may not actually be eligible for the trial. The ways around that are to do collaborative studies, which tend to be larger, and we can look at patient subgroups, [look to bring] the treatment early on in the treatment paradigm, [and examine] real world data. What happens to patients in the real-world setting, and can you translate this into the trial?
These sorts of trials where we are looking at next-generation drugs are important because everybody wants to get the best treatment for patients, particularly in therapies where we are using the treatment continuously and indefinitely. We do not know at the time of an approval what a 10- or 20-year AE profile will look like. Head-to-head comparisons are important going forward.