Ryan Jacobs, MD, and Alan Pierre Zausner Skarbnik, MD, discussed the use of acalabrutinib and zanubrutinib in patients with relapsed/refractory chronic lymphocytic leukemia.
Alan Pierre Zausner Skarbnik, MD, and Ryan Jacobs, MD, discussed the use of acalabrutinib (Calquence) and zanubrutinib (Brukinsa) in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), based on results from a matching-adjusted indirect comparison (MAIC), as part of a Between the Lines program.1 Both clinicians spoke to the analysis’ results and highlighted their typical approach to treating CLL.
Their discussion also centered on how clinical factors affect treatment selection, treatment sequencing in this population, and methods for evaluating available Bruton tyrosine kinase (BTK) inhibitors based on efficacy and safety profiles. Skarbnik was the second author of the analysis that was presented at the 2023 American Society of Clinical Oncology Annual Meeting. The analysis aimed to determine whether acalabrutinib or zanubrutinib had superior efficacy in the specified patient population.
To kick-start the conversation, Jacobs detailed his approach to treating patients with CLL. If a patient has previously been treated with chemotherapy, a BTK inhibitor or venetoclax (Venclexta)–based therapy in combination with obinutuzumab (Gazyva) may be appropriate. For patients who have previously received a novel therapy and have experienced a relapse, whether to re-treat with venetoclax or continue with a BTK inhibitor remains in question.
Jacobs queried whether waiting for clinical progression is appropriate prior to switching to venetoclax if a patient is on indefinite treatment. Skarbnik noted that treatment sequencing is something that is often debated in this setting but added that having options is positive.
When patients present with comorbidities or genetic mutations, and clinical factors are considered, Jacobs said he prefers to use BTK inhibitors because “they’re just so effective across the spectrum.” When a prognostic work-up is conducted, and patients have a chromosome 17 aberration, they typically respond well to indefinite BTK inhibition, he added.
Skarbnik noted that 3 BTK inhibitors are approved and asked for Jacobs’ thoughts on how he selects among them. Jacobs noted that he references the head-to-head studies on these agents that have been completed or relies on recommendations from the National Comprehensive Cancer Network (NCCN) guidelines.
Jacobs noted, “The NCCN tells us that ibrutinib [Imbruvica] is not one of the preferred regimens [for treatment of patients with CLL], so we are focusing mostly on prescribing acalabrutinib or zanubrutinib when we’ve decided that a BTK inhibitor is the right treatment for a patient.”
Investigators aimed to determine the efficacy and safety of acalabrutinib and zanubrutinib using individual patient data from the phase 3 ASCEND trial (NCT02970318) and aggregate data from the phase 3 ALPINE trial (NCT03734016).2,3
The ASCEND trial looked at acalabrutinib vs investigator’s choice of either rituximab (Rituxan) or bendamustine (Bendeka) plus rituximab in patients with relapsed/refractory CLL. The ALPINE trial assessed the use of zanubrutinib vs ibrutinib in the same patient population as the ASCEND trial. Both trial populations consisted of patients with unrestricted deletion 17p and/or deletion 11q, with 1 median line of prior therapy.
In the ASCEND trial, 155 patients were given acalabrutinib orally at 100 mg twice daily and 115 received investigator’s choice of therapy. In the ALPINE study, 327 patients were given oral zanubrutinib at 160 mg twice daily and 325 received 420 mg of oral ibrutinib once daily.
The primary efficacy analysis of the MAIC indicated that matching had little impact on the investigator-assessed progression-free survival (INV-PFS).1 Of note, there was no difference in the INV-PFS between acalabrutinib and zanubrutinib after matching (HR, 0.90; 95% CI, 0.60-1.36).
A secondary analysis determined that after matching, acalabrutinib had superior INV-PFS over ibrutinib (HR, 0.60; 95% CI, 0.40-0.90). Prior to matching, there was no difference between zanubrutinib and acalabrutinib.
The 12-month INV-PFS for acalabrutinib was 91% (95% CI, 84%-95%), 92% (95% CI, 88%-94%) for zanubrutinib, and 84% (95% CI, 79%-88%) for
ibrutinib. The 24-month INV-PFS was 76% (95% CI, 68%-84%) in the acalabrutinib arm, 78% (95% CI, 73%-83%) in the zanubrutinib arm, and 66% (95% CI, 60%-71%) in the ibrutinib arm.
Regarding safety, matching had little impact on acalabrutinib toxicities. Of note, the safety profiles for acalabrutinib and zanubrutinib were similar except for the risk of serious adverse effects (AEs; OR, 0.61; 95% CI, 0.39-0.97), any-grade hypertension (OR, 0.18; 95% CI, 0.09-0.37), grade 3 or higher hypertension (OR, 0.22; 95% CI, 0.09-0.54), any-grade hemorrhage (OR, 0.54; 95% CI, 0.34-0.87), and AEs leading to a dose reduction (OR, 0.30; 95% CI, 0.14-0.67).
In patients treated with acalabrutinib and prior to matching, the risk of any-grade hypertension was lower compared with those receiving zanubrutinib. There was also a lower cumulative incidence rate of any-grade hypertension observed with acalabrutinib vs zanubrutinib at 12 months (3% vs 16%, respectively), 24 months (5% vs 23%), and 42 months (10% vs 28%).
In conclusion, investigators of the MAIC analysis found no difference between acalabrutinib and zanubrutinib treatment. The safety profile was consistent across both groups, except for any-grade hemorrhage and dose reduction from AEs, which were lower in the acalabrutinib arm.
Jacobs noted that dose reduction was an interesting issue, specifically with ibrutinib. There are data suggesting a reduction in treatment does not affect PFS, but it is unclear whether the same can be said about new BTK inhibitors, they both agreed. Skarbnik suggested it is easier to reduce with zanubrutinib rather than acalabrutinib because of the dosing regimens.
Data from the ALPINE trial showed the essential PFS difference. “There was some level of surprise when the ALPINE data ultimately showed that PFS difference. I think we all inappropriately try to indirectly—in our own minds—compare across trials,” Jacobs said. “This [MAIC] is a bit more of a formal way to do it. It would be nice to someday get a direct comparison, but realistically we’re going to be stuck with these and maybe some real-world comparisons, and we’re going to have to draw our own conclusions.”
Skarbnik agreed that these data can help to identify the best treatment path and determine which patient populations can better tolerate certain drugs. In Jacobs’ opinion, both acalabrutinib and zanubrutinib “appear to be good options.”
When discussing future research, Jacobs said he hopes to see therapy options for patients who have double-refractory CLL. Pirtobrutinib (Jaypirca) is being investigated in the space, with an eye toward FDA approval.