A presentation at the American Society of Clinical Oncology (ASCO) 2022 Annual meeting, which was held 3-7 June 2022, in Chicago, IL, featured the 3-year follow-up results of the phase 3 ASCEND trial (NCT02970318) in relapsed/refractory chronic lymphocytic leukemia (R/R CLL) [1]. In this extended follow-up period, efficacy results continued to favor acalabrutinib monotherapy, while the safety profile did not worsen.

Bruton tyrosine kinase (BTK) inhibitors are a preferred treatment option in patients with R/R CLL. Acalabrutinib (acala) is a next-generation, highly selective, covalent BTK inhibitor approved for the treatment of patients with CLL including those with R/R disease. The primary analysis of the ASCEND trial, with a median follow-up of 16.1 months, demonstrated that patients treated with acalabritinib monotherapy had longer progression-free survival compared with patients treated with the physician’s choice of either idelalisib plus rituximab or bendamustine plus rituximab [2]. At ASCO 2022, Prof. Wojciech Jurczak (Maria Skłodowska-Curie National Institute of Oncology in Kraków, Poland) reported the results of the ASCEND study with 3 years of follow-up.

Physician’s Weekly interviewed Prof. Jurczak:

Would you please help us understand the background to this study?

On behalf of my coauthors I presented the final results with a long mature follow-up of the ASCEND study, which was performed in chronic lymphocytic leukemia patients, relapsing or refractory to previous therapy. This study compared acalabrutinib monotherapy with a standard of care combination treatment. At the time we planned the protocol, the standard care was chemo-immunotherapy or idelalisib plus rituximab. During the study, consequently, the physician’s choice available was idelalisib plus rituximab versus bendamustine plus rituximab. However, the majority of patients were treated with idelalisib plus rituximab.

Therefore, this is the first head-to-head comparison between a BTK inhibitor and PI3K inhibitor in this disease setting. There was a 1:1 randomization; we entered 310 patients and the patients were stratified according to their risk factors, like the presence of 17p deletion, ECOG status, and 1, 2, 3 versus >4 prior therapies.

We had one-to-one randomization for acalabrutinib versus physician’s choice of therapy, and the primary endpoint was progression-free survival. We also assessed overall response rate, overall survival and safety. The demographics of the patients reflected the treated population. The risk factors were evenly distributed between the cohorts.

At 4 years of follow up the median time of the study with acalabrutinib was similar to idelalisib plus rituximab and bendamustine plus rituximab. However, the duration of treatment exposure was considerably longer with acalabrutinib and we had to have this in consideration once we are discussing the adverse events.

Treatment discontinuation for any reason was considerably higher with idelalisib plus rituximab arm, which was supported at 85% of patients compared with 43% in acalabrutinib and 19% in bendamustine plus rituximab patients. The most common reason for treatment discontinuation were adverse events, which were the highest in the idelalisib plus rituximab arm.

Once we looked at the primary target was in progression-free survival, we could demonstrate a very clearly significant difference favoring acalabrutinib, and that was 62% median at 4 years for acalabrutinib versus less than 20% for physician’s choice. And once we truncated it, it was 25% for idelalisib plus rituximab versus 9% plus bendamustine plus rituximab .

Therefore, although idelalisib plus rituximab was still better than traditional chemo-immunotherapy, acalabrutinib monotherapy was way better. As for the high-risk group analysis, we analyzed  17p-deleted patients or those with unmutated IgVH status, and again, the difference was quite clear. In a subgroup analysis, we could demonstrate that investigator-assessed progression-free survival was better for pre-specified subgroups for idelalisib regardless of cytogenetic risk factors, ECOG status,  age, or complex karyotype. It’s of notice that we could demonstrate the overall survival difference, which was not planned because this study was not designed to detect this difference, and moreover, nearly half of the patients who progressed were actually crossed over from physician’s choice to acalabrutinib. Therefore, the analysis of overall survival had to be somehow distorted.

The response rates were similar and we had 83% and 85% of overall response rate. Complete regression rates were rare, although we couldn’t find any particular differences in disrespect. The incidence of treatment-related adverse events of grade 3 or higher, serious adverse events, treatment-related adverse events, and adverse events leading to therapy discontinuation was highest in idelalisib plus rituximab arm.

What were the safety results?

It is of notice that if we look at this idelalisib plus rituximab, we had 92% of patients experiencing grade 3 or greater adverse events compared with 62% for acalabrutinib and 49% for bendamustine + rituximab. Serious adverse events were reported in over 5% of the patients, in any patient’s subgroup, and these events included pneumonia, diarrhea, and pyrexia. And again, in idelalisib + rituximab, specifically for diarrhea, we had a great difference.

Unfortunately, we could observe more grade 4 adverse events in patients treated with idelalisib. Adverse events rates were similar and reported in previous analysis, including analysis after 3 years and earlier. In the acalabrutinib arm, the most common adverse events of any grade was transient headache, in addition to neutropenia, diarrhea, and upper respiratory tract infections which were mostly reported at grade 1 or 2.

Most common adverse events of any grade were reported, as I mentioned, in the idelalisib plus rituximab arm; those were diarrhea, neutropenia pyrexia, and upper respiratory tract infections. In the bendamustine plus rituximab arm, most common adverse events were neutropenia, fatigue, and infusion-related reaction.

Were there differences in treatment exposure that may account for the safety differences?

I’ve mentioned previously, treatment exposure was considerably longer with acalabrutinib compared to investigator’s choice, which must be considered when interpreting safety results. Among the events of clinical interest for acalabrutinib, hemorrhage events of any grade were more common in the acalabrutinib arm than in competitor arms. However, the incidents of major hemorrhage events were similar. To conclude, after 3 years of follow-up, acalabrutinib maintained a favorable efficacy and safety profile over the standard-of-care regimens reported in relapse and refractory chronic lymphocytic leukemia. Progression-free survival was significantly prolonged with acalabrutinib versus idelalisib plus rituximab and bendamustine plus rituximab, regardless of high-risk genomic characteristics. Median overall survival was not reached in either arm. Fewer patients treated with acalabrutinib than idelalisib plus rituximab discontinued therapy due to adverse events, despite their longer exposure in the acalabrutinib arm. There were no new safety findings seen in the acalabrutinib arm with a longer follow-up.

The take-home message?

Overall, data from ASCEND study support the use of acalabrutinib in patients in relapsing, refractory chronic lymphocytic leukemia, including those with high-risk genomic features.