Acalabrutinib Shows Survival Improvement in CLL When Used Earlier

"In conclusion, improved OS, PFS, and TTNT were consistently observed when acalabrutinib was initiated in earlier vs later LOTs," according to Paolo Ghia, MD, PhD.

Patients with chronic lymphocytic leukemia (CLL) who received acalabrutinib (Calquence) in earlier lines of treatment (LOTs) experienced improved overall survival (OS), progression-free survival (PFS), and time to next treatment (TTNT) increased vs patients who received treatment in later lines, according to a pooled analysis presented at the 2024 European Hematology Association (EHA) Congress.

A pooled analysis of the phase 3 ELEVATE-TN (NCT02475681), ELEVATE-RR (NCT02477696), and ASCEND (NCT02970318) trials demonstrated this benefit in the overall patient population and for patients with deletion 17p (del[17p]) with less prior LOTs.

“In the overall population, those with no prior LOTs had improved outcomes vs those with 1 prior LOT,” Paolo Ghia, MD, PhD, said in his presentation of the pooled analysis at the EHA Hybrid Congress. “Those with 1 prior LOT also had consistently improved outcome vs those with 2 or more prior LOTs in the overall population, as well as those with the del(17p).”

The second-generation Bruton’s kinase inhibitor acalabrutinib previously showed acceptable efficacy and safety profiles vs ibrutinib (Imbruvica) in patients with relapsed/refractory CLL who had a median of 2 prior LOTs. In a pooled analysis for ibrutinib, patients had better OS and PFS after 0 prior LOTs compared with 3 or more prior lines. Investigators from this presentation evaluated the impact of the number of prior LOTs for acalabrutinib in treatment naïve or relapsed/refractory CLL, which was previously unknown.

Data from the acalabrutinib monotherapy arms of the phase 3 trials were also reviewed. ELEVATE-TN had a data cut-off of March 3, 2023, median follow-up of 74.5 months, and 179 patients who received 0 prior LOTs; ELEVATE-RR had a data cut-off of September 15, 2020, median follow-up of 40.9 months, 132 patients who received 1 prior LOT, and 135 patients with 2 or more prior LOTs; and the ASCEND trial had a data cut-off of September 3, 2021, median follow-up of 46.5 months, 82 patients who received 1 prior LOT, and 73 patients with 2 or more prior lines.

The outcomes for the analysis included OS, PFS, and TTNT, and HR and log-rank P values comparing 0 vs 1 prior LOT and 1 vs 2 or more prior LOTs. In total, 601 patients were treated with acalabrutinib monotherapy: 179 with 0 prior LOTs, 214 with 1 prior LOT, and 208 with 2 or more prior LOTs. The number of patients with high-risk features and Rai stage IV disease was higher in the 1 and 2 or more prior LOTs groups than the 0 prior LOTs group.

In the overall population, patients with 0 prior LOTs had a 45% lower risk of death than those with 1 prior LOT (P = .0185); 92% vs 85% of patients were alive at 36 months, respectively. There was 56% lower risk of disease progression or death (P < .0001) and 52% lower risk of initiating subsequent therapy (P = .0001) for patients with 0 prior LOTs vs 1 prior line. At 36 months, 84% of patients with 0 prior LOTs were progression free and had not initiated subsequent therapy vs 73% and 75% with 1 prior LOT, respectively.

There was a 46% lower risk of death in patients with 1 prior LOT than in those with 2 or more prior LOTs (P = .0016), and at 36 months, 85% of 1-LOT patients were alive vs 76% of 2 or more–LOTs patients. The risk of disease progression or death was 39% lower with 1 prior line compared 2 or more prior lines (P = .0012), and 73% of patients were progression free vs 58% at 36 months. In patients with 1 prior line, there was a 33% lower risk of initiating subsequent therapy (P = .0070), and 75% had not initiated subsequent therapy compared with 64% at 36 months.

Increased risk of death in the overall population was associated with prior LOTs, TP53 mutation, ECOG performance status of 2 or more, Rai stage III or more, 65 years of age or more, and being male.

Although an analysis of patients with del(17p) with 0 vs 1 prior LOT was not sufficiently powered because of a small sample size of patients with 0 prior LOTs, investigators reviewed the OS, PFS, and TTNT in patients with del(17p) who had 1 and 2 or more prior LOTs.

“Findings were consistent in patients with del(17p), where in patients with 1 prior LOT had a significantly lower risk of death (P = .0072), disease progression or death (P = .0004), and initiating subsequent therapy compared with those with 2 or more prior lines of therapy (P = .0091),” Ghia explained.

At 36 months, 81% vs 65% of patients were alive, 74% vs 45% of patients were progression free, and 72% vs 56% of patients had not initiated subsequent therapy of those who received 1 prior LOTs vs 2 or more, respectively.

Treatment discontinuation of acalabrutinib monotherapy was most commonly due to adverse events in 17.9%, 13.1%, and 22.6% in the 0, 1, and 2 or more prior LOTs groups, respectively, and disease progression was seen in 14.0%, 23.4%, and 31.7%, respectively.

“In conclusion, improved OS, PFS, and TTNT were consistently observed when acalabrutinib was initiated in earlier vs later LOTs,” Ghia said.

Reference

Ghia P, John E, Stewart KM, Scalera A, Byrd JC. Impact of acalabrutinib treatment by line of therapy in patients with chronic lymphocytic leukemia: pooled analysis from ELEVATE-TN, ELEVATE-RR, and ASCEND. Poster presented at: European Hematology Association 2024 Hybrid Congress; Madrid, Spain and virtual; June 13-16, 2024. Abstract P703.