Acalabrutinib improves PFS in treatment-naive CLL patients in ELEVATE TN trial
Acalabrutinib is a highly selective, covalent, irreversible Bruton’s tyrosine kinase (BTK) inhibitor with minimal activity against off-target kinases. [J Pharmacol Exp Ther 2017;363:240-252] ELEVATE TN is the first randomized phase III trial to evaluate single-agent acalabrutinib and acalabrutinib plus obinutuzumab (A+O) vs obinutuzumab plus chlorambucil (O+Clb) in previously untreated CLL patients. [Sharman JP, et al, ASH 2019, abstract 31]
“On the basis of the CLL-11 trial, O+Clb was considered the standard-of-care frontline chemoimmunotherapy for CLL and served as the control arm in several recent phase III CLL trials,” said Sharman. [Goede V, et al, EHA 2018, abstract S151; Lancet 2019;20:43-45; N Engl J Med 2019;380:2225-2236] “Acalabrutinib’s previously established favourable safety profile has prompted its evaluation as frontline therapy with or without obinutuzumab in the ELEVATE TN trial.”
ELEVATE TN: Acalabrutinib regimens vs chemoimmunotherapy
In the ELEVATE TN trial, treatment-naïve CLL patients (age, ≥65 years, or <65 years with comorbidities; median age, 70 years) were randomized (1:1:1) to receive A+O (acalabrutinib 100 mg BID orally continuously plus obinutuzumab 1,000 mg intravenously on days 1, 2, 8 and 15 of cycle 2, and on day 1 of subsequent 28-day cycles for a total of 6 cycles; n=179), acalabrutinib monotherapy (n=179), or O+Clb (Clb at 0.5 mg/day on days 1 and 15 of each 28–day cycle for 6 cycles; n=177). [Sharman JP, et al, ASH 2019, abstract 31]
At baseline, 69 percent and 12 percent of patients had high-risk disease and very-high-risk disease, respectively, based on the CLL International Prognostic Index score. “High-risk features were evenly distributed across the treatment arms,” said Sharman.
Acalabrutinib regimens improve PFS
The trial achieved its primary endpoint, showing a significant improvement in independent review committee (IRC)-assessed PFS with A+O vs O+Clb. “Over a median follow-up of 28 months, median IRC-assessed PFS was not reached in the A+O arm vs 22.6 months in the O+Clb arm, with a hazard ratio [HR] of 0.10 [95 percent confidence interval (CI), 0.06 to 0.18; p<0.0001], translating into a 90 percent reduction in risk of disease progression or death with A+O vs O+Clb,” reported Sharman. (Figure 1) [Sharman JP, et al, ASH 2019, abstract 31]
PFS was also significantly improved with acalabrutinib monotherapy. “Among patients treated with acalabrutinib monotherapy, median IRC-assessed PFS was not yet reached, and the risk of disease progression or death was reduced by 80 percent vs those treated with O+Clb [HR, 0.20; 95 percent CI, 0.13 to 0.31; p<0.0001],” he continued. (Figure 1)
Estimated PFS rates at 30 months were 90 percent with A+O, 82 percent with acalabrutinib monotherapy, and 34 percent with O+Clb.
“The IRC-assessed PFS benefit consistently favoured A+O or acalabrutinib monotherapy, independent of patients’ age, sex, Rai stage, or Eastern Cooperative Oncology Group [ECOG] status,” said Sharman.
PFS improvement with A+O or single-agent acalabrutinib vs O+Clb was consistent in the del(17p) subgroup (A+O: HR, 0.13; 95 percent CI, 0.04 to 0.46) (acalabrutinib monotherapy: HR, 0.20; 95 percent CI, 0.06 to 0.64). “In contrast to previously reported studies, A+O was found to yield an overall PFS benefit vs O+Clb in both unmutated and mutated IGHD subgroups,” Sharman noted.
OS trend favours acalabrutinib
While median overall survival (OS) was not yet reached in any treatment arm, a positive trend in favour of A+O (HR, 0.47; 95 percent CI, 0.21 to 1.06; p=0.0577) and acalabrutinib monotherapy (HR, 0.60; 95 percent CI, 0.28 to 1.27; p=0.1556) was shown, despite crossover of 25 percent of patients in the O+Clb arm to the acalabrutinib monotherapy arm upon IRC-confirmed disease progression. Estimated 30-month OS rates were 95 percent, 94 percent and 90 percent with A+O, acalabrutinib monotherapy and O+Clb, respectively. [Sharman JP, et al, ASH 2019, abstract 31]
Higher ORR with acalabrutinib
The IRC-assessed overall response rate (ORR) was significantly higher with A+O vs O+Clb (94 percent vs 79 percent; p<0.0001); the ORR with acalabrutinib monotherapy was 85 percent. (Figure 2) [Sharman JP, et al, ASH 2019, abstract 31]
“Both complete response and partial response [PR] were demonstrated in the A+O arm [rate, 13 percent and 81 percent, respectively], whereas in the acalabrutinib monotherapy and O+Clb arms, responses were mostly PRs,” said Sharman. (Figure 2)
Favourable safety and tolerability
In the ELEVATE TN trial, headache and diarrhoea were the commonly reported adverse events (AEs) associated with acalabrutinib. Grade ≥3 headache was reported in 1.1 percent of patients in the A+O arm, 1.1 percent of those in the acalabrutinib monotherapy arm, and 0 percent of those in the O+Clb arm, while grade ≥3 diarrhoea occurred in 4.5 percent, 0.6 percent and 1.8 percent of the patients, respectively. [Sharman JP, et al, ASH 2019, abstract 31]
“The safety profile of acalabrutinib, including the profile of AEs of clinical interest, was consistent with previous reports,” said Sharman. (Table)
Grade ≥3 serious AEs were reported in 33 percent of patients in the A+O arm, 30 percent of patients in the acalabrutinib monotherapy arm, and 20 percent of patients in the O+Clb arm. AEs led to treatment discontinuation in 11 percent, 9 percent and 14 percent of the patients, respectively, while acalabrutinib dose reduction was required in 7 percent of patients in the A+O arm and 4 percent of those in the monotherapy arm. [Sharman JP, et al, ASH 2019, abstract 31; Calquence (acalabrutinib) US prescribing information]
“With more than 2 years of follow-up, 79.3 percent of patients in the A+O and acalabrutinib monotherapy arms remained on single-agent acalabrutinib treatment,” reported Sharman.
Acalabrutinib approved by US FDA for CLL and SLL treatment
Findings from the ELEVATE TN trial, together with positive results of the phase III ASCEND trial showing PFS benefit and tolerability of acalabrutinib monotherapy in patients with relapsed/refractory (R/R) CLL, led to the US FDA’s approval of acalabrutinib for treatment of CLL or small lymphocytic lymphoma (SLL). The approval, issued in November 2019, was one of the first granted under Project Orbis, an initiative of the US FDA Oncology Center of Excellence that provides a framework for concurrent submission and review of oncology drugs among international partners. [Ghia P, et al, EHA 2019, abstract LB2606; https://www.fda.gov/drugs/resources-information-approved-drugs/project-orbis-fda-approves-acalabrutinib-cll-and-sll; https://www.fda.gov/news-events/press-announcements/fda-takes-first-action-under-new-international-collaboration-australia-and-canada-designed-provide]
As of November 2019, 1,029 patients with haematologic malignancies had been treated with acalabrutinib (100 mg given approximately 12-hourly) in clinical trials, with 88 percent of the patients being exposed to acalabrutinib for ≥6 months and 79 percent being exposed for ≥1 year. Among these acalabrutinib-treated patients, 19 percent experienced serious or grade ≥3 infections, while 1.1 percent had grade ≥3 atrial fibrillation or flutter. Rates of major haemorrhage (ie, serious or grade ≥3 or any central nervous system bleeding) and fatal haemorrhage were low, at 3 percent and 0.1 percent, respectively. [Calquence (acalabrutinib) US prescribing information]