Acalabrutinib ups PFS in treatment-naïve CLL patients

Acalabrutinib, when combined with obinutuzumab or used as monotherapy, significantly improves progression-free survival (PFS) by 80–90 percent vs chemoimmunotherapy in patients with previously-untreated chronic lymphocytic leukaemia (CLL), results of the phase III ELEVATE TN trial have shown.

The trial, reported at the American Society of Hematology 61^st Annual Meeting (ASH 2019), achieved its primary endpoint, showing a significant improvement in independent review committee (IRC)-assessed PFS with acalabrutinib plus obinutuzumab (A+O) vs obinutuzumab plus chlorambucil (O+Clb). [Sharman JP, et al, ASH 2019, abstract 31]

“At 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 investigator Dr Jeff P. Sharman of the Willamette Valley Cancer Institute and Research Center in Eugene, Oregon, US.

“Acalabrutinib monotherapy also significantly improved PFS vs O+Clb. 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.

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 ECOG status,” said Sharman. “The PFS benefit was also consistent in patients with del(17p) [HR, 0.13 (95 percent CI, 0.04 to 0.46) and 0.20 (95 percent CI, 0.06 to 0.64), respectively].”

“In contrast to several recent studies, A+O was found to yield overall PFS benefit vs O+Clb in both unmutated and mutated IGHD subgroups,” he added.

While median overall survival (OS) was not yet reached in any treatment arm, a trend towards improvement was seen with A+O (HR, 0.47; 95 percent CI, 0.21 to 1.06; p=0.0577) and with acalabrutinib monotherapy (HR, 0.60; 95 percent CI, 0.28 to 1.27; p=0.1556), 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 with A+O, 94 percent with acalabrutinib monotherapy, and 90 percent with O+Clb, respectively.

In terms of treatment response, IRC-assessed overall response rate (ORR) was 93.9 percent with A+O vs 78.5 percent with O+Clb (p<0.0001), and was 85 percent with acalabrutinib monotherapy.

“In the A+O arm, 13 percent of the responders had complete response [CR] and 81 percent had partial response [PR]. In the O+Clb arm, 74 percent of responses were PRs, and only 5 percent were CRs,” said Sharman. “Similarly, almost all responses in the acalabrutinib monotherapy arm were PRs [85 percent].”

In the ELEVATE TN trial, 535 treatment-naïve CLL patients (age ≥65 years, or <65 years with coexisting conditions) were randomized to receive A+O (n=179), acalabrutinib monotherapy (n=179), or O+Clb (n=177). At baseline, the patients’ median age was 70–71 years, most patients had ECOG status 0/1, and the proportion of patients with stage III or IV disease was similar across all treatment arms. Sixty-nine percent of patients had high-risk disease and 12 percent had very-high-risk disease, as measured by the CLL International Prognostic Index score, with high-risk features evenly distributed across the treatment arms.

“At the time of interim analysis, treatment was ongoing in 79.3 percent of patients in both the A+O and acalabrutinib monotherapy arms,” said Sharman. 

Acalabrutinib, given orally at 100 mg BID until disease progression or unacceptable toxicity in the trial, was most commonly associated with headache and diarrhoea as adverse events (AEs). Headache of any grade and grade ≥3 was reported in 40 percent and 1 percent of patients in the A+O arm, as well as 37 percent and 1 percent of those in the acalabrutinib monotherapy arm, compared with 12 percent and 0 percent of those in the O+Clb arm. Diarrhoea of any grade and grade ≥3 occurred in 38.3 percent and 4.5 percent of patients in the A+O arm, 34.6 percent and 0.6 percent of those in the acalabrutinib monotherapy arm, compared with 21.3 percent and 1.8 percent in the O+Clb arm.

Atrial fibrillation of any grade and grade ≥3 was reported in 3.4 percent and 0.6 percent of patients treated with A+O, 3.9 percent and 0 percent of those treated with acalabrutinib monotherapy, and 0.6 percent and 0 percent of those on O+Clb.

Overall, 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. Treatment discontinuation due to AEs was required in 11 percent, 9 percent and 14 percent of the patients, respectively.

“The safety profile of acalabrutinib in the trial was consistent with previous reports, with no new or unexpected safety signals identified,” said Sharman. “With its demonstrated efficacy and consistent safety profile, acalabrutinib is now an approved treatment for patients with CLL.”