Acalabrutinib appears effective, safe for advanced CLL
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Acalabrutinib appeared effective and safe compared with standard regimens for relapsed or refractory chronic lymphocytic leukemia, according to long-term study results presented at Society of Hematologic Oncology Annual Meeting.
Patients treated with acalabrutinib (Calquence, AstraZeneca) achieved longer PFS than those treated with standard regimens regardless of genetic characteristics, and fewer acalabrutinib-treated patients discontinued treatment due to adverse events.
“Overall, these data ... support use of acalabrutinib [for] patients with relapsed/refractory CLL, including patients with high-risk features,” Paolo Ghia, MD, PhD, associate professor in internal medicine at Universita Vita-Salute San Raffaele and deputy chairman of the division of experimental oncology at San Raffaele Scientific Institute in Italy, said during a presentation.
Combination therapies — such as the PI3 kinase inhibitor idelalisib (Zydelig, Gilead) plus the anti-CD20 antibody rituximab (Rituxan; Genentech, Biogen), or bendamustine plus rituximab — are standard for relapsed or refractory CLL. However, toxicities can limit the use of these regimens, according to study background.
Acalabrutinib — a next-generation, highly selective Bruton tyrosine kinase inhibitor — received FDA approval in 2019 for initial or subsequent treatment of patients with CLL or small lymphocytic lymphoma.
The randomized phase 3 ASCEND trial compared acalabrutinib monotherapy with physician’s choice of two standard regimens — rituximab plus idelalisib, or rituximab plus bendamustine — for patients with relapsed or refractory CLL.
The analysis included 310 patients (median age, 67 years), of whom 16% had 17p deletion, 27% had 11q deletion, and 42% had Rai stage III or stage IV disease.
Researchers assigned 155 patients to oral acalabrutinib dosed at 100 mg twice daily.
They assigned 119 patients to eight IV infusions of rituximab plus idelalisib dosed at 150 mg twice daily.
The other 36 patients received six cycles of IV rituximab plus bendamustine dosed at 70 mg/m2 via IV.
Treatments continued until disease progression or unacceptable toxicity. Patients assigned one of the standard regimens could cross over to acalabrutinib treatment upon confirmed disease progression.
The experimental and standard treatment groups were well-balanced with regard to age (median, 66 years vs. 67 years), sex (men, 69.7% vs. 64.5%), prevalence of bulky disease (49% vs. 48.4%), Rai stage, and number and type of prior therapies.
PFS served as the primary endpoint. Overall response rate, OS and safety served as key secondary endpoints.
Results of a preplanned interim analysis — based on median 16.1 months follow-up — showed acalabrutinib significantly prolonged PFS compared with the other regimens.
At SOHO, Ghia and colleagues reported final results based on median 22-month follow-up.
Results showed significantly longer median investigator-assessed PFS (not reached vs. 16.8 months; HR = 0.27; P < .0001) and a higher 18-month PFS rate (82% vs. 48%) in the acalabrutinib group.
Researchers observed the benefit in investigator-assessed PFS with acalabrutinib across all prespecified subgroups, as well as among patients with high-risk features, such as 17p deletion, TP53 mutations and unmutated IGHV.
Median OS had not been reached in either treatment group. The 18-month OS rates were equivalent for the acalabrutinib and standard treatment groups (88% each); however, crossover may have contributed to the lack of OS difference, Ghia said.
ORRs were 80% with acalabrutinib vs. 84% with the standard regimens; however, median duration of response (not reached vs. 18 months; HR = 0.19; 95% CI, 0.11-0.33) and estimated percentage of patients to remain in response for 18 months (85.4% vs. 49.4%) favored acalabrutinib.
Adverse event rates were as follows:
- All-grade — 96% with acalabrutinib, 99% with idelalisib-rituximab and 80% with bendamustine-rituximab;
- Grade 3 or higher— 55% with acalabrutinib, 90% with idelalisib-rituximab and 49% with bendamustine-rituximab;
- Grade 5 — 7% with acalabrutinib, 5% with idelalisib-rituximab and 6% with bendamustine-rituximab.
- Treatment-related — 70% with acalabrutinib, 95% with idelalisib-rituximab and 89% with bendamustine-rituximab; and
- Serious — 33% with acalabrutinib, 56% with idelalisib-rituximab and 26% with bendamustine-rituximab.
The most common adverse events reported among acalabrutinib-treated patients included headache (any grade, 22%; grade 3 or higher, 1%), neutropenia (any grade, 21%; grade 3 or higher, 17%), diarrhea (any grade, 20%; grade 3 or higher, 2%), upper respiratory tract infection 9any grade, 20%; grade 3 or higher, 2%), cough (any grade, 16%; grade 3 or higher, 0%) and anemia (any grade, 16%; grade 3 or higher, 12%).
Serious adverse events among acalabrutinib-treated patients included pneumonia (6%), diarrhea (1%) and pyrexia (1%).
Any-grade bleeding events were more common with acalabrutinib (29%) than the standard regimens (8%); however, incidence of major hemorrhage events was low and comparable between the acalabrutinib and standard treatment groups (3% each).
Twenty-four patients (16%) assigned acalabrutinib discontinued treatment due to adverse events, compared with 66 patients (56%) assigned idelalisib-rituximab and six (17%) assigned bendamustine-rituximab.
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Ghia P, et al. Abstract CLL-091. Presented at: Society of Hematologic Oncology Annual Meeting (virtual meeting); Sept. 9-12, 2020.
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