AMSTERDAM – For patients with relapsed or refractory chronic lymphocytic leukemia (CLL), monotherapy with the Bruton tyrosine kinase (BTK) inhibitor acalabrutinib (Calquence) was associated with better progression-free survival and a more tolerable safety profile than rituximab combined with either idelalisib (Zydelig) or bendamustine, an interim analysis from the phase 3 ASCEND trial showed.
Among 310 patients with previously treated CLL followed for a median of 16.1 months, the primary endpoint of median progression-free survival (PFS), as assessed by independent reviewers, had not been reached for patients treated with acalabrutinib, compared with 16.5 months for patients treated with idelalisib and rituximab (IdR) or bendamustine and rituximab (BR), reported, from Università Vita-Salute San Raffaele in Milan.
“We show that acalabrutinib improved progression-free survival across all groups, including those with high-risk features,” he said at the annual congress of the European Hematology Association.
Acalabrutinib is approved in the United States for treatment of mantle cell lymphoma that has progressed on at least one prior therapy. It has been shown in preclinical studies to be more selective for BTK than the first-in-class agent ibrutinib (Imbruvica), with less off-target kinase inhibition, Dr. Ghia said.
was designed to see whether acalabrutinib monotherapy could offer superior PFS to IdR or BR in patients with CLL who had progressed or were refractory to at least one prior line of therapy.
Patients were randomly assigned, with 155 patients in each arm, to either acalabrutinib 100 mg orally twice daily or the investigator’s choice of either idelalisib 150 mg orally twice daily plus IV rituximab at an initial dose of 375 mg/m2, followed by up to seven doses at 500 mg/m2 delivered every 2 weeks for four infusions, then every 4 weeks for the remaining three infusions or IV bendamustine 70 mg/m2 on days 1 and 2 of each cycle, plus rituximab at the 375 mg/m2 dose on day 1 for the first cycle, followed by 500 mg/m2 for up to six total cycles.
Dr. Ghia presented results of an interim analysis planned for when two-thirds of the predicted PFS events (approximately 79) had occurred.
The baseline patient characteristics were generally similar, with a median age of 68 years in the acalabrutinib arm and 67 years in the comparison arm. Almost half of all patients in each arm had bulky disease, defined as 5 cm or greater. The majority of patients had two or more prior lines of therapy.
The primary endpoint of PFS as assessed by independent review favored acalabrutinib, with a hazard ratio of 0.31 (P less than .0001). Results were similar when acalabrutinib was compared with each of the regimens in the comparison arm (HR, 0.29 vs. IdR, 0.36 vs. BR; P less than .001 for each comparison).
Acalabrutinib was also superior in patients with high-risk cytogenetic features, compared with the other two regimens combined (HR, 0.27; P less than .001).
The benefit of the BTK inhibitor was consistent across all subgroups, including age, sex, performance status, Rai stage at screening, bulky/nonbulky disease, number of prior therapies, presence or absence of deletion 17p or TP53 mutation, mutated or unmutated immunoglobulin heavy chain, and complex/noncomplex karyotype.
Reviewer-assessed objective response rates were similar, occurring in 81% of patients on acalabrutinib and 76% of patients on other regimens.
There were no complete responses in the acalabrutinib arm, compared with two complete responses in the comparison arm. The majority of responses in each arm were partial responses (81% and 74%, respectively).
The median duration of response was not reached with acalabrutinib, compared with 13.6 months with the other therapies (HR, 0.33; P less than .0001).
In all, 85% of patients on acalabrutinib had a response lasting at least 12 months, compared with 60% of patients on the other regimens. There was no difference in overall survival at the 16.1-month median follow-up.
Adverse events of any grade occurred in 94% of patients on acalabrutinib, 99% on IdR, and 80% on BR; the respective incidences of serious adverse events were 29%, 56%, and 26%. Grade 3-4 adverse events occurred in 45%, 86%, and 43% of patients, respectively.
There were 13 treatment-related deaths. Six deaths in the acalabrutinib arm were caused by brain neoplasm, cachexia, cerebral ischemia, malignant lung tumor, neuroendocrine carcinoma, and sepsis. Five deaths among IdR-treated patients included chronic heart failure, cardiopulmonary disease, interstitial lung disease, MI, and pseudomonal pneumonia. Two deaths in BR-treated patients were attributed to acute cardiac failure and a gastric neoplasm.
The results show that “acalabrutinib has demonstrated efficacy in previously untreated and relapsed/refractory CLL and may be considered as an option in the future treatment paradigm,” Dr. Ghia said.
Acalabrutinib monotherapy is currently being compared with ibrutinib monotherapy in patients with relapsed/refractory CLL; in addition, the phase 3investigating acalabrutinib in combination with obinutuzumab (Gazyva) versus obinutuzumab plus chlorambucil has reached its primary PFS endpoint and will be reported soon, Dr. Ghia said.
The ASCEND trial is sponsored by Acerta Pharma; AstraZeneca holds majority shares in the company. Dr. Ghia reported consulting fees and honoraria from AstraZeneca and other companies, and research funding from several different companies.
SOURCE: Ghia P et al. EHA Congress, .