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Jennifer R. Brown, MD, PhD


AACR 2022: ATR Inhibitor Alone or With BTK Inhibitor in High-Risk Resistant CLL

By: Joseph Fanelli
Posted: Wednesday, April 27, 2022

According to early-phase findings presented at the American Association for Cancer Research (AACR) Annual Meeting 2022 (Abstract CT532), monotherapy with ceralasertib, a selective oral ATR inhibitor, may have limited clinical benefit as a treatment for patients already exposed to a Bruton’s tyrosine kinase (BTK) inhibitor who have high-risk chronic lymphocytic leukemia (CLL). However, treatment with ceralasertib plus acalabrutinib—a selective, irreversible BTK inhibitor—demonstrated preliminary clinical activity in patients with CLL and del(11q), concluded Wojciech Jurczak, MD, PhD, of the Maria Skłodowska-Curie Institute of Oncology, Kraków, Poland, and colleagues.

“[Pharmacokinetics] of acalabrutinib and ceralasertib were consistent with historical data, with no drug-drug interactions when combined,” the authors said. “Ceralasertib did not affect BTK occupancy.”

In this phase I/II proof-of-concept study, the authors enrolled 11 patients with high-risk relapsed or refractory CLL to receive treatment with ceralasertib alone (eight patients) or ceralasertib plus acalabrutinib (three patients). Those who received ceralasertib alone had TP53 mutations, P53 mutation, del(17p), or del(11q) and were considered to have exhausted all other available treatment options. The patients who received ceralasertib plus acalabrutinib had del(11q) and were considered suitable for treatment with a BTK inhibitor.

After a median follow-up of 15.1 months for those patients treated with ceralasertib, four patients reported dose-limiting toxicities of grade 4 thrombocytopenia, and the authors observed no responses to treatment. The median progression-free survival was 3.8 months, with a median survival of 16.9 months. All the patients had baseline telomeres within a “fusogenic range,” the authors said.

For those patients who received ceralasertib plus acalabrutinib, there were no grade 3 or higher adverse events or dose-limiting toxicities. The overall response rate was 100%, with a median duration of response that was not reached. The median progression-free survival and overall survival were also not reached.

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