Acalabrutinib Approved for MCL

The FDA has granted accelerated approval to a second-generation inhibitor of Bruton tyrosine kinase (BTK), a component of the B-cell receptor signaling pathway, for the treatment of mantle cell lymphoma (MCL).

The novel agent, acalabrutinib (Calquence; AstraZeneca), is more selective than ibrutinib (Imbruvica; AbbVie/Johnson & Johnson), previously the only BTK inhibitor on the market. As a result, it could have a more favorable safety profile—and offer an alternative for patients who are intolerant to ibrutinib. “This represents a very good option for patients,” says Jeff Sharman, MD, of the Willamette Valley Cancer Institute in Springfield, OR.

Acalabrutinib's approval on October 31 was based on data from the single-arm ACE-LY-004 trial of 124 patients with previously treated MCL, a rare and fast-growing type of non-Hodgkin lymphoma. In that study, 40% of the participants experienced a complete response (CR) and another 41% had a partial response. After 1 year, 72% of responders were still in remission—and although “it looks promising early,” says Brad Kahl, MD, of Washington University School of Medicine in St. Louis, MO, who was not involved in ACE-LY-004, “we need more time to see how durable these responses truly are.”

In a comparable ibrutinib trial, the median duration of response was 17.5 months, and only 21% experienced a CR. However, the ibrutinib study population was more heavily pretreated, which could explain the poorer outcomes, notes Richard Furman, MD, of Weill Cornell Medicine in New York, NY, who has led trials of ibrutinib and acalabrutinib to treat chronic lymphocytic leukemia (CLL). In fact, he doesn't expect the efficacy of the two agents to differ much given their shared mechanism of action. “Both irreversibly bind to BTK at the same amino acid residue,” Furman says—namely, a cysteine residue at position 481 of BTK's active site.

That means acalabrutinib won't work in cases where patients have developed resistance to ibrutinib—but it could help those who don't tolerate the first-generation drug, because, unlike ibrutinib, acalabrutinib does not inhibit EGFR and it binds TEC much less potently. Patients therefore experience fewer episodes of diarrhea, rash, and bleeding.

Another difference: Acalabrutinib has a shorter half-life, which means the drug requires twice-daily dosing; ibrutinib is administered once a day. The more-frequent dosing could make acalabrutinib a better option for rapidly growing cancers, because that regimen might more effectively block newly synthesized BTK. However, it might limit medication adherence, which could impede the drug's efficacy. Ultimately, says Peter Martin, MD, of Weill Cornell Medicine, the question of which BTK inhibitor is preferable “will have to be answered by phase III trials.”

A large, international head-to-head study of the two agents is currently ongoing for patients with refractory CLL. Acalabrutinib is also being evaluated in a phase III trial as a potential add-on to standard first-line therapy (with bendamustine and rituximab) for MCL, as well as in dozens of studies for other types of B-cell malignancies, solid tumors, and autoimmune conditions.

Other second-generation BTK inhibitors in clinical testing for B-cell malignancies include BGB-3111 (BeiGene), GS-4059 (Gilead Sciences), and M7583 (Merck KGaA). Additionally, there are several reversible inhibitors in or nearing human trials that can block BTK with a cysteine-to-serine substitution at position 481, a mutation responsible for the bulk of reported cases of ibrutinib resistance. These include ARQ-531 (ArQule), SNS-062 (Sunesis Pharmaceuticals), and LOXO-305 (Loxo Oncology)—and with around 10% of patients on ibrutinib currently developing resistance, says Furman, “there will be a need for those as well.” –Elie Dolgin