Acalabrutinib monotherapy promising for relapsed, refractory mantle cell lymphoma
medwireNews: Treatment with the second-generation Bruton tyrosine kinase (BTK) inhibitor acalabrutinib induces durable responses in patients with relapsed or refractory mantle cell lymphoma, indicates the phase II ACE-LY-004 trial.
Acalabrutinib was also well tolerated and demonstrated a toxicity profile that was different from that of the first-generation agent ibrutinib, which the researchers attribute to the highly selective action of acalabrutinib, thereby minimizing off-target effects.
Over a median 15.2 months of follow-up, oral acalabrutinib 100 mg twice daily elicited an overall response as per the Lugano criteria in 81% of 124 patients who had relapsed or been unresponsive to previous therapies. Of these, 41% were partial responses and 40% were complete responses.
The median duration of response, progression-free survival (PFS), and overall survival (OS) was not reached, and it was estimated that 72% of patients would have a response lasting a year. The estimated 12-month PFS and OS rates were 67% and 87%, respectively, according to the report published in The Lancet and simultaneously presented at the 2017 American Society of Hematology Annual Meeting in Atlanta, Georgia, USA.
Writing in an accompanying commentary, Prashant Kapoor and Stephen Ansell – both from Mayo Clinic in Rochester, Minnesota, USA – say that the response rates “compare favourably with those observed with the other approved monotherapies,” but they note that “cross-trial comparisons and excessive reliance on single-arm studies are fraught with caveats that cannot be overemphasised.”
The commentators also point out that “[a]lthough acalabrutinib-induced responses seem durable, the follow-up was short.”
With regard to the toxicity, the study authors comment that the observed side effects were “mostly grade 1 or 2,” while adverse events of grade 3–5 were “infrequent” and mainly comprised neutropenia (10%), anemia (9%), and pneumonia (5%).
They note that previous studies on ibrutinib have reported “grade 3 or worse atrial fibrillation (6–9% of patients), infection (14–29%), and bleeding (up to 6%),” but in the current study, there were no cases of atrial fibrillation and the incidence of grade 3 or more severe infections (13%) and hemorrhage (one patient) was low.
“An alternative BTK inhibitor with greater target selectivity and potency, compelling efficacy, and a differentiated safety profile provides an attractive new therapeutic option” for this patient population, say researcher Michael Wang (The University of Texas MD Anderson Cancer Center, Houston, USA) and team.
“As such, these data have the potential to change the current practice for relapsed or refractory mantle cell lymphoma.”
Kapoor and Ansell insert a note of caution, however, highlighting that “[t]here is insufficient information in the study to truly understand acalabrutinib’s toxicity profile, which is likely to become more discernible with time.”
And they conclude: “The single-agent activity of acalabrutinib […] is very encouraging, but for a malignancy with a median overall survival measured in years, managed with prohibitively expensive therapies, the time is ripe to focus on appropriate sequential strategies (approach A followed, at relapse, by B and C vs B followed by C and A) rather than regimens in isolation.
“To rest on our laurels is not an option.”
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