Crizotinib shows promise in pediatric ALCL and IMT
medwireNews: Pediatric patients with anaplastic large cell lymphomas (ALCL) and inflammatory myofibroblastic tumors (IMTs) respond well to crizotinib therapy, with more than 80% experiencing an objective response, US researchers report.
Yael Mossé (University of Pennsylvania, Philadelphia) and colleagues explain that “[i]ncreased attention is being placed on the development of targeted agents for patients with cancers that share a molecular etiology to expedite clinical testing of potentially active drugs for rare indications.”
In the current study, Mossé and team evaluated the activity of the anaplastic lymphoma kinase (ALK) inhibitor crizotinib in 26 patients with relapsed/refractory ALK-positive ALCL and 14 patients with metastatic or inoperable ALK-positive IMT. They note that fusions involving the ALK gene are the predominant genetic lesion underlying both of these conditions.
The patients with ALCL received oral crizotinib twice daily at doses of 165 mg/m2 (ALCL165 group; n=6) or the recommended phase II dose of 280 mg/m2 (ALCL280 group; n=20), while those with IMT received the drug at a dose of 100, 165, or 280 mg/m2.
Among the patients with ALCL, the objective response rates were 83% and 90% in the ALCL165 and ALCL280 groups, respectively. The corresponding complete response rates were 83% and 80%, and the partial response rates were 0% and 10%, with median treatment durations of 2.8 and 0.4 years for ALCL165 and ALCL280, respectively.
“The rate, type, and duration of response vastly exceeded those typically observed in any early-phase clinical trial for children with relapsed/refractory cancer, possibly owing to the less complex genomic landscape of ALCL and the addiction to a single driver oncogene,” Mossé and co-authors write in the Journal of Clinical Oncology.
They add that the response did not appear to be dose dependent and say that the findings have provided the rationale for a pilot phase II study combining crizotinib at 165 mg/m2 with conventional chemotherapy in newly diagnosed patients with ALCL.
For the patients with IMT, the objective, complete, and partial response rates were 86%, 36%, and 50%, respectively, and the median treatment duration was 1.6 years.
The researchers say this shows that “ALK inhibition was a highly effective therapy [in patients with ALK-positive unresectable IMTs] and supports consideration of frontline therapy with crizotinib, a strategy that could be also be relevant to adults with this rare disease.”
Of note, grade 3 or 4 adverse events were common, occurring in 83% of patients in the ALCL165 group, 100% of those in the ALCL280 group, and in 71% of patients with IMT. The most common drug-related adverse event of grade 3 or 4 was decreased neutrophil count, reported in 33%, 70%, and 43% of patients, respectively.
Mossé et al conclude: “The robust and sustained clinical responses to crizotinib in patients with relapsed or refractory ALK-driven ALCL and IMT highlight the importance of this oncogene and the sensitivity to ALK inhibition in these diseases.”
They add that their findings set “a precedent in pediatric oncology for studying the early-phase activity of a targeted agent in a biomarker-selected and histology-independent cohort of patients.”
By Laura Cowen
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