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Crizotinib Effective for Range of ALK-Driven Pediatric Tumors

Laino, Charlene

doi: 10.1097/01.COT.0000415889.85877.69


The targeted oral drug crizotinib has a high degree of anti-tumor activity in pediatric patients with refractory cancers driven by anaplastic lymphoma kinase (ALK), suggests a Phase I Children's Oncology Group study reported at the ASCO Annual Meeting (Abstract 9500).

The findings were highlighted at a media teleconference held in advance of the meeting, where the results were presented at an oral session by Yael P. Mosse, MD, Assistant Professor of Pediatrics at Children's Hospital of Philadelphia and the University of Pennsylvania.

Seven of eight children with ALK-driven anaplastic large cell lymphoma (ALCL) treated with crizotinib had a complete response, she said, and complete responses were also observed in two of eight children treated with crizotinib with refractory neuroblastoma and known ALK mutations.



Of 19 children with neuroblastoma whose ALK status was unknown, one had a complete response and six had stable disease.

Additionally, there were early signs the drug may benefit pediatric patients with inflammatory myofibroblastic tumors and germline mutations in ALK. Five of seven children with these tumors were too early to evaluate, but one child had a partial response and remained on the drug for 10 cycles. The other child had what Mosse termed a “minor response”—“The tumor cells did not meet criteria of an objective response, but the disease was less active. And a recommended amputation of the shoulder was no longer necessary. The primary aim of the study was safety, but the trial was designed so we could also see who was likely to benefit.”

The duration of the responses has been as long as 29 cycles of treatment—each cycle is 28 days.

Mosse received the inaugural James B. Nachman ASCO Junior Faculty Award in Pediatric Oncology, which was presented to her at the meeting.

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Approved for ALK-Driven Adult NSCLC

Crizotinib, a small molecule inhibitor of ALK and c-Met, is approved for adults with locally advanced or metastatic non-small cell lung cancers (NSCLC) harboring an ALK translocation.

Genetic aberrations in the ALK gene are also found in ALCL, neuroblastoma, and other pediatric tumors, which led to the design of the current trial, Mosse explained.

In the study, children with relapsed or refractory cancer received one of six doses of crizotinib orally twice daily for 28 days, with doses ranging from 100 mg/m2/d to 385 mg/m2/d, based on ALK status.

A total of 62 patients were evaluable for safety. “Overall the drug was well tolerated,” even though the 280 mg/m2/d dose recommended for future trials was about twice that of the recommended dose for adult disease, she said, adding that most adverse effects were transient and often resolved without drug interruption or dose reduction.

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Michael Link: ‘Glimpse of New Paradigm’

Commenting on the findings, ASCO 2011–2012 President Michael P. Link, the Lydia J. Lee Professor in Pediatric Cancer at Stanford University School of Medicine and staff physician at the Lucile Packard Children's Hospital there, said the study represents “a glimpse at the new paradigm for the understanding of cancer and for drug development—It is not sufficient to define tumors based on histology or the organ of origin. We now need to understand the particular molecular driver of the tumor and select the appropriate therapy for the appropriate patient.”

Drugs should no longer be thought of in terms of the tumor they treated, but in terms of the molecular pathways they target, he said. “If you understand the molecular driver of the tumor and take an appropriate inhibitor—in this case crizotinib—you can get dramatic responses.”

Mosse said that due to the excellent clinical benefit to refractory and relapsed ALCL patients, investigators are now proceeding directly to a Phase III study, which will also be conducted by the Children's Oncology Group.

A clinical trial for children with neuroblastoma, based on ALK status, is also in development.

If the early-phase findings are borne out in larger trials, crizotinib could become the second effective molecularly targeted therapy, Link said.

The study was funded by the National Cancer Institute and by Pfizer, Inc.

Copyright © 2012 Wolters Kluwer Health, Inc. All rights reserved.
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