Crizotinib Active in ALK-Positive Pediatric Cancer

Targeting the ALK gene with the oral agent crizotinib (Xalkori) slowed or eliminated signs of tumor growth in pediatric patients with aggressive forms of neuroblastoma, anaplastic large cell lymphoma (ALCL), and inflammatory myofibroblastic tumors (IMTs), according to the results of a phase I study. The research was presented at a press conference held in advance of ASCO 2012.

Crizotinib is a small-molecule inhibitor of ALK and c-Met, and is FDA approved for adults with locally advanced, non—small cell lung cancer that is ALK-positive. The 3 pediatric cancers examined in the trial are associated with mutations in the ALK gene, thus making them susceptible to ALK inhibition. ALCL, a type of non-Hodgkin lymphoma, harbors an ALK mutation in approximately 80% to 95% of tumors. Additionally, half of IMTs and 14% of neuroblastomas are known to contain ALK rearrangements.

A total of 70 children with refractory solid tumors and ALCL were enrolled in the dose escalation and pharmacokinetic trial, but only 42 were evaluable. Patients received one of 6 doses of crizotinib twice daily. Not all participants were required to harbor a known ALK mutation; as such, 19 patients in the neuroblastoma arm had an unknown ALK status.

The most impressive findings from the trial came in the ALCL arm. These 8 patients all had an ALK mutation and were heavily pretreated, with 88% (n = 7) experiencing a complete response to treatment. Patients remained on treatment for as long as 18 months.

“Our trial shows that crizotinib appears to have a high degree of activity in children with anaplastic large cell lymphoma, the majority of which are driven by the ALK oncogene,” said lead author, Yael Mossé, MD, from The Children’s Hospital of Philadelphia, Pennsylvania , who spoke at the ASCO press conference. “A larger anaplastic large cell lymphoma trial is currently in development to move this therapy upfront for newly diagnosed patients.”

Among the 7 patients with IMTs who were enrolled in the trial, most benefited, with results ranging from tumor shrinkage to complete tumor regression. Responses have lasted for up to 2 years, and all patients are still receiving therapy. No available anticancer agents have previously been found to be effective in this disease.

Two of the 27 patients with neuroblastoma had a complete response, and 8 had stable disease. Among neuroblastoma patients with an ALK abnormality, 2 of 8 experienced a complete response. Responders have remained on therapy for 9 months to more than 2 years without progression.

Patients with neuroblastoma treated with higher doses of crizotinib experienced demonstrable results. In some cases, these patients received 280 mg/m2 of crizotinib twice daily, or approximately twice the recommended adult dosage. The researchers speculated that some neuroblastoma patients with known ALK mutations did not respond to treatment because they received lower doses of the drug.

“This story is really a glimpse at the new paradigm for our understanding of cancer and for drug development,” said Michael Link, MD, outgoing ASCO president. “We now understand that it is not sufficient to identify a tumor based on the histology or the organ of origin, as we did traditionally. Tumors are heterogeneous, and we need to understand the particular molecular driver of the tumor to select appropriate therapy.”

The Children’s Oncology Group is developing a phase III trial to test crizotinib in ALK-positive children with ALCL. Additionally, separate phase II trials are planned to further investigate ALK inhibition in neuroblastoma and IMT.

Mosse YP, Balis FM, Lim MS, et al. Efficacy of crizotinib in children with relapsed/refractory ALK-driven tumors including anaplastic large cell lymphoma and neuroblastoma: a Children’s Oncology Group phase I consortium study.J Clin Oncol. 2012;30(suppl; abstr 9500).

Funding Source:None.

Author Disclosure:The authors reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Authorship Information:Concept and design; drafting of the manuscript; and critical revision of the manuscript for important intellectual content.

Crizotinib Active in ALK-Positive Pediatric Cancer