Crizotinib Yields Benefits in Aggressive Pediatric Tumors

Complete responses were observed in most patients with anaplastic large cell lymphoma.

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The value of the targeted agent crizotinib (Xalkori) may not be restricted to the 5% of patients with non–small cell lung cancer who have abnormalities in the ALK gene. In a phase I study conducted by the ­Children’s Oncology Group consortium, crizotinib halted tumor growth and, in some cases, eradicated all signs of cancer in children with anaplastic large cell lymphoma (ALCL), inflammatory myofibroblastic tumors, and aggressive forms of neuroblastoma, investigators reported at the 2012 ASCO Annual Meeting.1

Abnormalities in the ALK gene are common in these pediatric cancers, being found in 80% to 95% of anaplastic large cell lymphomas, 50% of inflammatory myofibroblastic tumors, and up to 15% of aggressive neuroblastomas.

The study’s principal investigator, Yael Mosse, MD, of the Children’s Hospital of Philadelphia, noted, “It’s remarkable that this targeted oral medication provided such a substantial benefit in these children with highly aggressive cancers, most of whom had already undergone every available therapy. Now that we know much more about the drivers of some pediatric cancers, we can target those changes and treat patients in a much smarter and potentially safer way.”

Patient Outcomes

The phase I dose-escalation study included 70 children (median age 10 years) with refractory solid tumors and ALCL. Patients received one of six different doses of crizotinib (100–365 mg/m2 per dose twice daily) in 28‑day cycles as long as tolerated.

By disease, the outcomes were as follows:

  • Anaplastic large cell lymphoma: 8 patients were enrolled; 7 of 8 achieved complete responses.
  • Inflammatory myofibroblastic tumor: 7 patients were enrolled; 1 of 7 had a partial response, 1 had a minor response (tumor shrinkage falling short of an objective response), and 5 are at a point too early to evaluate.
  • Neuroblastoma: 35 patients were enrolled, 27 are evaluable; of 8 with known ALK mutations, 1 had a complete response, 1 had a minor response, and 1 had stable disease as the best response. Of 19 patients whose ALK status is unknown, 1 had a complete response and 6 had prolonged stable disease.

Dr. Mosse noted that many of the responses were highly durable, and some patients have been on treatment for 18 months to 2 years or longer without disease progression.

‘Dramatic Potential’

Nicholas J. Volgelzang, MD, Chair of ASCO’s Cancer Communications Committee and Chair of Genitourinary Oncology for US Oncology, said he witnessed a dramatic response to crizotinib in an adult with ALK-positive ALCL treated by his colleague Fadi Braiteh, MD, in a clinical trial.

“The patient was very, very ill. She achieved a complete response with crizotinib and was able to receive a transplant. So this drug does have dramatic potential in older patients as well and in patients with other tumors,” he commented.

Elaborating on the study’s outcomes, Dr. Mosse noted that having seven complete responses in anaplastic large cell lymphoma “already meets the bar for what we look for in phase II.” The consortium will soon be studying crizotinib in combination with chemotherapy in ALCL, hoping not only to improve outcomes but also to reduce the toxicity associated with standard therapy.

In neuroblastoma, the benefit of the drug is less clear, but there is proof-of-concept that some patients with these tumors can benefit, and a phase II trial will further distinguish which patients are likely to benefit from this drug.

The recommended phase II dose will be 280 mg/m2 per dose twice daily, and additional studies will look for markers of sensitivity and resistance to inform future study designs.

Further Implications

Crizotinib was very well tolerated, with virtually all adverse events being low-grade. At the highest dose level, one patient developed elevated liver enzymes and another had a low neutrophil count, but this was reversible.

Dr. Mosse said the findings have implications beyond these pediatric cancers. “With next-generation sequencing, we may discover that the ALK gene is relevant to multiple human cancers,” she suggested.  ■

Disclosure: Drs. Mosse and Vogelzang reported no potential conflicts of interest.


1. 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. 2012 ASCO Annual Meeting. Abstract 9500. Presented June 2, 2012.

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