Roxanne Nelson

May 16, 2012

May 16, 2012 — Results from an early study show that crizotinib (Xalkori) could help children with aggressive forms of neuroblastoma, anaplastic large cell lymphoma (ALCL), or inflammatory myofibroblastic tumors, many of whom have genetic aberrations in the anaplastic lymphoma kinase (ALK) gene.

Crizotinib is available to treat ALK-positive nonsmall cell lung cancer (NSCLC); the US Food and Drug Administration granted accelerated approval for this indication in August 2011. Crizotinib is an orally available aminopyridine-based inhibitor of ALK and the c-Met/hepatocyte growth-factor receptor with demonstrated antineoplastic activity.

In this small phase 1 dose-escalation and pharmacokinetic trial, 7 of 8 patients with ALCL (88%) achieved a complete response and had no detectable disease. These responses have been long term; patients have remained on treatment with no progression for as long as 18 months.

In neuroblastoma patients, 2 of 27 patients achieved a complete response; in 7 patients, disease has been stable. Of the 7 patients in the study with inflammatory myofibroblastic tumors, 1 has achieved a partial response.

"Our trial shows that crizotinib appears to have a high degree of activity in children with anaplastic large cell lymphoma, the majority of which is driven by the ALK oncogene," said lead author Yael Mosse, MD, who presented the results during a press briefing held in advance of the annual meeting of the American Society of Clinical Oncology (ASCO). "A larger ALCL trial is currently in development to move this therapy up front for newly diagnosed patients."

"Early data suggest that crizotinib may have activity in select subsets of patients with inflammatory myofibroblastic tumors or neuroblastoma," explained Dr. Mosse, who is assistant professor of pediatrics at the Children's Hospital of Philadelphia and the University of Pennsylvania.

Clinical trials looking at the ALK status of children with neuroblastoma are currently in development, she added.

"This study is a glimpse at the new paradigm for our understanding of cancer and for drug development," said Michael Link, MD, who is president of ASCO. "We now understand that it's not sufficient to identify a tumor based on histology or organ of origin."

"Rather, we know now that tumors are heterogenous, and we need to understand the particular molecular driver of the tumor to select appropriate therapy," said Dr. Link, who was not involved in the study. "We see from this study that if we understand the molecular driver of a tumor and pick an appropriate inhibitor, we have the prospect of seeing dramatic responses."

Study Details

Dr. Mosse and colleagues enrolled 70 children with refractory solid tumors and ALCL. Crizotinib was administered twice daily without interruption in 28 day cycles, using a "rolling-6 design."

The cohort was divided into 3 groups. The authors evaluated 6 dose levels (100, 130, 165, 215, 280, 365 mg/m²) in 29 patients; patients with confirmed ALK fusion proteins, mutations, or amplification received 1 dose level lower than those in the first group. Patients with neuroblastoma were enrolled on a separate stratum.

"While the primary aim of this trial was safety, we also designed it to be able to distinguish which patients might benefit," said Dr. Mosse. Overall, "the trial has shown that this drug is exceedingly well tolerated, and the recommended phase 2 dose will be 280 mg/m², which is roughly twice the dose recommended for adults."

All 8 ALCL patients were heavily pretreated, and all currently remain on therapy — receiving a dose of 165 to 280 mg/m².

All 7 patients with inflammatory myofibroblastic tumors harbor an ALK mutation, explained Dr. Mosse. Of this group, 1 patient achieved a minor response and has been on therapy for more than 2 years. Another patient achieved a partial response, and has received 10 cycles of treatment to date. "The remaining 5 patients remain on the drug," she said; it is too early to report their responses.

Of the 35 patients with neuroblastoma, 27 are currently evaluable. Within this cohort, 8 patients have known ALK mutations. Of the 2 patients with germ-line mutations, 1 has achieved a complete response (on therapy for more than 6 months) and 1 has achieved a minor response (continues on therapy after more than 5 cycles). In addition, 1 patient with a known somatic mutation has had stable disease for more than 8 cycles.

In 19 patients, ALK status was unknown. Within this subgroup, 1 patient achieved a complete response (more than 24 cycles) and 6 patients have had prolonged stable disease (7 to 29 or more cycles).

A total of 57 patients were fully evaluable for toxic effects. In the first group, 2 patients developed dose-limiting toxicities (grade 3 dizziness and grade 5 intratumoral hemorrhage) at doses of 215 mg/m² and 1 patient developed grade 4 liver enzyme elevation at a dose of 365 mg/m².

Dose-limiting toxicities occurred in those with confirmed ALK fusion proteins, mutations, or amplification (1 patient; grade neutropenia) at 165 mg/m²; there were none in patients with neuroblastoma.

Previous Data Show Efficacy

Crizotinib has also shown efficacy in ALCL. As previously reported by Medscape Medical News, case studies presented at the 2010 annual meeting of the American Society of Hematology demonstrated "dramatic clinical activity" in a small group of patients who had developed resistance to cytotoxic therapy. At the time of the presentation, 3 of 4 patients were in complete remission after treatment with crizotinib.

At that time, lead author Carlo B. Gambacorti-Passerini, MD, professor of internal medicine at the University of Milan Bicocca and director of the Clinical Research Unit at S.  Gerardo Hospital, in Monza, Italy, cautioned that the number of patients is limited and the follow-up is very short. "All of them were terminal patients, so I cannot say anything about the duration of this response," Dr. Gambacorti-Passerini told Medscape Medical News. "But I can say that the clinical activity is definitely there."

Dr. Mosse reports receiving research funding from Pfizer.

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