The recently approved cancer drug crizotinib draws strong responses in children whose cancers have mutations in the gene targeted by the drug, according to early data from a phase I dose-escalating study.
The most dramatic improvements occurred in anaplastic large-cell lymphoma, with complete and durable responses observed in 7 of 8 children with the ALK mutation, which is common in the disease. Crizotinib (Xalkori) also appeared to be active in subsets of children with inflammatory myofibroblastic tumor and neuroblastoma, though the early data were less clear in these cancers.
Dr. Yael P. Mosse
"Crizotinib appears to have a high degree of activity in children with anaplastic large-cell lymphoma – the majority of whom are driven by the ALK oncogene," lead author Dr. Yael P. Mosse said during a press briefing in advance of the annual meeting of the American Society of Clinical Oncology. She noted that these are phase I results and should be taken with caution.
"Certainly for the eight patients that we enrolled with anaplastic large cell lymphoma – seven of whom have had a complete response and a durable response – I think that this is dramatic activity and has already met the bar for what you would look for in a phase-II trial ... for neuroblastoma there is still a lot of work to be done," said Dr. Mosse of Children’s Hospital of Philadelphia and the University of Pennsylvania.
"The story is really a glimpse at the new paradigm for understanding of cancer and drug development," said ASCO President Dr. Michael Link, comoderator of the press briefing.
"It’s no longer adequate to identify a tumor based on histology organ of origin. It’s now understood that tumors are heterogeneous and it’s key to understand the particular molecular driver," said Dr. Link of Stanford (Calif.) University.
"If you understand the molecular driver of the tumor and pick an appropriate inhibitor – in this case crizotinib for ALK-driven tumors – we have the prospect of seeing dramatic responses."
The ALK (anaplastic lymphoma receptor tyrosine kinase) gene is part of a family of proteins called receptor tyrosine kinases, which transmit signals from the cell surface into the cell via signal transduction. Though the specific function of ALK is unknown, it is thought to act early in development to help regulate the proliferation of nerve cells.
ALK is involved in the formation of several human cancers, including anaplastic large cell lymphoma (ALCL), which typically occurs in childhood. Activating mutations in the ALK gene "are the leading cause for most cases of the hereditary form of neuroblastoma and ... these mutations are also somatically acquired in 14% of patients with the aggressive form of this disease," Dr. Mosse said.
Crizotinib, an oral small-molecule inhibitor of ALK, was approved in August 2011 for the treatment of patients with locally-advanced or metastatic non–small cell lung cancer (NSCLC) that is ALK positive based on a diagnostic test approved concurrently by the Food and Drug Administration.
Dr. Mosse and colleagues conducted the phase I study to assess the safety and efficacy of crizotinib in pediatric patients aged 1-21 years with relapsed or refractory cancer. The children received the drug orally, twice daily for 28-day cycles. Based on the results, the recommended phase II dose for children is 280 mg/m2 per day. This is roughly twice the recommended phase II dose for adults, according to Dr. Mosse.
Eight patients with anaplastic large-cell lymphoma were enrolled in the current study. All had an ALK translocation and were heavily pretreated. Seven children had a complete response with doses ranging from 165 mg/m2 per day to 280 mg/m2 per day. They remain on the drug, with no progression observed for as long as 18 months.
Investigators also enrolled seven patients with inflammatory myofibroblastic tumor – all had an ALK translocation. Of these, one had a minor response and remains on the drug after 2 years. One patient had a partial response and remains on the drug after 10 cycles. It is too early to determine response for five patients.
Lastly, the researchers enrolled 35 patients with neuroblastoma; 27 were evaluable. Eight of these patients had known ALK mutations. Two of these patients have germline mutations. One of these patients had a complete response to therapy and remains on treatment (more than 6 months). The second patient with a germline mutation had a minor response and continues treatment (more than 15 months). A third patient with a somatic ALK mutation has had stable disease for more than eight cycles.
There were 19 neuroblastoma patients who had unknown ALK status. One patient had a complete response and remains on treatment (more than 24 cycles). Six patients have had prolonged stable disease and remain on treatment (7-29 cycles).