In a phase I study the targeted drug crizotinib, a small molecule inhibitor of anaplastic lymphoma kinase and met proto oncogene, delayed or eliminated signs of tumor growth in pediatric patients with aggressive cancers.
CHICAGO-The targeted drug crizotinib (Xalkori), a small molecule inhibitor of anaplastic lymphoma kinase (ALK) and c-met proto-oncogene (MET), delayed or eliminated signs of tumor growth in pediatric patients with aggressive forms of neuroblastoma, anaplastic large cell lymphoma (ALCL), and inflammatory myofibroblastic tumors (IMTs), in a phase I study conducted by the Children’s Oncology Group. Findings were reported by lead author Yael Mosse, MD, of the Children’s Hospital of Philadelphia.
Human anaplastic lymphoma kinase in complex with crizotinib; source: A2-33, Wikimedia Commons
The three pediatric cancers examined in the trial are associated with mutations in the ALK gene and thus susceptible to ALK inhibition. ALCL harbors an ALK mutation in approximately 80% to 95% of tumors. Half of IMTs and 14% of neuroblastomas also contain ALK rearrangements. “While the primary aim of this trial is safety, we also designed it so as to be able to distinguish which patients are likely to benefit from this therapy,” said Dr. Mosse.
Seventy children with relapsed or refractory solid tumors and ALCL were enrolled in the dose-escalation and pharmacokinetic trial, 42 of whom were evaluable. Not all participants were required to harbor a known ALK mutation; 19 patients in the neuroblastoma arm had an unknown ALK status. All eight patients in the ALCL arm had an ALK mutation and were heavily pretreated. Crizotinib was administered twice daily without interruption in 28-day cycles using the “rolling-six” design to evaluate dose levels ranging from 100 mg/m2 to 365 mg/m2 .
In the ALCL arm, 88% (7/8) of patients experienced a complete response, with patients remaining on treatment with no progression for as long as 18 months. "Our trial shows that crizotinib appears to have a high degree of activity in children with ALCL, the majority of which are driven by the ALK oncogene," said Dr. Mosse. All doses were well tolerated. “A larger ALCL trial is currently in development to move this therapy up front for newly diagnosed patients," she continued. The recommended phase II dose for children will be 280 mg/m2 twice daily, roughly twice the dose recommend for adults in phase II.
The majority of the seven patients with IMTs enrolled in the trial have experienced substantial benefit, ranging from tumor shrinkage to complete tumor regression, reported Dr. Mosse. Responses have lasted for up to 2 years, and all patients are still receiving therapy. Despite the small number of patients, these findings are encouraging because no available anticancer agents have been found to be effective against these tumors.
Two of the 27 patients with neuroblastoma had a complete response, and eight have had no progression of disease. Two of the eight neuroblastoma patients with an ALK abnormality experienced a complete response. Responders have remained on therapy for 9 months to more than 2 years without progression.
Neuroblastoma patients treated with higher doses of up to 280 mg/m2 crizotinib twice daily experienced demonstrable results. The investigators speculated that some neuroblastoma patients with known ALK mutations did not respond to treatment because they received lower doses of the drug.
“The high complete response rate and favorable toxicity profile in ALK-positive lymphoma is very impressive and suggests this may have a significant future role in treating both adults and pediatric patients with this disease,” commented John C. Byrd of the Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James). “Future work exploring the single agent and combination potential of crizotinib in anaplastic ALK-positive lymphoma is warranted.”
"This story is really a glimpse at the new paradigm for our understanding of cancer and for drug development," said ASCO president Michael Link, MD. "We now understand that it is not sufficient to identify a tumor based on the histology or the organ of origin … Tumors are heterogeneous and we need to understand the particular molecular driver of the tumor to select appropriate therapy.
“A second key theme is that these molecular drivers are present in very different and sometimes unrelated cancers, and that an inhibitor may thus work in very different cancers, so this drug, developed and approved for treatment of ALK-driven lung cancers, may turn out to be even more effective in non-Hodgkin lymphoma and ALCL as well as neuroblastoma.” This, added Link, “demonstrates the kinds of new collaborations that must be nurtured to make this happen: Lung cancer experts, pediatricians, sarcoma experts and lymphoma doctors-and people interested in developing new therapies for these kinds of tumors-all have an interest in the same drug. This is the kind of collaboration and the kind of science that will need to be done to develop these new targeted agents. Certainly it is the way forward.”